Details for Patent: 5,053,407
Summary for Patent: 5,053,407
| Title: | Optically active pyridobenzoxazine derivatives and anti-microbial use | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | An optically action pyridobenzoxazine derivative, a process for preparing the same and a novel intermediate useful for preparing the optically active pyridobenzoxazine derivative are disclosed. The optically active pyridobenzoxazine derivative possesses increased antimicrobial activity and reduced toxicity. The intermediate is useful for preparing such optically active pyridobenzoxazine derivatives such as Ofloxacin and anolog compounds. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Isao Hayakawa, Shohgo Atarashi, Masazumi Imamura, Shuichi Yokohama, Nobuyuki Higashihashi, Katsuichi Sakano, Masayuki Ohshima | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Daiichi Sankyo Co Ltd | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US06/876,623 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Patent Claim Types: see list of patent claims | Use; Compound; | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | United States Drug Patent 5,053,407: Claim Scope, Levofloxacin Coverage, Expiration, and Patent LandscapeU.S. Patent No. 5,053,407 covered optically active S(-)-pyridobenzoxazine antibacterial compounds, including levofloxacin. Claims 1 and 4 were genus claims covering defined structural classes and antimicrobial treatment methods. Claims 2 and 5 specifically covered levofloxacin, while claims 3 and 6 covered the corresponding 4-ethyl piperazine analog. The patent issued to Daiichi Seiyaku Co., Ltd. on October 1, 1991. Its pre-URAA patent term expired on October 1, 2008, subject to any applicable regulatory exclusivity. The patent no longer creates a barrier to generic levofloxacin manufacture, approval, or sale in the United States.[1][2] What drug does U.S. Patent 5,053,407 protect?Claim 2 covers levofloxacin, the S(-)-enantiomer of ofloxacin:
Levofloxacin is marketed as the hemihydrate of the S(-) enantiomer. The racemate of levofloxacin is ofloxacin. The patent therefore occupies the transition from the earlier racemic ofloxacin estate to the later single-enantiomer levofloxacin product. What is the chemical scope of claim 1?Claim 1 covers an S(-)-pyridobenzoxazine compound containing the structural core shown in the patent and three variable substituent definitions:
On the literal wording supplied, the claim is a Markush-style genus claim. It is broader than claim 2 because it does not require the specific combination of fluorine, a 3-methyl substituent, and a 4-methyl piperazinyl group. The principal legal limitations are structural rather than functional:
A compound outside the claimed stereochemistry, ring system, or substituent ranges would not literally satisfy claim 1. A racemic compound would not literally be the claimed S(-) compound, although infringement and validity analysis could depend on how the product is made, labeled, and sold. How broad is the claim 1 genus?The carbon-range language creates a potentially substantial chemical genus. It covers multiple combinations of halogen and lower alkyl substituents, subject to the fixed structure in formula VI. The claim is not limited to levofloxacin. Its practical scope is narrower than a purely functional antibacterial claim because the accused product must have the specified molecular architecture. The claim also does not cover every fluoroquinolone or every optically active quinolone. It is directed to the particular pyridobenzoxazine scaffold. The commercial value of the genus claim came from its ability to cover levofloxacin before and during development, rather than from continued protection of every later fluoroquinolone product. What does claim 2 cover?Claim 2 specifically covers levofloxacin. The chemical name in the claim corresponds to:
This is a composition-of-matter claim. Composition claims generally provide stronger product coverage than claims limited to a particular indication, dosage, or formulation. During the patent term, a commercially supplied levofloxacin active ingredient would have faced direct infringement risk unless licensed, authorized, or otherwise protected by a successful noninfringement or validity position. Claim 2 did not require a particular dosage form. It therefore reached levofloxacin supplied as tablets, oral solution, injectable solution, or other pharmaceutical presentations, provided the claimed active compound was present. What does claim 3 cover?Claim 3 covers the corresponding S(-) compound with a 4-ethyl-1-piperazinyl substituent rather than the 4-methyl-1-piperazinyl substituent found in levofloxacin. This compound is structurally distinct from levofloxacin. Claim 3 should not be treated as a second claim to levofloxacin. Its commercial importance is materially lower unless the compound itself was developed or included in a marketed product. The distinction illustrates the patent’s strategy: claim 1 established a variable genus, while claims 2 and 3 identified specific preferred members. A genus claim and a species claim can overlap, but they protect different claim scopes and may present different validity and enablement questions. What do claims 4 through 6 cover?Claims 4 through 6 are process-of-treatment claims. Claim 4 covers administering an antimicrobially effective amount of a claim 1 compound to a patient requiring antimicrobial therapy. Claim 5 narrows that method to levofloxacin. Claim 6 narrows it to the 4-ethyl piperazine analog. The method claims add treatment limitations that are absent from claims 1 through 3. They require:
