United States Patent 4,591,592: Stable PASS Formulations and Citric-Acid Stabilization

United States Patent US 4,591,592 claims stable pharmaceutical compositions that use a pharmaceutically acceptable acid addition salt (PASS) of a thieno-pyridine-derived active, stabilized by a non-volatile acidic compound selected from ascorbic, benzoic, citric, fumaric, or tartaric acid, with defined excipient windows and, in dependent claims, specific formulation embodiments.

What is the core claim scope in US 4,591,592?

Claim 1: Stable PASS + non-volatile acidic stabilizer + excipients

Claim 1 is the independent claim and is structured as a formulation claim, not a process claim. It requires:

A therapeutically effective amount of an active ingredient that is a PASS of a compound of formula (not reproduced here as plaintext in the prompt, but defined by substituent variables).
The active ingredient is specifically a salt form (PASS) and not the free base.
The composition includes:
- A non-toxic stabilizing amount of a pharmaceutically non-volatile acidic compound, selected from:
  - Ascorbic acid
  - Benzoic acid
  - Citric acid
  - Fumaric acid
  - Tartaric acid
- At least one pharmaceutically acceptable excipient.

The claim then defines the active ingredient structure by substituent variables:

R is phenyl or benzyl, with optional substitution on the phenyl ring by:
- 1 to 3 halogen atoms
- alkyl (1 to 6 carbon atoms)
- alkoxy (1 to 6 carbon atoms)
- hydroxy or nitro
R1 is hydrogen, halogen, hydroxy, or alkyl (1 to 6 carbon atoms)
R2 is hydrogen or halogen
n is 1 or 2
- If n = 2, R1 may vary across each CHR1 position.

This structure-variable approach gives the claim breadth around the thieno-pyridine-derived scaffold and allowed substitution patterns, but the salt + stabilizer + excipient requirements narrow functional coverage.

Claim 2: Tight stabilizer loading window

Claim 2 limits Claim 1 by requiring the stabilizing acid is present at:

0.5 to 5.0% (w/w) relative to the active ingredient.

This is a key narrowing limitation: the stabilization must be within a defined range.

Claim 3: Specific drug + specific acid + specific amount

Claim 3 is a dependent formulation embodiment with the following locked elements:

Active ingredient: hydrochloride salt of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
Stabilizer acid: citric acid
Citric acid amount: 1.0 to 1.5% (w/w) relative to the active ingredient

This claim ties the generic concept to an explicit API identity and a preferred stabilizer.

Claim 4: Composition with explicit excipient fractions

Claim 4 recasts the formulation as a percentage-by-weight composition, requiring four excipient groups plus diluent:

40 to 90% by weight of a PASS of the thieno-pyridine-derived compound
0.5 to 5% by weight of the non-volatile organic acid (ascorbic/benzoic/citric/fumaric/tartaric)
0.2 to 5% by weight lubricant
5 to 15% by weight disintegrant
1 to 5% by weight binder
remainder a diluent

This is broader in some respects than Claim 1 because it gives numeric spans for excipient categories, but it is narrower because it fixes the overall percentage scheme and requires the “PASS” to comprise 40 to 90% by weight of the composition.

Claim 5: Locked embodiment

Claim 5 narrows Claim 4 to:

API salt: hydrochloride salt of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
Stabilizer acid: citric acid
Lubricant: magnesium stearate

Notably, Claim 5 does not lock the disintegrant, binder, or diluent identity, only that they fall within the Claim 4 categories and ranges.

How broad are the claim variables (API structure) versus formulation constraints?

Breadth from the API scaffold definition

The formula variables indicate the claim is not limited to a single thieno-pyridine substitution pattern. The claim permits:

Phenyl or benzyl (R) substituents with 1 to 3 halogens or other specified groups on the phenyl ring
R1 being hydrogen/halogen/hydroxy/alkyl (1 to 6 carbons)
R2 being hydrogen or halogen
n = 1 or 2, with the n = 2 case allowing R1 to vary across positions

This structure-variable language supports coverage of a family of thieno-pyridine derivatives, so long as the active is in the required acid addition salt form and the formulation includes the required non-volatile acidic stabilizer.

Narrowing from required stabilization chemistry

The functional narrowing comes from the stabilization mechanism in claim language:

Stabilizer must be a pharmaceutically non-volatile acidic compound from a defined list (ascorbic, benzoic, citric, fumaric, tartaric).
It must be present at a non-toxic stabilizing amount with quantitative constraints in Claims 2, 3, and 4.

This means the claim is not simply “a PASS formulation”; it is a PASS formulation with a specific stabilizer acid family.

