Details for Patent: 4,316,897
Summary for Patent: 4,316,897
| Title: | Method of lowering serum prolactin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | Benzodiazepine derivatives which have tranquillizing activity, especially 1,4-benzodiazepine derivatives, can lower the serum prolactin concentration. They can reduce, dosage-dependently, the increase in the serum prolactin concentration induced by the administration of neuroleptics, which can lead to undesirable side-effects, when about 0.01 to 100 parts by weight of benzodiazepine derivatives are administered per part by weight of neuroleptic, it being immaterial whether the benzodiazepine derivative is administered before or after the neuroleptic or simultaneously therewith. The simultaneous administration of the active substances can be carried out as an ad hoc combination or in the form of a pharmaceutical combination. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Wolfgang Lotz | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | F Hoffmann La Roche AG , Hoffmann La Roche Inc | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US06/185,812 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | United States Drug Patent 4,316,897: Claim Scope, Expiration, Litigation Risk, and Patent LandscapeU.S. Patent No. 4,316,897 covers a method of reducing neuroleptic-induced hyperprolactinemia by administering specified benzodiazepines to patients receiving specified neuroleptic drugs. The patent issued on February 23, 1982, and its ordinary 17-year patent term expired on February 23, 1999. It has no current U.S. exclusionary value, no live Paragraph IV exposure, and no meaningful biosimilar relevance. Its principal value today is historical, freedom-to-operate, and prior-art analysis. What does U.S. Patent 4,316,897 protect?The patent claims a treatment method involving two therapeutic agents:
The independent claim requires the patient to have high prolactin caused by administration of one of nine specified neuroleptics:
The claimed benzodiazepine group includes:
The claim is a treatment-method claim, not a composition claim, product claim, formulation claim, or manufacturing claim. It does not cover the listed benzodiazepines as molecules, nor does it cover the listed neuroleptics as products. Claim-by-claim scope
How broad is independent claim 1?Claim 1 has several cumulative limitations. A potential infringement theory would need to establish all of the following:
The closed lists are significant. A treatment using risperidone, olanzapine, quetiapine, aripiprazole, amisulpride, or another neuroleptic not listed in the claim would not literally satisfy the neuroleptic limitation. A treatment using alprazolam, midazolam, zolpidem, or another unlisted compound would not literally satisfy the benzodiazepine limitation. The claim also requires causation or at least the claimed treatment context: the high prolactin concentration must be induced by the administration of the specified neuroleptic. A benzodiazepine administered to a patient with idiopathic hyperprolactinemia would fall outside the express language of claim 1. The phrase “prolactin lowering amount” is functional. It does not specify a single dose, concentration, administration route, or treatment duration. The relevant amount would be determined by whether the administered benzodiazepine lowers prolactin in the treated individual under the claim’s circumstances. What formulations and dosage forms are protected?The patent does not expressly claim a particular formulation or dosage form. Its claims are directed to administration of an active benzodiazepine derivative in a treatment method. The claims therefore potentially encompass administration through conventional dosage forms, including:
The absence of formulation limitations increases the theoretical breadth of the method claims. It also limits modern commercial relevance because the patent does not create a separate barrier around a specific sustained-release formulation, combination tablet, injectable depot product, or delivery system. The patent does not claim:
What is the legal significance of claim 2's nitrazepam language?Claim 2 presents a material drafting issue. Claim 1 defines the benzodiazepine derivative by a closed Markush group that does not include nitrazepam. Claim 2 then states that the 1,4-benzodiazepine derivative is nitrazepam. A dependent claim normally incorporates all limitations of the parent claim and adds a further limitation. Under 35 U.S.C. § 112(d), claim 2 must be read together with claim 1. Because nitrazepam is not expressly listed in claim 1, two possible interpretations arise:
The first interpretation creates a validity and construction vulnerability. The second interpretation could preserve a narrower nitrazepam claim if the specification, prosecution history, or original claim set clearly establishes that nitrazepam was intended to be covered. The issue would have mattered during enforcement, but it has no current U.S. blocking effect because the patent expired in 1999. When did U.S. Patent 4,316,897 lose exclusivity?U.S. Patent 4,316,897 issued on February 23, 1982. For a U.S. patent governed by the pre-Uruguay Round patent-term regime, the ordinary term was 17 years from grant under the former version of 35 U.S.C. § 154.
