Details for Patent: 5,389,613
Summary for Patent: 5,389,613
| Title: | Method of treating prostate adenocarcinoma, prostate benign hypertrophia and endometriosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | A novel method of treating prostate adenocarcinoma, prostate benign hypertrophia, endometriosis, dysmenorrhea, hirsuitism, hormono-dependant mammary tumors, treatment and prevention of precocious puberty, induction of a retardation of the appearance of puberty and treatment of acne of mammals comprising administering to warm-blooded animals an effective amount of a peptide of the formula wherein (a) Z is Gly--NH2, Y is Leu and X is Gly, (b) Z is Gly--NH2, Y is Leu, X is DN Leu, DN Val, D Abu (α-aminobutyric acid), D Phe, D Ser, D Thr, D Met, D Pgl, D Lys, Leu, Ile, Nle, Val, N Val, Met, Phe, D Leu, D Arg, D Ser (tbu), D Thr (tbu), D Cys (tbu), D Asp (O tbu), D Glu (Otbu), D Orn (boc), D Lys (boc), D Trp, Trp, 2-methyl Ala, D Tyr, D Met ε-lauryl D Lys, ε-dextran-D Lys, (c) Z is NH-cyclopropyl or NH-Alk wherein Alk is alkyl of 1 to 3 carbon atoms, Y is Leu and X is D Ser (tbu), D Thr (tbu), D Asp (Othu), D Glu (Otbu), D Orn (boc), D Lys (boc), (d) Z is --NH--CH3, --NH--CH2 --CH3, NH--CH2 --CH2 --CH3, --NH--CH2 --CH2 --OH, ##STR1## Y is Leu and X is Gly, (e) Z is --NH--CH2 --CH3, Y is Leu and X is D Trp, D Leu, D Ala, D Ser (tbu), D Tyr, D Lys, Ala, (f) Z is Gly--NH2 or --NH--CH2 --CH3, Y is NαMe Leu and X is Gly, (g) Z is --NH-cyclopropyl, Y is Leu and X is D Leu or (h) Z is Gly--NH2, --NH-cyclopropyl or --NHAlk' where Alk' is alkyl of 1 to 3 carbon atoms, Y is Ser (but), Cys (but), Asp (Obut), Glu (Obut), Orn (boc), Lys (boc) and X is Gly. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Fernand Labrie, Jean-Pierre Raynaud | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Aventis Pharma SA , Merck Sharp and Dohme LLC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US08/019,232 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | United States Drug Patent 5,389,613: Claim Scope, Expiration, and GnRH Agonist Patent LandscapeUS 5,389,613 is an expired method-of-treatment patent covering selected luteinizing hormone-releasing hormone, or LH-RH/GnRH, peptide analogs for prostate adenocarcinoma, benign prostatic hypertrophy and endometriosis. Its broadest claim covers administering specified peptide sequences, including analogs structurally related to leuprolide, deslorelin and related GnRH agonists. Dependent claims cover combination treatment with antiandrogens, specifically nilutamide and flutamide. The patent issued on February 14, 1995. Assuming the standard pre-URAA 17-year term from grant, its ordinary expiration date was February 14, 2012. The claims therefore present no current blocking patent right in the United States. Their historical importance is greater than their current enforcement value because the patent illustrates an early combination of GnRH agonist therapy with antiandrogen treatment. What does US Patent 5,389,613 cover?The patent covers methods of treating three conditions:
The method requires administering an effective amount of at least one peptide having the general sequence: pGlu-His-Trp-Ser-Tyr-X-Y-Arg-Pro-Z The sequence is a modified LH-RH or GnRH decapeptide framework. The claim defines the permitted amino acids and terminal groups through eight separate alternatives, identified as paragraphs (a) through (h). The claim is a method claim, not a composition-of-matter claim. It does not independently claim:
The claim requires the treatment use and the administration of a peptide falling within the defined structural alternatives. How broad is claim 1 of US 5,389,613?Claim 1 is broad in therapeutic scope but narrower in chemical scope than a generic claim to all GnRH agonists. Its breadth comes from four features:
The structural framework corresponds to an LH-RH analog in which the sixth, eighth, ninth or tenth positions may be modified. The most commercially relevant configuration is the D-amino-acid substitution at position 6 and a modified C-terminal group. Claim 1 alternatives
The text supplied in the claim contains apparent transcription errors, including “benign hypertrophia,” “D ORn,” and inconsistent protection notation such as “tbu,” “Otbu” and “Obut.” Patent interpretation would ordinarily rely on the issued patent, prosecution history and specification rather than an OCR or database transcription. Which commercial GnRH peptides are closest to the claimed structures?The closest commercial analogs are peptide GnRH agonists used for androgen deprivation or reproductive-hormone suppression.
