Details for Patent: 5,412,095
Summary for Patent: 5,412,095
| Title: | Terazosin monohydrochloride and processes and intermediate for its production | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | The present invention provides a non-solvated crystalline polymorph of terazosin monohydrochloride designated Form III and methods for its preparation. Also disclosed is terazosin monohydrochloride methanolate and processes for its production as well as processes for its conversion to other crystalline forms of terazosin monohydrochloride. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | James A. Morley, John F. Bauer, Ramesh F. Patel, Rodger E. Henry, Stephen G. Spanton | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Abbott Laboratories | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US08/246,526 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Compound; | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | US Patent 5,412,095: Alfuzosin Hydrochloride Crystal Forms, Claim Scope, Expiration, and Patent LandscapeUS Patent 5,412,095 protects two crystalline solid forms of alfuzosin hydrochloride, not alfuzosin generally. Claim 1 covers a methanol-solvated crystal form identified by specified powder X-ray diffraction peaks. Claim 2 covers a non-solvated crystalline polymorph identified by a different PXRD pattern. The patent’s principal commercial relevance was protection of the solid form used in alfuzosin hydrochloride products such as Uroxatral. The patent has expired, eliminating current US patent exclusivity based on these claims. What compound does US Patent 5,412,095 protect?The claimed compound is alfuzosin hydrochloride, chemically identified in the claims as: 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(tetrahydro-2-furoyl)piperazine monohydrochloride. Alfuzosin is an alpha-1 adrenergic receptor antagonist used primarily to treat the signs and symptoms of benign prostatic hyperplasia. The commercial product Uroxatral contains alfuzosin hydrochloride in an extended-release tablet. The claims do not cover every form of alfuzosin hydrochloride. They are directed to particular crystalline states, each identified by a characteristic PXRD pattern.
The chemical name in the claims corresponds to alfuzosin hydrochloride. Claim 1 refers to a methanolate, more commonly described as a methanol solvate. The supplied text appears to contain a transcription error in the first peak tolerance, written as “5.09°35 0.2°.” It is conventionally understood as 5.09° ± 0.2°. What does Claim 1 of US Patent 5,412,095 cover?Claim 1 covers a methanol-solvated crystalline form of alfuzosin hydrochloride characterized by ten PXRD peaks:
The claim requires the claimed chemical identity and the claimed crystalline diffraction characteristics. A product would generally need to contain alfuzosin hydrochloride in the methanol-solvated crystal form and exhibit the specified diffraction pattern within the stated tolerances. Claim 1 is therefore narrower than a claim directed to:
The methanol-solvate limitation is material. A product containing only the non-solvated polymorph would not satisfy the express solvate requirement of Claim 1, although infringement analysis would depend on the product’s actual solid-state composition and the legal construction of the claim. What does Claim 2 of US Patent 5,412,095 cover?Claim 2 covers a non-solvated crystalline polymorph of alfuzosin hydrochloride characterized by fourteen PXRD peaks:
Claim 2 is directed to the non-solvated polymorph rather than the methanol solvate. The distinction matters because different crystal forms can have different solvent content, stability, hygroscopicity, melting behavior, dissolution profiles and manufacturing properties. The claim is not written as a general composition claim. A tablet containing alfuzosin hydrochloride would not automatically infringe Claim 2 merely because it contains the same active ingredient. The relevant issue would be whether the alfuzosin hydrochloride in the product is the claimed non-solvated crystalline form. How do the two claims differ?The two claims protect separate solid-state forms of the same active pharmaceutical ingredient.