Narrowing from excipient category windows (Claim 4/5)

Claim 4 adds structural formulation constraints through weight ranges:

PASS (40 to 90%)
Stabilizer acid (0.5 to 5%)
Lubricant (0.2 to 5%)
Disintegrant (5 to 15%)
Binder (1 to 5%)
Diluent is the remainder

Claim 5 locks one lubricant to magnesium stearate and locks the API salt and citric acid, but leaves the other excipients to fall within Claim 4’s windows.

What are the practical “design-around” pressure points implied by the claims?

Based on the claim language, the main infringement pressure points are:

1) Salt form requirement (PASS)

Claim language repeatedly requires the active ingredient to be a pharmaceutically acceptable acid addition salt. Any product that uses a different salt category (e.g., different salt class not qualifying as PASS under the patent’s definitions) could aim to avoid the “PASS” requirement.

2) Stabilizer acid must be in the enumerated list

The stabilizer acid is restricted to:

ascorbic, benzoic, citric, fumaric, or tartaric acid and the claim also requires the stabilizer to be non-volatile.

A formulation using a different acid (for example, other non-volatile acids) would fall outside the enumerated list, unless it can be argued as part of one of the listed acids.

3) Concentration windows

Key numeric boundaries:

Claim 2: 0.5 to 5.0% (w/w) relative to active ingredient
Claim 4: 0.5 to 5% by weight of stabilizer acid
Claim 3: citric acid 1.0 to 1.5% (w/w) relative to active ingredient
Claim 4: PASS occupies 40 to 90% by weight, which impacts whether a low-dose formulation could fit

4) Lubricant identity (only in Claim 5)

Claim 5 only specifically requires magnesium stearate as lubricant. A product that uses a different lubricant could avoid Claim 5 while still potentially falling within Claim 4 (if other requirements are met).

How does the claims set map to likely dosage form types?

The excipient categories in Claim 4 (lubricant/disintegrant/binder plus diluent) are consistent with solid oral dosage forms, especially tablets or tablets-like blends, where:

binders and disintegrants are standard
lubricants like magnesium stearate are standard

Claim 1 is broader and could cover a wider set of solid formulations, but Claims 4/5 strongly indicate a tablet/compressible solid formulation architecture.

What is the patent landscape impact of this composition patent (US 4,591,592)?

1) It is a formulation IP anchor for PASS stability

The patent’s claim emphasis on:

PASS of a thieno-pyridine scaffold
stabilization by a defined, non-volatile acid list
specific weight ranges and excipient classes

makes it an IP anchor for later formulation entrants. In practice, any generic or follow-on brand that uses the same active in the same salt form and stabilizes with one of the enumerated non-volatile acids at qualifying levels is likely to face claim coverage.

2) It creates a “substitute formulation” field

Even if the active molecule is licensed or known, this patent claims composition stability through stabilizer selection and formulation ratios. That typically forces market entrants to either:

use different stabilizers outside the list
change salt form away from the PASS requirement
shift stabilizer levels outside the numeric windows
adjust excipient fractions so the composition is outside Claim 4’s structural ranges
avoid the magnesium stearate lubricant if pursuing non-infringement of Claim 5

3) It is structured to survive partial overlap

The claim set combines:

a broad scaffold formula in Claim 1
list-based stabilizer limitation
numeric stabilizer amounts in Claim 2/3/4
detailed excipient category windows in Claim 4

That layered structure can reduce the ability of a competitor to “partially comply” with one dimension while escaping all others.

Claim chart style: which elements must be present for each claim?

Claim 1 checklist

[ ] Active is a PASS of a thieno-pyridine-derived compound with permitted R/R1/R2/n substitution patterns
[ ] Composition contains a therapeutically effective amount of that PASS active
[ ] Contains non-volatile acidic stabilizer in non-toxic stabilizing amount chosen from: ascorbic, benzoic, citric, fumaric, tartaric acid
[ ] Contains at least one pharmaceutically acceptable excipient

Claim 2 adds

[ ] Stabilizer present at 0.5 to 5.0% (w/w) relative to active

Claim 3 adds (locked embodiment)

[ ] Active is hydrochloride salt of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
[ ] Stabilizer is citric acid
[ ] Citric acid is 1.0 to 1.5% (w/w) relative to active

Claim 4 adds full blend percentage scheme

[ ] PASS content: 40 to 90% by weight
[ ] Stabilizer acid: 0.5 to 5% by weight
[ ] Lubricant: 0.2 to 5% by weight
[ ] Disintegrant: 5 to 15% by weight
[ ] Binder: 1 to 5% by weight
[ ] Remainder diluent

