Details for Patent: 5,198,533

« Back to Dashboard

Summary for Patent: 5,198,533

Title:	LHRH antagonists
Abstract:	The present invention deals with LHRH antagonists which possess improved water solubility and while having the high antagonist potency of the basic peptides, are free of the edematogenic effects. These compounds are highly potent in inhibiting the release of gonadotropins from the pituitary gland in mammals, including humans.The compounds of this invention are represented by the formula --Leu--Arg--Pro--R10 --NH2 whereinX is an acyl group derived from straight or branched chain aliphatic or alicyclic carboxylic acids having from 1 to 7 carbon atoms, or H2 N--CO,R1 is D-- or L--Pro, D-- or L--Δ3 --Pro, D--Phe, D--Phe(4--H1), D--Ser, D--Thr, D--Ala, D--Nal(1) or D--Nal (2),R2 is D--Phe or D--Phe(4--C1)R3 is D--Trp, D--Phe, D--Pal(3), D--Nal(1) or D--Nal(2),R6 is D--Cit, D--Hci, D--Cit(Q) or D--Hci(Q) andR10 is Gly or D--Alawhere Q is lower alkyl of 1-3 carbon atoms and H1 is fluoro, chloro or bromo, and the pharmaceutically acceptable acid addition salts thereof and methods of use pertaining to these compounds.
Inventor(s):	Andrew V. Schally, Sandor Bajusz
Assignee:	Tulane University
Application Number:	US07/197,153
Patent Claim Types: see list of patent claims	Compound;

US Patent 5,198,533: Claim Scope, Ganirelix and Cetrorelix Coverage, Expiration, and Patent Landscape

US Patent 5,198,533 covers a narrowly defined class of 10-amino-acid gonadotropin-releasing hormone, or GnRH, antagonists. The claims require a fixed peptide backbone and permit limited substitutions at positions 3 and 6. The claim set encompasses the active ingredients associated with ganirelix and cetrorelix, along with two less-commercialized analogues. The patent issued on March 30, 1993, and its standard 17-year post-issuance term placed expiration on March 30, 2010, absent a terminal disclaimer or patent-term extension. The claims are therefore expired and no longer block U.S. manufacture, sale, or use of the covered compounds.

What compounds does US Patent 5,198,533 claim?

The patent claims peptide GnRH antagonists with the following core structure:

Ac-D-Nal(2)-D-Phe(4-Cl)-R3-Ser-Tyr-R6-Leu-Arg-Pro-D-Ala-NH2

The permitted residues are:

Position	Claimed residue	Chemical identity
N-terminus	Ac	Acetyl
R1	D-Nal(2)	D-2-naphthylalanine
R2	D-Phe(4Cl)	D-4-chlorophenylalanine
R3	D-Trp or D-Pal(3)	D-tryptophan or D-3-pyridylalanine
Position 4	Ser	Serine
Position 5	Tyr	Tyrosine
R6	D-Cit or D-Hci	D-citrulline or D-homocitrulline
Position 7	Leu	Leucine
Position 8	Arg	Arginine
Position 9	Pro	Proline
R10	D-Ala	D-alanine
C-terminus	NH2	C-terminal amide

The patent also claims pharmaceutically acceptable acid-addition salts. Those salts do not create a separate active-moiety class. They cover protonated forms of the basic peptide, including commercially relevant acetate salts.

The claim language is composition-of-matter language. It does not depend on a particular indication, dose, formulation, manufacturing process, or route of administration.

How many peptide species are covered by claim 1?

Claim 1 covers four distinct sequence combinations generated by the two R3 options and two R6 options.

R3	R6	Resulting peptide class
D-Trp	D-Cit	D-Trp/D-Cit analogue
D-Trp	D-Hci	D-Trp/D-Hci analogue
D-Pal(3)	D-Cit	Cetrorelix-type analogue
D-Pal(3)	D-Hci	Ganirelix-type analogue

Claim 2 narrows claim 1 by requiring D-Pal(3) at R3. It therefore covers two compounds:

1. The D-Pal(3)/D-Cit analogue, commonly associated with cetrorelix.
2. The D-Pal(3)/D-Hci analogue, commonly associated with ganirelix.

The claims do not cover arbitrary substitutions at any other position. A peptide that changes the acetyl group, the D-Nal(2) residue, the D-4-chlorophenylalanine residue, the serine, tyrosine, leucine, arginine, proline, D-alanine, or terminal amide would fall outside the literal wording unless another claim or an equivalents theory applied.

Does US Patent 5,198,533 cover ganirelix?

