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Details for Patent: 5,674,710
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Summary for Patent: 5,674,710
| Title: | Recombinant techniques for production of human brain natriuretic peptide | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | The cDNA sequence encoding porcine brain natriuretic peptide and related genes encoding canine and human peptides with natriuretic activity are disclosed. The gene is shown to make accessible the DNAs encoding analogous natriuretic peptides in other vertebrate species. The genes encoding these NPs can be used to effect modifications of the sequence to produce alternate forms of the NPs and to provide practical amounts of these proteins. The NPs of the invention can also be synthesized chemically. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | J. Jeffrey Seilhamer, John Lewicki, Robert M. Scarborough, J. Gordon Porter | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Scios LLC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US07/477,226 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | US Patent 5,674,710: Claim Scope, Expiration, Orange Book Status, and Nesiritide Patent LandscapeUS Patent 5,674,710 covers recombinant DNA constructs, expression systems, host cells, and production methods for natriuretic peptides corresponding principally to human brain natriuretic peptide, or BNP. Its narrowest and commercially important embodiment is recombinant human BNP-32, the active ingredient in Natrecor, also known as nesiritide. The patent issued on October 7, 1997, and its 17-year patent term expired on October 7, 2014, subject to any recorded term adjustment. It therefore presents no current patent barrier to generic or alternative production of nesiritide. The claims do not cover nesiritide formulations, therapeutic use, dosing regimens, or the manufacture of the finished drug product independently of the claimed recombinant production technology. [1] What invention does US Patent 5,674,710 protect?The patent protects the recombinant production of natriuretic peptides having the core sequence:
This sequence corresponds to the central ring-forming region of human BNP. The cysteine residues support the disulfide-bonded structure associated with natriuretic activity. The claims also cover selected amino-terminal and carboxy-terminal extensions. The principal sequence combinations include:
The full BNP-32 sequence identified by the dependent claims is:
The claims are directed to recombinant production rather than to a product defined only by its amino-acid sequence. How many independent claims does US 5,674,710 contain?The patent has four independent claims:
Claims 5 through 8 narrow those categories to the specific BNP-32 sequence with:
Claims 5 and 8 are especially important because they capture the recombinant expression system and DNA encoding the 32-amino-acid human BNP sequence associated with nesiritide. What is the scope of claim 1?Claim 1 covers an isolated and purified recombinant DNA that encodes a peptide with the claimed natriuretic sequence architecture. The claim has four material limitations:
The phrase “consisting essentially of” limits the claim to DNA whose additional sequence content does not materially alter the claimed natriuretic peptide encoding function. It does not necessarily require the DNA molecule to contain only the coding sequence and nothing else. However, DNA sequences that encode materially different peptides, unrelated signal sequences, or non-BNP natriuretic factors would fall outside the literal sequence definition. Claim 1 is broader than claim 8 because it covers multiple N-terminal and C-terminal variants. It is narrower than a general claim to any DNA encoding BNP, any natriuretic peptide, or any recombinant peptide with BNP-like activity. What is the scope of claims 2 and 3?Claim 2: Recombinant expression systemsClaim 2 covers an expression system capable of expressing DNA encoding the claimed peptide when present in a recombinant host cell. The claim is functional. It does not require one particular promoter, plasmid, vector, codon sequence, host species, or secretion signal. A qualifying system could therefore use different molecular components, provided the system is capable of expressing a DNA sequence encoding the claimed peptide. Potentially relevant expression platforms include:
The claim remains limited by the peptide sequence and the requirement that the system be capable of expression in a recombinant host cell. Claim 3: Recombinant host cellsClaim 3 covers a recombinant host cell or cell culture containing the expression system of claim 2. The claim is cell-platform neutral. It does not expressly require a specific bacterial, fungal, insect, or mammalian host. Infringement would generally turn on whether the host contains an expression system meeting claim 2 and whether the encoded product falls within the claimed peptide structure. A host that merely contains unrelated BNP DNA without the claimed expression capability would not necessarily meet claim 3. Conversely, a host cell using a different vector or promoter could still fall within the claim if it contains a qualifying expression system. What is the scope of claim 4?Claim 4 covers a recombinant manufacturing process with two required steps:
This is a process claim, not a claim to a finished injectable formulation. It reaches production workflows that use a qualifying host cell and recover the peptide from the culture medium or cellular material. The claim does not expressly recite:
Those steps may be commercially necessary, but they are not independently required by the text of claim 4. The process must still use the claimed recombinant cell and produce a peptide within the defined sequence scope. What do claims 5 through 8 protect?Claims 5 through 8 narrow the patent to the sequence corresponding to human BNP-32.