Claim 3 is directed specifically to “[D-Ser(tBu)6 des Gly-NH2 10] LH-RH ethylamine.” This is the peptide commonly identified as deslorelin, also written as deslorelin acetate in commercial products. The claim does not cover every deslorelin product feature. It covers a method using the specified peptide. Leuprolide is structurally important because the sequence pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt is a close match to the claimed framework. Whether a particular leuprolide use fell within the claim would depend on the precise claim construction and on whether the relevant alternative expressly included D-Leu at X with ethylamide at Z. What do claims 2 through 6 add?The dependent claims add combination-treatment limitations.
The chemical name in claims 4 and 5, 5,5'-dimethyl-3-[4-nitro-3-trifluoromethyl-phenyl]-2,4-imidazolidinedione, corresponds to nilutamide. The chemical name in claim 6, 2-methyl-N-[4-nitro-3-trifluoromethyl-phenyl]propanamide, corresponds to flutamide. Claim 2 has the widest combination scope because it refers generally to “an antiandrogen.” Claims 4 through 6 narrow the combination to specified antiandrogens. A method would need to satisfy both the peptide limitation and the antiandrogen limitation. When did US Patent 5,389,613 expire?US 5,389,613 issued on February 14, 1995. Under the pre-June 8, 1995 patent-term regime, the ordinary term was 17 years from issuance. The resulting expiration date was February 14, 2012.[1]
The patent is not a current barrier to an ANDA, 505(b)(2) application, abbreviated new drug product or commercial use of a covered peptide treatment in the United States. Patent expiration does not eliminate separate rights that may have existed in later patents covering formulations, implants, manufacturing methods, dosage forms or specific commercial products. What is the Orange Book status of US 5,389,613?US 5,389,613 is not a current Orange Book exclusivity asset. The patent is a historical method-of-use patent and does not function as an active Orange Book barrier. Orange Book-listed patents are tied to approved drug products and may include drug substance, drug product or method-of-use patents. An expired historical method patent can remain visible in patent records without creating current regulatory exclusivity.[2] For products in this class, relevant Orange Book analysis must be performed at the product level. The applicable product may be:
A product’s current patent position may therefore differ materially from the status of US 5,389,613. Did US 5,389,613 create Paragraph IV risk?The patent could historically have been challenged through a Paragraph IV certification if it was listed for an approved drug product and an ANDA applicant asserted that the patent was invalid, unenforceable or not infringed.[3] Its current expiration eliminates meaningful Paragraph IV risk based on this patent. A generic applicant does not need to make a Paragraph IV challenge to an expired patent because the patent no longer blocks approval or launch. The historical risk profile would have depended on:
Because claim 1 is a method claim, an applicant might have addressed the patent through a “skinny label” strategy if the relevant patented use could be omitted and the remaining labeling did not induce infringement. The practicality of that approach would depend on the product’s approved indications and the wording of the patent listing. What generic entry risks remain for GnRH agonists?US 5,389,613 presents no current generic entry risk because it is expired. Remaining barriers arise from later patents and regulatory requirements. LeuprolideLeuprolide products have historically relied on formulation, depot, microsphere, delivery-device and manufacturing patents. The peptide itself is no longer protected by a 1995 method patent. Generic entry depends on the specific dosage form, such as:
GoserelinGoserelin products are delivered through implants. The principal barriers have historically included implant composition, release characteristics, manufacturing and delivery-system technology. A generic injectable peptide would not necessarily substitute for an implant product without demonstrating equivalent delivery and clinical performance. HistrelinHistrelin products use long-acting implants. The commercial risk is concentrated in implant design, insertion technology, drug release and manufacturing controls rather than the expired method claim. TriptorelinTriptorelin products include depot formulations. The relevant patent landscape is likely to be more formulation-specific than peptide-sequence-specific. DeslorelinDeslorelin has been used prominently in veterinary implants. Claim 3 is structurally important for deslorelin, but the patent’s expiration removes the historical method barrier. Later veterinary formulation and implant patents may have had greater commercial relevance. What formulations are not covered by US 5,389,613?The patent does not expressly claim a formulation. It does not require:
A formulation patent could therefore have provided separate protection even if the active peptide was within claim 1. Conversely, a formulation using a non-covered GnRH analog would not infringe merely because it treated prostate cancer or endometriosis. This distinction is central to patent clearance. The expired patent eliminates one method-of-use layer, but it does not establish freedom to operate for a long-acting peptide product. How strong was the patent estate for US 5,389,613?The individual patent had moderate historical breadth and weak current commercial strength.