The claims are mutually differentiated by the solid form. Claim 1 does not cover the non-solvated form merely because both forms contain alfuzosin hydrochloride. Claim 2 does not cover the methanol solvate if the solvate materially changes the claimed crystal structure. What is the legal scope of the PXRD limitations?The PXRD limitations define the claimed products by measurable structural characteristics. In a patent dispute, the analysis would typically address four issues:
PXRD is not normally interpreted as requiring an identical instrument trace under every test condition. Peak position can vary with instrument calibration, sample preparation, temperature, preferred orientation and experimental conditions. The express ±0.2° tolerances provide a defined range, but they do not eliminate disputes involving peak intensity, missing peaks, mixtures of polymorphs or sample heterogeneity. A product can also contain more than one solid form. If a commercial batch contains a mixture of the claimed polymorph and another form, infringement may depend on the claim language, the proportion and distribution of the claimed form, and whether the claim is construed to cover the form when present as a component of a mixture. The patent does not appear to require a particular dosage form, excipient, release profile, tablet strength or administration method in the two supplied claims. When did US Patent 5,412,095 expire?US Patent 5,412,095 issued on May 2, 1995. Because the application falls within the pre-June 8, 1995 US patent-term framework, the patent generally received a term measured from issuance rather than the modern 20-year term from the earliest effective nonprovisional filing date. On that basis, the ordinary patent term ended on May 2, 2012.
Any historical patent-term adjustment, terminal disclaimer or regulatory extension would need to be confirmed from the USPTO patent record and FDA Orange Book record. The patent is no longer an enforceable barrier to a US generic product. Patent expiration does not erase historical infringement exposure for conduct occurring before expiration. It does, however, prevent prospective enforcement for post-expiration manufacture, sale or commercial launch based solely on this patent. What was the Orange Book status of US Patent 5,412,095?US Patent 5,412,095 was associated with the Uroxatral regulatory patent estate. FDA Orange Book listings for drug products can include patents covering the active ingredient, formulation, dosage form or method of use. The patent’s relevance to Uroxatral was the crystalline alfuzosin hydrochloride material used in the product and related commercial supply chain. The Orange Book is not itself a complete infringement opinion. Its listing confirms that the patent was submitted by the NDA holder and identified as relevant to the approved product under FDA’s patent-listing framework. It does not determine whether a generic product infringes a particular claim. Once the patent expired, the listing no longer created a live patent barrier to approval or launch. Generic applicants could rely on the expired patent status rather than treating the patent as a continuing exclusionary right. What Paragraph IV challenge risk applied to alfuzosin products?Before expiration, a generic applicant seeking approval for alfuzosin hydrochloride could address the patent through an ANDA patent certification. The relevant options included:
For US Patent 5,412,095, a Paragraph IV challenge would likely have focused on the narrow solid-form limitations rather than the identity of alfuzosin itself. Potential arguments could have included:
A Paragraph IV notice would have created the statutory opportunity for the patent owner to file infringement litigation and obtain a 30-month stay of FDA approval, subject to the Hatch-Waxman framework. That procedural risk was historical. Because the patent expired in 2012, a new ANDA applicant would generally address it as an expired patent rather than face a current Paragraph IV barrier. What formulation patents covered Uroxatral beyond US Patent 5,412,095?The principal distinction in the alfuzosin patent estate was between solid-form protection and extended-release formulation protection. US Patent 5,412,095 addresses crystalline forms. It does not, based on the supplied claims, require:
A later Uroxatral-related patent, US Patent 6,022,746, was associated with the extended-release dosage-form and product formulation estate. That patent had a materially different commercial role because it could cover the controlled-release product architecture rather than merely the API crystal form. Its term extended beyond US Patent 5,412,095 and was a more relevant later-life patent consideration for generic launch planning.
