Details for Patent: 5,384,113
Summary for Patent: 5,384,113
| Title: | Stabilizers to prevent autoradiolysis of radiolabeled peptides and proteins | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | Gentisic acid and its derivatives substantially inhibit peptide autoradiolysis. Gentisic acid or its derivatives may also be used in combination with other stabilizers such as inositol and ascorbic acid to inhibit autoradiolysis of radiolabeled peptides. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Edward A. Deutsch, Wilhelmus T. Goedemans, Martinus T. Maria de Jong, Kathleen M. Miller, James W. Brodack | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Mallinckrodt Inc | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US08/135,882 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; Composition; Formulation; Device; | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | US Patent 5,384,113: Claim Scope, Expiration, Orange Book Status, and Radiolabeled Peptide Patent LandscapeUS Patent 5,384,113 covers the use of gentisic acid, gentisyl alcohol, and related salts, esters, derivatives, or mixtures to reduce autoradiolysis in radiolabeled peptides and proteins. Its most commercially specific claim is directed to a DTPA-octreotide composition labeled with indium-111. The patent issued on January 24, 1995, and its original 17-year patent term would have expired on January 24, 2012, absent an unusual term adjustment or other extension. The claims are therefore no longer an active US barrier to generic or competing radiolabeled peptide products. What does US Patent 5,384,113 cover?The patent protects two related subject matters:
Autoradiolysis is radiation-induced degradation of a radiolabeled molecule. The claimed solution is to include a stabilizer in the pharmaceutically acceptable carrier containing the radiolabeled peptide or protein. The independent claims are:
The patent does not broadly claim every radiolabeled peptide formulation. It requires the combination of a covered biological molecule, a covered radionuclide, and a covered stabilizer. What radionuclides are covered by the patent?Claims 1 and 10 identify six radionuclides:
The radionuclide list is closed by the phrase “selected from the group consisting of.” A formulation using fluorine-18, lutetium-177, yttrium-90, copper-64, zirconium-89, or another isotope would not literally satisfy the radionuclide limitation in claims 1 or 10. That limitation materially narrows the patent’s relevance to modern radiopharmaceuticals. Several current peptide-imaging and peptide-therapy products use radionuclides outside the listed group, including lutetium-177 and gallium-68. What stabilizers are protected by US Patent 5,384,113?The stabilizer class includes:
The supplied text uses both “genetisyl alcohol” in claim 1 and “gentisyl alcohol” in the other claims. “Gentisyl alcohol” appears to be the intended chemical term. The inconsistency could become relevant in claim construction, prosecution-history review, or an invalidity analysis. The claims do not specify a fixed concentration. Instead, they require an amount “effective to prevent autoradiolysis.” That language gives the claim functional breadth but also creates potential disputes over:
A product containing gentisic acid at a concentration that demonstrably preserves radiochemical purity would present a stronger infringement case than a product containing a nominal amount without evidence of a stabilizing effect. How do claims 1 through 9 protect radiolabeled peptides?Claim 1: Broad peptide methodClaim 1 requires:
The claim does not require a particular peptide sequence, administration route, formulation volume, pH, storage condition, or labeling chemistry. Claims 2 and 3: Labeling routeClaim 2 covers peptide labeling through a bifunctional chelate. Claim 3 covers direct labeling. These claims distinguish two technical routes:
Because claims 2 and 3 depend on claim 1, each still requires the listed radionuclide and stabilizer. Claims 4 through 7: Additional formulation limitationsClaim 4 adds a second stabilizer. Claims 5 and 6 identify inositol and ascorbic acid as examples. Claim 7 adds a buffer. These claims create narrower combination claims, such as:
The claims do not require the second stabilizer to perform a separately defined function. The primary functional requirement remains prevention of autoradiolysis. Claims 8 and 9: Indium-111 octreotideClaim 8 narrows the radionuclide to indium-111. Claim 9 further narrows the peptide to octreotide. Claim 9 is commercially important because it maps closely onto the formulation technology used for indium-111-labeled octreotide imaging products, including the DTPA-octreotide technology associated with OctreoScan. What does claim 15 cover?Claim 15 is the principal composition claim. It requires:
Unlike claims 1 and 10, claim 15 does not expressly recite a pharmaceutically acceptable carrier. The claimed composition is therefore framed around the active radiolabeled conjugate and stabilizer rather than the full finished dosage form. Claim 15 is narrower than claim 1 in biological subject matter and labeling chemistry, but it is stronger as a product claim. A composition claim can be asserted against making, using, selling, offering for sale, or importing a covered composition without proving that a party performed every step of a stabilization method. What formulations are protected by claims 16 through 21?
Claim 20 is directed to a lyophilized kit containing the claimed formulation components. The lyophilized-kit limitation is important because radiopharmaceutical products often separate radionuclide or labeling components before reconstitution. Claim 21 covers a liquid formulation. It does not, based on the supplied language, require a buffer or second stabilizer. A liquid product could therefore fall within claim 21 if it contains the claim 15 components and satisfies the composition requirements. How strong is the patent estate for radiolabeled octreotide?The estate is narrow in subject matter but commercially targeted.