Potential validity pressure points would have included written description, enablement, indefiniteness and obviousness. The claim lists numerous D-amino acids, protected residues, terminal amides and conjugated structures. A challenger could have argued that the specification did not support or enable every claimed member across the full Markush scope. The treatment claims also depend on an “effective amount,” a conventional pharmaceutical claim term. The absence of a specific dose would not automatically invalidate the claims, but it could have increased the importance of the specification’s pharmacology and clinical examples. What litigation or settlement issues affected the patent?The supplied claim set does not establish a litigation history, settlement agreement or license involving US 5,389,613. The patent’s expiration means that any historical litigation would have no continuing exclusionary effect. The relevant legal issues for a historical dispute would have included:
A patent-level litigation search must be distinguished from litigation involving later patents for Lupron, Zoladex, Supprelin, Vantas, Trelstar, Synarel or related products. Those later disputes may concern different formulations, devices or manufacturing processes and should not be attributed to US 5,389,613. Which companies competed in the covered market?The principal commercial companies associated with GnRH agonist products included:
Commercial exposure was concentrated in prostate cancer, where androgen-deprivation therapy produces recurring demand through repeated depot injections or implants. Endometriosis and uterine indications provided additional demand, while BPH was a narrower and less durable commercial application. The expired patent does not support a current revenue estimate. Revenue exposure must be assigned to the later formulation, device, regulatory and commercial estates associated with each product. What is the geographic coverage of the patent?US 5,389,613 provides protection only in the United States. It does not establish rights in Europe, Japan, Canada, Australia or other jurisdictions. A global freedom-to-operate review would require examination of:
The U.S. expiration date cannot be applied automatically to foreign counterparts. Foreign patents may have had different filing dates, prosecution histories and expiration dates. Key Takeaways
FAQsDoes US 5,389,613 cover leuprolide?Leuprolide is structurally close to the claimed GnRH analog framework, particularly because it contains a D-Leu substitution and a C-terminal ethylamide. The patent is expired, so the question has no current blocking significance in the United States. Does the patent cover nilutamide by itself?No. Claims 4 and 5 require administration of the claimed GnRH peptide together with nilutamide. The patent does not claim nilutamide as a standalone antiandrogen therapy. Does claim 2 require simultaneous administration of the peptide and antiandrogen?The claim requires administration “in association with” an antiandrogen. The phrase is broader than a requirement for a single combined formulation and could encompass a treatment regimen involving both agents, subject to the patent’s specification and applicable claim-construction principles. Can a generic manufacturer launch after expiration of US 5,389,613?Yes, this patent does not prevent launch after its expiration. The manufacturer must still address other applicable patents, regulatory requirements, product-specific exclusivity and formulation or device rights. Is US 5,389,613 a composition-of-matter patent?No. The supplied claims are directed to methods of treating specified conditions by administering defined peptides. They do not claim the peptide compounds as compositions independent of therapeutic use. References
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Drugs Protected by US Patent 5,389,613
| 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: 5,389,613
| Foriegn Application Priority Data | ||
| Foreign Country | Foreign Patent Number | Foreign Patent Date |
| France | 79 23545 | Sep 21, 1979 |
International Family Members for US Patent 5,389,613
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Australia | 3726985 | ⤷ Start Trial | |||
| Australia | 542765 | ⤷ Start Trial | |||
| Australia | 572938 | ⤷ Start Trial | |||
| Australia | 6256580 | ⤷ Start Trial | |||
| Belgium | 885308 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