The specified peptide is:
This is the most direct connection between the patent and nesiritide. The claims do not require the drug to be called nesiritide, Natrecor, or BNP-32. A product meeting the sequence and recombinant-production limitations could fall within the claims regardless of branding. When did US Patent 5,674,710 expire?The patent issued on October 7, 1997. For a patent governed by the pre-Uruguay Round 17-year term rule, the ordinary term runs 17 years from issuance. On that basis, the expiration date was October 7, 2014. [1, 5]
The patent’s expiration eliminates enforceable exclusion based on claims 1 through 8. It does not eliminate possible rights under later patents covering formulations, manufacturing improvements, purification, dosing, or unrelated therapeutic uses. What is the Orange Book status of US 5,674,710?US Patent 5,674,710 was associated with the recombinant BNP technology underlying Natrecor, a recombinant human BNP product approved by FDA under NDA 20-920. FDA approved Natrecor in 2001 for use in certain patients with acute decompensated heart failure. [2, 3] The relevant regulatory position is:
An Orange Book patent listing does not extend the patent term. Once the listed patent expires, it cannot block an otherwise approvable abbreviated application. FDA regulatory exclusivity and patent exclusivity are separate rights. Any five-year new chemical entity exclusivity associated with the 2001 approval would have expired years before the patent. [2, 3] Are there Paragraph IV challenges to US 5,674,710?A Paragraph IV certification would have been relevant before October 7, 2014 if an ANDA applicant sought approval for a product referencing Natrecor and challenged the patent as invalid, unenforceable, or not infringed. The commercial significance of a Paragraph IV challenge has now ended because the patent is expired. A current applicant does not need to defeat an unexpired claim to enter after the patent term. The remaining regulatory issues would concern pharmaceutical equivalence, product quality, analytical characterization, manufacturing controls, and approval of the appropriate application pathway. There is no continuing 30-month litigation stay attributable to an expired patent. A historical Paragraph IV case, if any, would not restore exclusivity or prevent post-expiration entry. Does nesiritide have biosimilar risk or generic risk?Nesiritide presents generic and biologic-like manufacturing issues, but its US approval pathway is important. Natrecor was approved as an NDA product rather than as a licensed biologic under a BLA. A follow-on applicant would therefore generally evaluate the 505(b)(2) or ANDA pathways rather than assume that the biosimilar pathway under section 351(k) is required.
The central barrier is not US 5,674,710. The practical barriers are product characterization, potency assays, peptide aggregation, impurities, oxidation, disulfide-bond control, sterility, stability, and comparability of the recombinant manufacturing process. What formulations are protected by this patent?US 5,674,710 does not expressly claim:
The patent covers the recombinant DNA, expression system, host cell, and culture-and-recovery method. A later formulation patent could have provided separate protection, but such protection would need to be evaluated independently from the claims supplied here. This distinction matters because a manufacturer could avoid an expired recombinant-production patent only in the legal sense that the patent no longer blocks production. It would still need to satisfy FDA requirements for the finished injectable product. Does the patent cover therapeutic use of nesiritide?No. The supplied claims do not claim administering BNP-32 to treat heart failure, reducing pulmonary capillary wedge pressure, improving hemodynamics, treating renal dysfunction, or managing any other disease. The patent also does not claim:
Any patent covering those subjects would be a separate method-of-use or treatment patent. The expiration of US 5,674,710 would not automatically establish that every later-use patent had expired. How strong is the patent estate for nesiritide?The patent was strong during its enforceable term because it reached multiple layers of recombinant production:
That structure created overlapping protection around the biological production platform. A competitor could potentially avoid one claim category but still encounter another if it used the same BNP sequence and recombinant production architecture. The estate is weak as a current exclusivity asset because the foundational patent expired in 2014. Its remaining value is historical, evidentiary, and technical rather than exclusionary.
Which companies challenged or competed with the patent estate?The commercial reference product was developed by Scios and later associated with Johnson & Johnson following Johnson & Johnson’s acquisition of Scios. The relevant competitive landscape included:
The principal product competitors were not necessarily direct BNP sequence competitors. In acute heart failure, competing therapeutic classes included loop diuretics, vasodilators, inotropes, and other hemodynamic agents. Carperitide and ularitide represented alternative natriuretic-peptide programs in non-US or investigational markets, but they were not necessarily covered by the specific BNP sequence claims in US 5,674,710. What geographic coverage does US 5,674,710 provide?The patent provides US rights only. It does not, by itself, establish protection in:
Related foreign applications may have been filed from the same priority family, but each jurisdiction required separate prosecution, maintenance, and term analysis. The US expiration date cannot be applied automatically to foreign counterparts. For international production, a manufacturer would need to evaluate:
What generic launch scenarios exist after patent expiration?Three entry scenarios are commercially relevant:
The principal commercial constraints are likely market size, clinical demand, manufacturing economics, hospital formulary positioning, and the need to establish a reliable quality-control package for a recombinant peptide injectable. Key Takeaways
FAQsWhat exact peptide is covered by claim 8 of US 5,674,710?Claim 8 covers recombinant DNA encoding BNP-32 with the sequence Does US 5,674,710 cover synthetic chemical manufacture of nesiritide?No. The claims require recombinant DNA, a recombinant expression system, a recombinant host cell, or a method using those cells. Purely chemical synthesis is outside the supplied claim language. Can a company launch a nesiritide generic after October 7, 2014?The expired patent does not prevent launch. FDA approval, product characterization, manufacturing controls, and applicable regulatory exclusivity remain separate requirements. Is Natrecor protected by a biologic patent or a small-molecule patent?US 5,674,710 is a biotechnology patent covering recombinant production of a peptide. Natrecor was approved through an NDA rather than the conventional BLA pathway used for many biological products. Does the patent cover BNP diagnostic tests?No. The claims do not cover measuring endogenous BNP, using BNP as a biomarker, antibody assays, diagnostic kits, or patient-risk stratification. References
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Drugs Protected by US Patent 5,674,710
| 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 5,674,710
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Austria | 126522 | ⤷ Start Trial | |||
| Australia | 3768189 | ⤷ Start Trial | |||
| Canada | 1339210 | ⤷ Start Trial | |||
| Germany | 68923878 | ⤷ Start Trial | |||
| European Patent Office | 0418308 | ⤷ Start Trial | |||
| Ireland | 68889 | ⤷ Start Trial | |||
| Ireland | 891792 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