Yes. Ganirelix corresponds to the D-Pal(3)/D-Hci embodiment:

Ac-D-Nal(2)-D-4-ClPhe-D-Pal(3)-Ser-Tyr-D-Hci-Leu-Arg-Pro-D-Ala-NH2

Ganirelix is marketed as ganirelix acetate, including the product Orgalutran outside the United States and Ganirelix Acetate Injection in the United States. The compound is a synthetic GnRH antagonist used to prevent premature luteinizing hormone surges during controlled ovarian stimulation.

The relevant correspondence is:

Ganirelix feature	Patent requirement
Acetylated N-terminus	Ac
D-2-naphthylalanine	D-Nal(2)
D-4-chlorophenylalanine	D-Phe(4Cl)
D-3-pyridylalanine	D-Pal(3)
D-homocitrulline	D-Hci
C-terminal D-alanine amide	D-Ala-NH2

Ganirelix is therefore within both claim 1 and claim 2.

Does US Patent 5,198,533 cover cetrorelix?

Yes. Cetrorelix corresponds to the D-Pal(3)/D-Cit embodiment:

Ac-D-Nal(2)-D-4-ClPhe-D-Pal(3)-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2

Cetrorelix is marketed as cetrorelix acetate under the brand Cetrotide. Like ganirelix, it is a synthetic GnRH antagonist used in assisted reproductive technology.

Cetrorelix falls within claim 1 because it uses one of each permitted R3 and R6 substitution. It also falls within claim 2 because R3 is D-Pal(3).

The patent therefore claims the same core peptide sequence used by both important commercial GnRH antagonists, although commercial products may have been supported by additional patents, regulatory exclusivities, formulation rights, manufacturing know-how, or later-filed patent families.

What is the legal scope of the patent claims?

Composition-of-matter protection

The principal legal value of US 5,198,533 was composition-of-matter protection. A product containing one of the claimed peptide sequences in a pharmaceutically acceptable acid-addition salt would have been within the literal scope of the claims.

The claim does not require:

• A particular pharmaceutical dosage form.
• A particular concentration.
• Subcutaneous or injectable administration.
• Use in infertility treatment.
• Suppression of luteinizing hormone.
• Treatment of endometriosis, uterine fibroids, or prostate cancer.
• A specific counterion, provided the salt qualifies as pharmaceutically acceptable.

This structure gives the patent broader product protection than a method-of-use claim, but narrower sequence protection than a claim covering an entire genus of GnRH antagonists.

Salt coverage

The phrase "pharmaceutically acceptable acid addition salts" extends the claim to salt forms of the basic peptide. It can cover acetate and other acceptable acid salts, subject to the ordinary requirements of claim construction and pharmaceutical acceptability.

The salt language does not necessarily cover:

• Covalent derivatives of the peptide.
• Prodrugs with altered chemical structures.
• Non-pharmaceutically acceptable salts.
• Formulations in which the peptide is merely present as an impurity.
• Polymorphs or physical forms that do not correspond to the claimed peptide salt.

Markush limitations

The R3 and R6 alternatives are closed limitations. A competitor using D-Pal(3) at R3 but a residue other than D-Cit or D-Hci at R6 would not meet the literal requirements of claim 1. A competitor using D-Trp at R3 and D-Cit at R6 would remain within claim 1.

The claim is therefore commercially important because it covers two clinically relevant products while retaining two additional sequence combinations.

When did US Patent 5,198,533 expire?

Event	Date
Patent issued	March 30, 1993
Standard U.S. term for pre-URAA patent	17 years from issue
Expected statutory expiration	March 30, 2010
Current status	Expired by term

US Patent 5,198,533 was issued before the change to the 20-year-from-earliest-effective-filing-date term under the Uruguay Round Agreements Act. For this patent class, the governing term was generally 17 years from issuance. The patent therefore expired in 2010 under the ordinary term calculation.[1]

No current U.S. exclusivity can be based on the expired composition claims. A later patent could have protected a formulation, manufacturing process, delivery system, or new use, but such a patent would not revive the expired compound claims.

What was the Orange Book status of ganirelix and cetrorelix?

Ganirelix and cetrorelix are FDA-approved synthetic peptides rather than biologic medicines. Their abbreviated-product pathway is generally the ANDA framework under section 505(j), not the biosimilar pathway under section 351(k).