Claim 5 adds locked components

[ ] Active is the specified hydrochloride salt
[ ] Stabilizer is citric acid
[ ] Lubricant is magnesium stearate

Key takeaways

US 4,591,592 is a formulation-stability patent built around a PASS active and stabilization using one of five non-volatile acids: ascorbic, benzoic, citric, fumaric, tartaric.
The independent claim (Claim 1) is broad on API substitution but narrow on the salt form requirement and the enumerated stabilizer acid list plus requirement for excipients.
Dependent claims introduce enforceable quantitative boundaries:
- 0.5 to 5.0% (w/w) stabilizer relative to active (Claim 2)
- 1.0 to 1.5% (w/w) citric acid for the locked embodiment (Claim 3)
- 40 to 90% PASS and excipient windows for lubricant/disintegrant/binder/diluent (Claim 4)
The landscape implication is that later market entrants using the same active as a PASS and stabilizing with one of the listed non-volatile acids within qualifying amounts face direct claim exposure; “escape routes” concentrate on salt form, stabilizer identity, stabilizer concentration, and excipient fraction architecture.

FAQs

1) Does US 4,591,592 protect the drug molecule itself or only the formulation?

It protects a pharmaceutical composition with specified salt form, stabilizer acid identity, and excipients. The claims are composition claims tied to formulation features.

2) Which stabilizers are explicitly covered?

The stabilizers explicitly listed are ascorbic acid, benzoic acid, citric acid, fumaric acid, and tartaric acid.

3) What is the tightest numeric stabilizer requirement in the claim set?

For the locked embodiment in Claim 3, citric acid is 1.0 to 1.5% (w/w) relative to the active ingredient.

4) Is magnesium stearate required to infringe the whole patent?

No. Magnesium stearate is required only in Claim 5. Claim 4 covers lubricant broadly within a range without locking identity.

5) What aspect most commonly creates infringement risk for follow-on formulations?

The combination of using the same PASS active plus including an enumerated non-volatile acid stabilizer at a qualifying weight or relative-to-active level.

References

[1] United States Patent 4,591,592. “Stable pharmaceutical compositions comprising acid addition salt and non-volatile acidic stabilizer.” Claims as provided in user prompt.