These claims could be asserted against a manufacturer or distributor through induced infringement if the product labeling, promotional materials, or other conduct encouraged the claimed treatment. They would generally be less direct against a manufacturer than a composition claim because the method claim requires proof concerning intended use and administration. For generic products, label-based method-of-use risk depends on whether the approved label induces use within the claimed scope. Levofloxacin’s broad antibacterial labeling historically made the method claims commercially relevant, but the composition claim remained the principal barrier during the patent term. When did U.S. Patent 5,053,407 expire?U.S. Patent 5,053,407 issued on October 1, 1991. Because the application was filed before the June 8, 1995 transition to the modern patent-term regime, its ordinary term was 17 years from issuance. The resulting expiration date was October 1, 2008.[1][3]
Levofloxacin also received FDA regulatory exclusivity associated with pediatric studies. That exclusivity extended the regulatory protection period after patent expiration, but it did not extend the patent term itself. FDA approval and exclusivity records should therefore be separated from the patent expiration date.[2][4] What was the FDA and Orange Book status of levofloxacin?Levofloxacin was approved by the FDA as Levaquin, with products including tablets, injectable formulations, and oral solution. The reference product sponsor was Ortho-McNeil Pharmaceutical, associated with Johnson & Johnson, while Daiichi developed the underlying compound.[2][5] The Orange Book historically listed U.S. Patent No. 5,053,407 against levofloxacin products. Because the patent expired in 2008, it is no longer an operative listed patent blocking generic approval. Current FDA Orange Book treatment of levofloxacin should be understood in the context of an expired primary patent and the absence of an active patent term under this patent number.[2]
Levofloxacin is a chemically synthesized small molecule. It is not a biologic and does not proceed through the biosimilar pathway under section 351(k) of the Public Health Service Act. Generic manufacturers use the ANDA pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act.[4][6] Which companies challenged the levofloxacin patent?The principal commercial challenge to the levofloxacin estate arose from generic manufacturers seeking approval before or around patent expiry. Generic companies typically filed ANDAs with Paragraph IV certifications where they alleged that the listed patent was invalid, unenforceable, or would not be infringed. The commercial record should be separated into three periods:
Public FDA records document generic levofloxacin approvals and the transition away from exclusive Levaquin supply. Once the patent expired, a Paragraph IV challenge to Patent No. 5,053,407 no longer created the same commercial leverage because the patent could no longer prevent post-expiration launch. Any analysis of a particular generic company requires review of the company’s ANDA certification, litigation docket, settlement agreement, and launch terms. Patent No. 5,053,407 itself is not a current basis for blocking generic entry. What patent litigation affected levofloxacin?Historical litigation involving levofloxacin focused on three issues:
The core composition claim created the clearest infringement theory. A generic manufacturer that produced levofloxacin would have been exposed to a direct infringement claim during the patent term. Method claims could create additional risk if the generic label encouraged the patented antimicrobial treatment. The present litigation position is different. Patent No. 5,053,407 expired in 2008. It cannot support a new injunction against a generic levofloxacin launch. Any historical settlement involving the patent would have commercial significance only for the period before expiration or for contractual obligations that survived expiration. No biosimilar litigation applies because levofloxacin is not a biologic. What formulations were protected by Patent No. 5,053,407?Patent No. 5,053,407 is primarily a compound and treatment patent. The supplied claims do not recite:
The claims therefore do not provide dedicated formulation protection in the manner of a later patent directed to a tablet composition, injectable formulation, or sustained-release delivery system. Claim 2 could reach levofloxacin regardless of dosage form because it claims the active compound itself. That is composition coverage, not formulation coverage. A later formulation patent could have created a separate barrier even after Patent No. 5,053,407 expired, but such a patent would need to be identified independently from the claims supplied here and the Orange Book record applicable to the relevant product. How does Patent No. 5,053,407 compare with the earlier ofloxacin estate?Levofloxacin and ofloxacin are closely related but occupy different patent positions.