Product	Active ingredient	FDA product category	Principal commercial use
Ganirelix Acetate Injection	Ganirelix acetate	Synthetic peptide drug	Controlled ovarian stimulation
Cetrotide	Cetrorelix acetate	Synthetic peptide drug	Controlled ovarian stimulation

Orange Book treatment depends on whether an NDA holder submitted a patent for listing and whether FDA accepted that submission under the applicable regulations. An Orange Book listing would not extend the underlying patent beyond its statutory expiration. After March 30, 2010, US 5,198,533 could not support a new Paragraph IV enforcement action based on a live patent right.[2]

Regulatory exclusivity and patent exclusivity are separate. FDA approval dates for ganirelix and cetrorelix occurred after issuance of US 5,198,533, but those approvals did not restore the expired patent term. Any later-listed patent would need to be analyzed independently by patent number, claims, and expiration date.

Were Paragraph IV challenges available against this patent?

A Paragraph IV certification could have been relevant while US 5,198,533 was listed for an approved product and remained unexpired. The applicant would have asserted that the patent was invalid, unenforceable, or not infringed.

Because the patent expired in 2010:

• A new ANDA applicant cannot create a current Paragraph IV risk against this patent.
• A patent certification based on an expired patent would not generate a present term-based exclusion.
• A historical Paragraph IV dispute would matter only for assessing launch timing, damages, or settlement history.
• Any current generic or alternative supplier would need to evaluate later patents and regulatory requirements, not this expired composition patent.

The 30-month stay mechanism under Hatch-Waxman is tied to a timely patent infringement action involving a listed patent. It does not apply as a continuing barrier after the patent has expired.[3]

What formulation patents protect ganirelix or cetrorelix?

US 5,198,533 is not a formulation patent. It does not require a particular excipient, vial, syringe, concentration, preservative system, pH range, lyophilization cycle, or device.

Potential later patent categories include:

Injectable formulations

Commercial products may raise patent issues involving:

• Aqueous peptide solutions.
• Lyophilized compositions.
• Acetate-buffered formulations.
• Stabilizers and tonicity agents.
• Peptide concentration ranges.
• Container-closure systems.
• Prefilled syringes or injection devices.

A formulation claim must be read separately from the expired composition claim. A generic manufacturer could avoid a formulation patent by using a different excipient combination or manufacturing process, provided the alternative remains pharmaceutically acceptable and regulatorily approvable.

Manufacturing patents

Synthetic peptide production can generate process and know-how barriers involving:

• Solid-phase peptide synthesis.
• Protection and deprotection chemistry.
• Control of deletion sequences.
• Purification of highly basic peptide intermediates.
• Removal of diastereomeric or epimeric impurities.
• Salt conversion and crystallization.
• Sterile filling and stability control.

These barriers are commercially relevant even when the basic molecule is no longer patent-protected. They affect yield, impurity profiles, batch consistency, and the cost of regulatory validation.

Device and packaging rights

A syringe, autoinjector, cartridge, or specialized package may be subject to separate patents. Device patents generally do not prevent manufacture of the peptide itself but can constrain a competitor's preferred presentation.

Does biosimilar risk apply to ganirelix or cetrorelix?

Traditional biosimilar risk is limited because ganirelix and cetrorelix are chemically synthesized peptides approved as drugs rather than reference biologics approved under the Public Health Service Act.

The more relevant competition model is:

1. An ANDA for a pharmaceutically equivalent product, if the FDA pathway is available.
2. A 505(b)(2) application for a product with formulation, delivery, or clinical differences.
3. A full NDA if the proposed product cannot rely on the reference product's required evidence.
4. Direct competition from another GnRH antagonist, including leuprolide, nafarelin, or newer reproductive-endocrinology products.

The expired composition patent materially lowers the intellectual-property barrier. Manufacturing complexity and FDA product-specific requirements remain more important than biosimilar patent risk.

Which companies compete with ganirelix and cetrorelix?

The competitive landscape includes direct GnRH antagonists and longer-acting GnRH agonists.

Product	Ingredient	Mechanism	Commercial relevance
Ganirelix	Ganirelix acetate	GnRH antagonist	Controlled ovarian stimulation
Cetrotide	Cetrorelix acetate	GnRH antagonist	Controlled ovarian stimulation
Lupron and related products	Leuprolide acetate	GnRH agonist	Broad reproductive and oncology uses
Synarel	Nafarelin acetate	GnRH agonist	Reproductive indications
Oriahnn, Myfembree, and related products	Other hormonal regimens	Varies	Competing hormonal management in selected indications

Ganirelix and cetrorelix compete most directly in assisted reproduction. Their commercial differentiation can depend on dosing schedule, physician familiarity, reimbursement, supply reliability, device format, and clinic purchasing agreements rather than on the expired composition patent.

How strong is the patent estate around US 5,198,533?