Title:	Acid stabilized compositions of thieno-pyridine derived compounds
Abstract:	A novel pharmaceutical composition which comprises an acid salt of a thieno-pyridine derived compound, a pharmaceutically acceptable, non-volatile organic acid (particularly citric acid) and optionally other suitable pharmaceutical excipients.
Inventor(s):	Zaka-Ud-Din T. Chowhan
Assignee:	Hoffmann La Roche Inc , Syntex USA LLC , Roche Holdings Inc
Application Number:	US06/665,675
Patent Claim Types: see list of patent claims	Composition; Compound;
Patent landscape, scope, and claims:	United States Patent 4,591,592: Stable PASS Formulations and Citric-Acid Stabilization United States Patent US 4,591,592 claims stable pharmaceutical compositions that use a pharmaceutically acceptable acid addition salt (PASS) of a thieno-pyridine-derived active, stabilized by a non-volatile acidic compound selected from ascorbic, benzoic, citric, fumaric, or tartaric acid, with defined excipient windows and, in dependent claims, specific formulation embodiments. What is the core claim scope in US 4,591,592? Claim 1: Stable PASS + non-volatile acidic stabilizer + excipients Claim 1 is the independent claim and is structured as a formulation claim, not a process claim. It requires: A therapeutically effective amount of an active ingredient that is a PASS of a compound of formula (not reproduced here as plaintext in the prompt, but defined by substituent variables). The active ingredient is specifically a salt form (PASS) and not the free base. The composition includes: A non-toxic stabilizing amount of a pharmaceutically non-volatile acidic compound, selected from: Ascorbic acid Benzoic acid Citric acid Fumaric acid Tartaric acid At least one pharmaceutically acceptable excipient. The claim then defines the active ingredient structure by substituent variables: R is phenyl or benzyl, with optional substitution on the phenyl ring by: 1 to 3 halogen atoms alkyl (1 to 6 carbon atoms) alkoxy (1 to 6 carbon atoms) hydroxy or nitro R1 is hydrogen, halogen, hydroxy, or alkyl (1 to 6 carbon atoms) R2 is hydrogen or halogen n is 1 or 2 If n = 2, R1 may vary across each CHR1 position. This structure-variable approach gives the claim breadth around the thieno-pyridine-derived scaffold and allowed substitution patterns, but the salt + stabilizer + excipient requirements narrow functional coverage. Claim 2: Tight stabilizer loading window Claim 2 limits Claim 1 by requiring the stabilizing acid is present at: 0.5 to 5.0% (w/w) relative to the active ingredient. This is a key narrowing limitation: the stabilization must be within a defined range. Claim 3: Specific drug + specific acid + specific amount Claim 3 is a dependent formulation embodiment with the following locked elements: Active ingredient: hydrochloride salt of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Stabilizer acid: citric acid Citric acid amount: 1.0 to 1.5% (w/w) relative to the active ingredient This claim ties the generic concept to an explicit API identity and a preferred stabilizer. Claim 4: Composition with explicit excipient fractions Claim 4 recasts the formulation as a percentage-by-weight composition, requiring four excipient groups plus diluent: 40 to 90% by weight of a PASS of the thieno-pyridine-derived compound 0.5 to 5% by weight of the non-volatile organic acid (ascorbic/benzoic/citric/fumaric/tartaric) 0.2 to 5% by weight lubricant 5 to 15% by weight disintegrant 1 to 5% by weight binder remainder a diluent This is broader in some respects than Claim 1 because it gives numeric spans for excipient categories, but it is narrower because it fixes the overall percentage scheme and requires the “PASS” to comprise 40 to 90% by weight of the composition. Claim 5: Locked embodiment Claim 5 narrows Claim 4 to: API salt: hydrochloride salt of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Stabilizer acid: citric acid Lubricant: magnesium stearate Notably, Claim 5 does not lock the disintegrant, binder, or diluent identity, only that they fall within the Claim 4 categories and ranges. How broad are the claim variables (API structure) versus formulation constraints? Breadth from the API scaffold definition The formula variables indicate the claim is not limited to a single thieno-pyridine substitution pattern. The claim permits: Phenyl or benzyl (R) substituents with 1 to 3 halogens or other specified groups on the phenyl ring R1 being hydrogen/halogen/hydroxy/alkyl (1 to 6 carbons) R2 being hydrogen or halogen n = 1 or 2, with the n = 2 case allowing R1 to vary across positions This structure-variable language supports coverage of a family of thieno-pyridine derivatives, so long as the active is in the required acid addition salt form and the formulation includes the required non-volatile acidic stabilizer. Narrowing from required stabilization chemistry The functional narrowing comes from the stabilization mechanism in claim language: Stabilizer must be a pharmaceutically non-volatile acidic compound from a defined list (ascorbic, benzoic, citric, fumaric, tartaric). It must be present at a non-toxic stabilizing amount with quantitative constraints in Claims 2, 3, and 4. This means the claim is not simply “a PASS formulation”; it is a PASS formulation with a specific stabilizer acid family. Narrowing from excipient category windows (Claim 4/5) Claim 4 adds structural formulation constraints through weight ranges: PASS (40 to 90%) Stabilizer acid (0.5 to 5%) Lubricant (0.2 to 5%) Disintegrant (5 to 15%) Binder (1 to 5%) Diluent is the remainder Claim 5 locks one lubricant to magnesium stearate and locks the API salt and citric acid, but leaves the other excipients to fall within Claim 4’s windows. What are the practical “design-around” pressure points implied by the claims? Based on the claim language, the main infringement pressure points are: 1) Salt form requirement (PASS) Claim language repeatedly requires the active ingredient to be a pharmaceutically acceptable acid addition salt. Any product that uses a different salt category (e.g., different salt class not qualifying as PASS under the patent’s definitions) could aim to avoid the “PASS” requirement. 