The patent predates the modern 20-year term measured from the earliest effective nonprovisional filing date. Patent-term adjustment and patent-term extension regimes that apply to newer patents do not ordinarily revive a patent that completed its pre-1995 statutory term. An expired patent cannot support a current infringement action or block a generic, branded, or combination-product launch in the United States. It can remain relevant as prior art, technical disclosure, and evidence of historical development. What is the Orange Book status of U.S. Patent 4,316,897?U.S. Patent 4,316,897 is not a current Orange Book exclusivity asset. The patent expired more than two decades ago, and an expired patent does not create an Orange Book patent-based barrier to an abbreviated new drug application. Orange Book relevance is also limited by the claim type. FDA patent listing generally concerns patents claiming an approved drug substance, drug product, or approved method of use submitted for listing by the applicable new drug application holder. U.S. Patent 4,316,897 is a broad historical method-of-treatment patent involving multiple neuroleptics and benzodiazepines. It is not a patent on a single currently marketed drug product. A current generic applicant would not need a Paragraph IV certification directed to this patent because the patent is expired. If the patent appeared in historical Orange Book records, its expired status would still eliminate any current statutory stay or launch-blocking effect under the Hatch-Waxman framework. [2] Were Paragraph IV challenges or generic disputes associated with the patent?No current Paragraph IV risk exists for U.S. Patent 4,316,897. A Paragraph IV certification challenges the validity, enforceability, or infringement of an unexpired listed patent. Once the patent expired in 1999, it ceased to present a live patent-term obstacle. The patent's structure also made it an unlikely modern Paragraph IV target:
No current generic launch strategy should allocate litigation resources to this patent. What patent litigation and settlement agreements affect the patent?The patent's expiration eliminates current litigation significance. There is no continuing injunction, royalty stream, settlement-based launch restriction, or enforceable patent covenant arising solely from U.S. Patent 4,316,897. A historical litigation search would need to distinguish:
Those categories should not be combined. A lawsuit involving haloperidol, sulpiride, diazepam, or another listed compound does not necessarily implicate this patent. The absence of current patent enforceability also means that any historical settlement would have no remaining ability to defer entry after the statutory expiration date, except for obligations independently surviving under contract law. How strong was the patent estate?The estate was narrow in portfolio depth but relatively broad in therapeutic-method wording. Its historical strength can be assessed as follows:
Claim 1 would have been difficult to design around if a company administered one of the listed benzodiazepines specifically to control prolactin elevation caused by one of the listed neuroleptics. The same claim would have been easier to avoid by:
The claim's functional “prolactin lowering amount” limitation could also have created proof issues. An enforcement case would likely require clinical, pharmacological, or prescribing evidence showing that the accused administration was intended and effective to lower prolactin. What manufacturing and intellectual-property barriers remain?No patent barrier from U.S. Patent 4,316,897 remains. The listed benzodiazepines and neuroleptics are generally old chemical entities, and the patent does not claim a proprietary manufacturing route. Current barriers, if any, would arise from other sources:
Those barriers are separate from the expired patent. A company developing a modern product for antipsychotic-induced hyperprolactinemia would need to conduct a fresh freedom-to-operate search covering the selected active ingredient, formulation, delivery technology, indication language, and manufacturing process. Does the patent create biosimilar risk?No. Biosimilar risk is not relevant to this patent. The patent concerns small-molecule benzodiazepines and neuroleptics. It does not claim a biologic, recombinant protein, monoclonal antibody, peptide, cell therapy, or other product regulated through the biosimilar pathway under the Public Health Service Act. Any competitive risk would arise from conventional generic drugs, reformulated small-molecule products, or new branded therapies for antipsychotic-induced hyperprolactinemia. It would not arise from biosimilar substitution. How does this patent compare with later prolactin-management patents?U.S. Patent 4,316,897 uses an older pharmacological approach: administering a benzodiazepine to reduce prolactin elevation associated with specified neuroleptics. Later patent strategies in this area would more likely focus on:
Compared with those strategies, U.S. Patent 4,316,897 has no surviving exclusivity but remains relevant as an early disclosure of pharmacological management of neuroleptic-induced prolactin elevation. It could be cited against later claims directed to the same use of the same benzodiazepine-neuroleptic combinations. What is the commercial exposure associated with the patent?The patent itself has no current revenue exposure because it cannot block sales. Historical commercial exposure would have depended on sales of the listed neuroleptics and benzodiazepines during the patent term. The commercial model was also structurally weak:
A modern company cannot claim lost market exclusivity from this patent. Any valuation should assign zero current patent-term value to the U.S. patent, while assigning possible residual prior-art value in later patent prosecution or invalidity analysis. What geographic coverage does the patent provide?U.S. Patent 4,316,897 provided rights only in the United States. It did not create worldwide protection. Foreign counterparts, if any, would have required separate prosecution and separate term analysis. A U.S. expiration date does not establish the status of corresponding patents in Europe, Japan, Canada, Australia, or other jurisdictions. Foreign rights would also have been subject to national maintenance fees, local patent-term rules, and national claim amendments. For current global freedom-to-operate work, the U.S. patent should be treated as an expired U.S. asset, not as evidence that all corresponding foreign rights expired on the same date. What generic launch scenarios exist today?There is no launch scenario in which U.S. Patent 4,316,897 delays entry. A company could launch a product involving a listed benzodiazepine or listed neuroleptic without infringing an enforceable term of this patent, subject to other patents, FDA requirements, controlled-substance rules, and product-specific regulatory obligations. The practical scenarios are:
Key Takeaways
FAQsCan an expired patent still be used against a generic manufacturer?No. An expired patent cannot support an infringement injunction or delay generic entry. It can remain relevant as prior art against later patent applications. Does administering diazepam to a patient taking haloperidol infringe the patent today?No. The patent expired in 1999. The historical claim language would have covered the claimed treatment context if all limitations were met during the patent term, but it creates no current infringement risk. Is nitrazepam covered by claim 2?Claim 2 expressly identifies nitrazepam, but claim 1 does not include nitrazepam in its closed benzodiazepine list. That inconsistency would have created a claim-construction and validity issue. The expired status makes the issue commercially immaterial today. Does the patent cover treatment with modern antipsychotics such as risperidone or olanzapine?Not literally. Those drugs are not among the neuroleptics identified in claim 1. The patent also expired, so no current infringement action could be based on the claim. Could this patent block a new fixed-dose benzodiazepine-neuroleptic combination?No. The patent expired and does not currently block a fixed-dose combination. A new product could still face other patents covering its formulation, dosage regimen, method of use, or manufacturing process. References
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Drugs Protected by US Patent 4,316,897
| Applicant | Tradename | Generic Name | Dosage | NDA | Approval Date | TE | Type | RLD | RS | Patent No. | Patent Expiration | Product | Substance | Delist Req. | Patented / Exclusive Use | Submissiondate |
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| >Applicant | >Tradename | >Generic Name | >Dosage | >NDA | >Approval Date | >TE | >Type | >RLD | >RS | >Patent No. | >Patent Expiration | >Product | >Substance | >Delist Req. | >Patented / Exclusive Use | >Submissiondate |