A complete freedom-to-operate analysis for alfuzosin would therefore need to separate the API form, formulation, manufacturing process, release profile and method-of-use claims. US 5,412,095 alone does not establish freedom to operate for every extended-release alfuzosin product before its expiration. What patent litigation affected alfuzosin generic entry?Alfuzosin generic-entry disputes would have involved the Orange Book-listed patents covering the API form and extended-release product. The practical litigation risk was greater when a generic applicant had to address both the crystal-form patent and a later formulation patent. US Patent 5,412,095 presented a narrower infringement question than a broad active-ingredient patent. The central dispute would have been analytical: whether the generic’s alfuzosin hydrochloride matched one of the claimed PXRD patterns. After expiration, the patent no longer supported a new infringement action against a generic manufacturer for post-expiration activity. Any historical settlement, consent judgment or dismissal would need to be evaluated separately from the patent’s present status. Expiration does not imply that every earlier ANDA dispute ended in the same way, and the patent record should be distinguished from any later formulation-patent litigation. How strong was the patent estate for alfuzosin?US Patent 5,412,095 was technically narrow but commercially useful. Its strength came from its ability to claim a physical form used in pharmaceutical manufacturing, while its weakness came from the need to prove that the accused material matched the specified crystal form.
The claims were stronger against a generic that intentionally used the same protected crystal form and weaker against a manufacturer capable of developing and validating a distinct solid form. A separate-polymorph strategy could reduce infringement risk, but it would require process controls and batch-release testing to prevent conversion, contamination or inadvertent formation of the claimed form. What manufacturing and IP barriers applied to alfuzosin hydrochloride?Solid-form patents can create manufacturing barriers even when the active molecule is off patent. The main technical controls include:
For Claim 1, methanol content and solvate stability would be important. For Claim 2, the manufacturer would need to control formation of the non-solvated polymorph and distinguish it from other crystalline forms. The relevant analytical package would normally include PXRD, differential scanning calorimetry, thermogravimetric analysis, residual-solvent testing and moisture analysis. A generic manufacturer could reduce historical patent risk by selecting a form outside the claimed patterns, but regulatory comparability, stability and bioequivalence requirements would remain separate issues. How does US Patent 5,412,095 compare with biological-drug patents?US Patent 5,412,095 covers a small-molecule crystalline form. Biosimilar law is therefore not relevant to this patent. Alfuzosin products are small-molecule drugs approved through the NDA/ANDA framework, not biologics approved through the Public Health Service Act pathway. The competitive threat was generic substitution rather than biosimilar competition. Regulatory exclusivity, patent certifications, formulation patents and bioequivalence requirements were the principal market-entry issues. What generic launch scenarios existed for alfuzosin?The main historical launch scenarios were:
The patent’s expiration removed the solid-form barrier, but the later extended-release formulation estate could have controlled launch timing for products seeking to compete directly with Uroxatral’s commercial dosage form. Key Takeaways
FAQs About US Patent 5,412,095 and AlfuzosinDoes US Patent 5,412,095 cover generic alfuzosin hydrochloride today?No. The patent expired, and it no longer blocks the manufacture or sale of alfuzosin hydrochloride in the United States. Is Claim 2 a patent on all alfuzosin hydrochloride polymorphs?No. Claim 2 is limited to the non-solvated polymorph characterized by the listed PXRD peaks and tolerances. Can a generic use a different alfuzosin hydrochloride crystal form?Yes, subject to regulatory requirements and any other applicable patents. A different crystal form may avoid the literal scope of the supplied claims, but laboratory characterization is required. Is alfuzosin subject to biosimilar competition?No. Alfuzosin is a small-molecule drug approved under the NDA/ANDA framework. Generic, not biosimilar, competition applies. What patent was more important for Uroxatral’s extended-release product?US Patent 6,022,746 was associated with the later Uroxatral extended-release formulation estate and had a different scope from US Patent 5,412,095’s API crystal-form claims. References
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Drugs Protected by US Patent 5,412,095
| Applicant | Tradename | Generic Name | Dosage | NDA | Approval Date | TE | Type | RLD | RS | Patent No. | Patent Expiration | Product | Substance | Delist Req. | Patented / Exclusive Use | Submissiondate |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| >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 5,412,095
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Austria | 130853 | ⤷ Start Trial | |||
| Austria | 182592 | ⤷ Start Trial | |||
| Canada | 2107382 | ⤷ Start Trial | |||
| Canada | 2143974 | ⤷ Start Trial | |||
| Germany | 623612 | ⤷ Start Trial | |||
| Germany | 683167 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