2) Stabilizer acid must be in the enumerated list The stabilizer acid is restricted to: ascorbic, benzoic, citric, fumaric, or tartaric acid and the claim also requires the stabilizer to be non-volatile. A formulation using a different acid (for example, other non-volatile acids) would fall outside the enumerated list, unless it can be argued as part of one of the listed acids. 3) Concentration windows Key numeric boundaries: Claim 2: 0.5 to 5.0% (w/w) relative to active ingredient Claim 4: 0.5 to 5% by weight of stabilizer acid Claim 3: citric acid 1.0 to 1.5% (w/w) relative to active ingredient Claim 4: PASS occupies 40 to 90% by weight, which impacts whether a low-dose formulation could fit 4) Lubricant identity (only in Claim 5) Claim 5 only specifically requires magnesium stearate as lubricant. A product that uses a different lubricant could avoid Claim 5 while still potentially falling within Claim 4 (if other requirements are met). How does the claims set map to likely dosage form types? The excipient categories in Claim 4 (lubricant/disintegrant/binder plus diluent) are consistent with solid oral dosage forms, especially tablets or tablets-like blends, where: binders and disintegrants are standard lubricants like magnesium stearate are standard Claim 1 is broader and could cover a wider set of solid formulations, but Claims 4/5 strongly indicate a tablet/compressible solid formulation architecture. What is the patent landscape impact of this composition patent (US 4,591,592)? 1) It is a formulation IP anchor for PASS stability The patent’s claim emphasis on: PASS of a thieno-pyridine scaffold stabilization by a defined, non-volatile acid list specific weight ranges and excipient classes makes it an IP anchor for later formulation entrants. In practice, any generic or follow-on brand that uses the same active in the same salt form and stabilizes with one of the enumerated non-volatile acids at qualifying levels is likely to face claim coverage. 2) It creates a “substitute formulation” field Even if the active molecule is licensed or known, this patent claims composition stability through stabilizer selection and formulation ratios. That typically forces market entrants to either: use different stabilizers outside the list change salt form away from the PASS requirement shift stabilizer levels outside the numeric windows adjust excipient fractions so the composition is outside Claim 4’s structural ranges avoid the magnesium stearate lubricant if pursuing non-infringement of Claim 5 3) It is structured to survive partial overlap The claim set combines: a broad scaffold formula in Claim 1 list-based stabilizer limitation numeric stabilizer amounts in Claim 2/3/4 detailed excipient category windows in Claim 4 That layered structure can reduce the ability of a competitor to “partially comply” with one dimension while escaping all others. Claim chart style: which elements must be present for each claim? Claim 1 checklist [ ] Active is a PASS of a thieno-pyridine-derived compound with permitted R/R1/R2/n substitution patterns [ ] Composition contains a therapeutically effective amount of that PASS active [ ] Contains non-volatile acidic stabilizer in non-toxic stabilizing amount chosen from: ascorbic, benzoic, citric, fumaric, tartaric acid [ ] Contains at least one pharmaceutically acceptable excipient Claim 2 adds [ ] Stabilizer present at 0.5 to 5.0% (w/w) relative to active Claim 3 adds (locked embodiment) [ ] Active is hydrochloride salt of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ ] Stabilizer is citric acid [ ] Citric acid is 1.0 to 1.5% (w/w) relative to active Claim 4 adds full blend percentage scheme [ ] PASS content: 40 to 90% by weight [ ] Stabilizer acid: 0.5 to 5% by weight [ ] Lubricant: 0.2 to 5% by weight [ ] Disintegrant: 5 to 15% by weight [ ] Binder: 1 to 5% by weight [ ] Remainder diluent Claim 5 adds locked components [ ] Active is the specified hydrochloride salt [ ] Stabilizer is citric acid [ ] Lubricant is magnesium stearate Key takeaways US 4,591,592 is a formulation-stability patent built around a PASS active and stabilization using one of five non-volatile acids: ascorbic, benzoic, citric, fumaric, tartaric. The independent claim (Claim 1) is broad on API substitution but narrow on the salt form requirement and the enumerated stabilizer acid list plus requirement for excipients. Dependent claims introduce enforceable quantitative boundaries: 0.5 to 5.0% (w/w) stabilizer relative to active (Claim 2) 1.0 to 1.5% (w/w) citric acid for the locked embodiment (Claim 3) 40 to 90% PASS and excipient windows for lubricant/disintegrant/binder/diluent (Claim 4) The landscape implication is that later market entrants using the same active as a PASS and stabilizing with one of the listed non-volatile acids within qualifying amounts face direct claim exposure; “escape routes” concentrate on salt form, stabilizer identity, stabilizer concentration, and excipient fraction architecture. FAQs 1) Does US 4,591,592 protect the drug molecule itself or only the formulation? It protects a pharmaceutical composition with specified salt form, stabilizer acid identity, and excipients. The claims are composition claims tied to formulation features. 2) Which stabilizers are explicitly covered? The stabilizers explicitly listed are ascorbic acid, benzoic acid, citric acid, fumaric acid, and tartaric acid. 3) What is the tightest numeric stabilizer requirement in the claim set? For the locked embodiment in Claim 3, citric acid is 1.0 to 1.5% (w/w) relative to the active ingredient. 4) Is magnesium stearate required to infringe the whole patent? No. Magnesium stearate is required only in Claim 5. Claim 4 covers lubricant broadly within a range without locking identity. 5) What aspect most commonly creates infringement risk for follow-on formulations? The combination of using the same PASS active plus including an enumerated non-volatile acid stabilizer at a qualifying weight or relative-to-active level. References [1] United States Patent 4,591,592. “Stable pharmaceutical compositions comprising acid addition salt and non-volatile acidic stabilizer.” Claims as provided in user prompt. More… ↓ ⤷ Start Trial

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Details for Patent: 4,591,592

Summary for Patent: 4,591,592