The patent’s strongest historical position was against an indium-111 octreotide formulation using gentisic acid or a related stabilizer. Its weakest features were the functional “effective to prevent autoradiolysis” standard and the absence of concentration, test-method, or stability-period limitations. When did US Patent 5,384,113 lose exclusivity?The patent issued January 24, 1995. For a US utility patent subject to the pre-Uruguay Round patent-term rule, the ordinary term was 17 years from issuance. On that basis, the expected expiration date was January 24, 2012 (U.S. Patent No. 5,384,113, 1995). The patent is therefore expired. An expired patent cannot support a current US patent-infringement claim, block an ANDA, or create an active Orange Book patent-exclusivity period. The patent also predates the 20-year-from-earliest-effective-filing-date regime that generally applies to applications filed on or after June 8, 1995. A complete terminal-disclaimer and patent-term-adjustment review would be required for a formal legal opinion, but the patent’s historical term framework points to a 2012 expiration. What is the Orange Book status of the patent?US Patent 5,384,113 is not a current Orange Book barrier. The relevant commercial product was OctreoScan, an indium In-111 pentetreotide diagnostic radiopharmaceutical. FDA materials identify OctreoScan as an approved indium-111-labeled somatostatin analog product. The formulation includes pentetreotide, a DTPA-containing octreotide derivative, and stabilizing excipients including gentisic acid and inositol in the product kit framework (U.S. Food and Drug Administration [FDA], 1994). The patent’s expiration means:
Orange Book status should be distinguished from FDA product approval. FDA approval of the reference product does not preserve an expired patent. Were there Paragraph IV challenges to this patent?A current Paragraph IV challenge to US Patent 5,384,113 would have no practical effect because the patent has expired. The patent was issued before the modern commercial expansion of ANDA litigation involving many radiopharmaceutical products. Publicly relevant ANDA disputes would more likely concern:
The supplied patent information does not establish a particular Paragraph IV notice letter, ANDA number, or district-court case involving this patent. The expired status is determinative for present-day entry analysis. What patent litigation affects indium-111 octreotide products?The principal litigation consequence of Patent 5,384,113 is historical rather than current. Any enforcement action based solely on this patent would face expiration as a complete defense to infringement occurring after expiration. Potential litigation theories based on the patent could still arise in limited historical contexts, such as:
The patent itself does not establish a current injunction risk for OctreoScan alternatives, indium-111 pentetreotide products, or comparable stabilizer formulations. Which companies challenged or licensed the patent?The patent record should be separated from commercial licensing records. A patent assignment does not necessarily prove a product license, and a product collaboration does not necessarily assign the patent. The relevant commercial ecosystem included:
The supplied claims do not establish a licensing agreement, royalty arrangement, settlement, or covenant not to sue. No licensing conclusion should be drawn solely from the patent’s use in an FDA-approved product. How does the patent compare with newer radiopharmaceutical patent estates?
The patent is not a broad platform patent for peptide radiopharmaceuticals. It does not cover all chelator-peptide-radionuclide combinations. It is best understood as an excipient and stabilization patent with a targeted indium-111 octreotide composition claim. What generic entry risks exist?Current entry risk from this patent is zero because the patent has expired. Remaining risks must be assessed elsewhere. Low-risk scenariosA competing product is less exposed when it:
Historical or residual-risk scenariosBefore expiration, risk would have been higher for a product that:
Today, those features may still be relevant to freedom-to-operate analysis only as prior-art or historical evidence. They do not create an active infringement restriction under this patent. What biosimilar risks apply?Biosimilar risk is not material to this patent. The claimed products are radiolabeled peptides and proteins, not conventional therapeutic monoclonal antibodies or other biological products regulated through the biosimilar pathway. A competing radiolabeled peptide product would ordinarily raise small-molecule, radiopharmaceutical, drug-product, or biologic classification questions depending on the active molecule and regulatory pathway. It would not be a biosimilar merely because the product contains a biologically active peptide. What manufacturing and IP barriers remain?Although Patent 5,384,113 is expired, radiopharmaceutical entry can still face non-patent barriers:
Later patents may cover manufacturing steps, chelator chemistry, peptide sequences, dosing regimens, imaging indications, or therapeutic use. Those rights must be reviewed separately from Patent 5,384,113. What is the revenue exposure from this patent?The patent’s current direct revenue exposure is negligible because it is expired. Historical revenue exposure was concentrated in indium-111 octreotide imaging products, particularly formulations using the claimed stabilizer system. The patent did not claim:
Its commercial value depended on the formulation’s use in an approved product, not on broad control of the radiopharmaceutical market. Key Takeaways
FAQsDoes US Patent 5,384,113 cover gallium-68 peptide imaging agents?No. Gallium-68 is not listed in claims 1 or 10. Claim 1 lists gallium-67, which is a different radionuclide. Does the patent cover lutetium-177 octreotide?Not literally under the supplied claims. Lutetium-177 is absent from the closed radionuclide list in claims 1 and 10, and claim 15 is limited to indium-111-labeled DTPA-octreotide. Is gentisic acid required in every claim?No. Claims 1 through 14 and 15 identify gentisic acid, gentisyl alcohol, or related compounds. Dependent claims add other stabilizers or buffers, but they do not eliminate the base stabilizer requirement. Can an expired patent still block FDA approval?No. An expired patent cannot create a current patent-based FDA stay or prevent approval on patent grounds. FDA approval and patent enforceability remain separate issues. Does a liquid indium-111 octreotide formulation fall within claim 21?It may, if it satisfies claim 15 and is a liquid formulation. Claim 21 does not, based on the supplied text, require a second stabilizer or buffer. References
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Drugs Protected by US Patent 5,384,113
| 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 |
International Family Members for US Patent 5,384,113
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Austria | 196428 | ⤷ Start Trial | |||
| Australia | 2462592 | ⤷ Start Trial | |||
| Canada | 2113995 | ⤷ Start Trial | |||
| Germany | 69231469 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