The distinction between the racemate and the S(-) enantiomer was central to the commercial strategy. A patent covering ofloxacin did not automatically provide the same claim coverage as a patent specifically directed to levofloxacin. Patent No. 5,053,407 supplied that specific enantiomer coverage. How strong was the patent estate?The strongest feature of Patent No. 5,053,407 was claim 2’s direct composition coverage of levofloxacin. The principal weaknesses or limits were:
During its effective term, the estate had high commercial blocking value because a generic levofloxacin product would have implicated the active compound claim. After expiration, the remaining value is historical, evidentiary, and relevant to freedom-to-operate analyses concerning old acts. It is not a current exclusionary right. What generic entry risks exist today?Generic levofloxacin faces no current entry prohibition from U.S. Patent No. 5,053,407. The relevant business risks are instead:
The injectable product can present more manufacturing and regulatory complexity than tablets because of sterile manufacturing, container-closure systems, particulate control, and supply reliability. Those issues are operational barriers, not barriers created by Patent No. 5,053,407. What is the commercial exposure from levofloxacin patent expiry?Levaquin was a major branded product before generic entry. Expiration of the principal compound patent removed the central legal barrier to generic competition and produced substantial price and market-share pressure. The exposure profile was concentrated in:
Patent expiry did not terminate FDA approval or clinical demand. It changed the market from an originator-controlled product to an ANDA-driven multisource market. The most significant commercial loss was therefore exclusivity-driven revenue erosion rather than product withdrawal. What geographic rights did Patent No. 5,053,407 provide?U.S. Patent No. 5,053,407 provided rights only in the United States. It did not directly confer protection in Europe, Japan, Canada, or other jurisdictions. The broader levofloxacin estate depended on corresponding foreign applications and national patents. Foreign expiration dates could differ because of:
A U.S. freedom-to-operate conclusion cannot be exported to another jurisdiction without reviewing the relevant national patent family. Key Takeaways
FAQs About U.S. Patent 5,053,407 and LevofloxacinDoes Patent 5,053,407 cover the R(+) enantiomer of ofloxacin?No. The claims are directed to the S(-) configuration. The R(+) enantiomer is not literally the claimed S(-) compound. Did Patent 5,053,407 cover generic levofloxacin tablets?During its term, claim 2 could cover the levofloxacin active ingredient in a generic tablet. The patent did not require a particular tablet formulation. It expired on October 1, 2008. Is levofloxacin subject to a biosimilar patent dance?No. Levofloxacin is a synthetic small molecule regulated through the ANDA pathway, not a biologic regulated through the 351(k) biosimilar pathway. Could a later patent still block a levofloxacin injectable product?Yes, in principle. A later patent could claim a specific formulation, manufacturing process, container system, or use. That would be separate from U.S. Patent No. 5,053,407 and would require an independent patent and Orange Book review. Does the expired patent still matter in a freedom-to-operate opinion?Yes, as historical context and for assessing prior litigation, settlement rights, and the development history of levofloxacin. It does not, by itself, create a current U.S. infringement risk for making or selling levofloxacin. References
More… ↓ |
Drugs Protected by US Patent 5,053,407
| 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 |
Foreign Priority and PCT Information for Patent: 5,053,407
International Family Members for US Patent 5,053,407
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| European Patent Office | 0206283 | ⤷ Start Trial | SPC/GB97/085 | United Kingdom | ⤷ Start Trial |
| European Patent Office | 0206283 | ⤷ Start Trial | C980016 | Netherlands | ⤷ Start Trial |
| European Patent Office | 0206283 | ⤷ Start Trial | 98C0041 | Belgium | ⤷ Start Trial |
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