The original composition patent was strong during its effective term because it directly covered the active peptide sequences used in two major products. Its protection was narrow in chemical breadth but commercially concentrated.

Patent-strength factor	Assessment
Compound coverage	Strong for the four expressly claimed sequences
Coverage of ganirelix	Direct
Coverage of cetrorelix	Direct
Formulation coverage	Not provided by the quoted claims
Method-of-use coverage	Not provided by the quoted claims
Manufacturing coverage	Not provided by the quoted claims
Current blocking value	None after expiration
Historical launch protection	High if no earlier invalidating prior art or competing patent applied
Design-around potential during term	Possible through residue substitutions outside the closed alternatives
Current generic-entry barrier	Primarily regulatory, manufacturing, and later-patent based

The patent did not create a perpetual franchise around the GnRH antagonist class. It protected a defined sequence set for a defined term.

What patent litigation and settlement risks remain?

US 5,198,533 itself no longer creates a current infringement risk. Historical litigation could still matter if a dispute involved pre-expiration sales, damages, validity, or a settlement restricting launch before March 30, 2010.

For current diligence, the relevant questions are:

• Whether later patents were listed for ganirelix or cetrorelix products.
• Whether any later patent claims a formulation or delivery system used by the reference product.
• Whether a manufacturer has settled a historical Paragraph IV case.
• Whether a settlement includes a license, authorized-generic arrangement, or supply restriction.
• Whether a later patent has claims broad enough to cover the same peptide salt or only a specific presentation.

The expired patent should be treated as historical background, not as a current litigation asset.

What generic launch scenarios exist after patent expiration?

The principal launch scenarios are:

Immediate composition-based entry

A manufacturer can pursue a product containing the claimed peptide sequence because the basic composition claims are expired. The manufacturer still must satisfy FDA requirements for identity, strength, quality, sterility, bioequivalence or other applicable product-specific standards.

Formulation workaround

If a later formulation patent remains active, a competitor can develop a different buffer, excipient system, concentration, container, or lyophilization process.

505(b)(2) entry

A 505(b)(2) applicant may pursue a differentiated formulation, delivery system, or dosing presentation while relying partly on FDA findings for an approved product.

Contract-manufacturing entry

A peptide manufacturer may supply active pharmaceutical ingredient or finished product without owning the original compound patent. Process know-how, analytical methods, impurity controls, and regulatory documentation become the principal barriers.

Key Takeaways

• US Patent 5,198,533 claims four specific GnRH antagonist peptide sequences.
• Claim 2 narrows the scope to the two D-Pal(3) compounds associated with cetrorelix and ganirelix.
• The claims cover the peptide active moiety and pharmaceutically acceptable acid-addition salts.
• The quoted claims do not independently protect formulations, medical uses, delivery devices, or manufacturing processes.
• The patent issued March 30, 1993, and its ordinary 17-year term expired March 30, 2010.
• No current U.S. generic-entry risk can be based on this expired patent.
• Current diligence should focus on later formulation, process, device, and method-of-use patents, plus FDA product-specific requirements.
• Ganirelix and cetrorelix are synthetic peptide drugs, so ANDA and 505(b)(2) analysis is more relevant than traditional biosimilar analysis.

FAQs

Is ganirelix acetate still protected by US Patent 5,198,533?

No. The patent's ordinary term expired on March 30, 2010. Later patents, if any, must be analyzed separately.

Is cetrorelix acetate the same compound as the D-Pal(3)/D-Cit embodiment?

Yes. Cetrorelix corresponds to the D-Pal(3)/D-Cit sequence claimed by claims 1 and 2.

Does the patent cover all GnRH antagonists?

No. It covers only the expressly defined peptide sequence and the limited R3 and R6 alternatives. Other GnRH antagonists require separate claim analysis.

Can a competitor make ganirelix acetate without infringing this patent?

Yes, this patent no longer blocks manufacture or sale because it expired. The competitor must still assess later patents, FDA requirements, and contractual restrictions.

Does the patent cover a ganirelix injection device?

No. The quoted claims cover peptide molecules and their acid-addition salts. A device would require separate patent claims.

References

1. U.S. Patent No. 5,198,533. (1993). United States Patent and Trademark Office.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (2024). ANDA submissions: Refuse-to-receive standards and patent certification requirements.
4. U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs.
5. U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products.

Drugs Protected by US Patent 5,198,533

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 5,198,533

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0299402		C990029	Netherlands
European Patent Office	0299402		099C0031	Belgium
European Patent Office	0299402		31/1999	Austria
Austria	90362
Brazil	1100478
Canada	1339623
Germany	19975052