Details for Patent: 6,180,608

Summary for Patent: 6,180,608

Title:	Pharmaceutical formulations for sustained drug delivery
Abstract:	Sustained delivery formulations comprising a water-insoluble complex of a peptidic compound (e.g., a peptide, polypeptide, protein, peptidomimetic or the like) and a carrier macromolecule are disclosed. The formulations of the invention allow for loading of high concentrations of peptidic compound in a small volume and for delivery of a pharmaceutically active peptidic compound for prolonged periods, e.g., one month, after administration of the complex. The complexes of the invention can be milled or crushed to a fine powder. In powdered form, the complexes form stable aqueous suspensions and dispersions, suitable for injection. In a preferred embodiment, the peptidic compound of the complex is an LHRH analogue, preferably an LHRH antagonist, and the carrier macromolecule is an anionic polymer, preferably carboxymethylcellulose. Methods of making the complexes of the invention, and methods of using LHRH-analogue-containing complexes to treat conditions treatable with an LHRH analogue, are also disclosed.
Inventor(s):	Malcolm L. Gefter, Nicholas Barker, Gary Musso, Christopher J. Molineaux
Assignee:	GlaxoSmithKline LLC
Application Number:	US08/988,851
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Delivery;

US Patent 6,180,608: Claim Scope, Expiration, LHRH Formulation Coverage, and Patent Landscape

US Patent 6,180,608 protects a platform for forming solid ionic complexes between pharmaceutically active peptides and oppositely charged carrier macromolecules. The central limitation is a peptide content of 57% to 80% by weight. The patent reaches LHRH analogues, including leuprolide, cetrorelix, and specified LHRH antagonists, but only when formulated within the claimed ionic-complex architecture. The patent is no longer an enforceable U.S. exclusionary right because its ordinary 20-year patent term expired no later than 2018, subject to any recorded patent-term adjustment or extension. The claims remain relevant as prior art and as a technical map of the formulation concept, but they do not presently block generic or follow-on development.

What does US Patent 6,180,608 protect?

The patent claims a peptide-drug delivery platform based on electrostatic association between a charged peptide and an oppositely charged macromolecule.

The principal technical elements are:

Claim element	Scope
Active substance	Pharmaceutically active peptide, including LHRH analogues
Complex type	Solid ionic complex
Charge relationship	Cationic peptide with anionic carrier, or anionic peptide with cationic carrier
Peptide loading	57% to 80% by weight
Carrier class	Broadly, anionic or cationic macromolecules
Named carrier	Carboxymethylcellulose
Dosage forms	Lyophilized solid, liquid suspension, or semisolid dispersion
Delivery profile	Sustained delivery for at least one to four weeks
Administration	Parenteral, intramuscular, subcutaneous, intradermal, and oral routes
Therapeutic use	Hormone-dependent cancers, prostate cancer, benign prostatic hypertrophy, precocious puberty, endometriosis, uterine fibroids, IVF, and contraception

The broadest platform claims are claims 24 and 25. Claims 1 through 23 focus on packaged formulations, syringes, and treatment methods. Claims 26 through 50 narrow the platform by specifying charge, peptide length, carrier identity, dosage form, LHRH analogue, or therapeutic use.

How do the independent claims divide the patent scope?

Claims 1 and 3: packaged formulations and prefilled syringes

Claim 1 covers a packaged formulation containing:

1. A solid ionic complex;
2. An LHRH analogue;
3. A carrier macromolecule;
4. Peptide content of 57% to 80% by weight; and
5. Instructions for using the complex to treat an LHRH-responsive condition.

Claim 3 covers a syringe containing a liquid suspension of the solid ionic complex. This claim is directed to a product configuration rather than merely the composition.

A product would need to satisfy the peptide-loading range and the ionic-complex requirement. A formulation containing an LHRH analogue in a polymer depot without a solid ionic complex would not literally meet these claims.

Claims 5 through 23: treatment methods

Claim 5 covers administering the claimed complex to treat an LHRH-responsive condition. Claims 6 through 9 add sustained delivery for at least one, two, three, or four weeks.

Claims 10 through 16 narrow the active ingredient and carrier:

• LHRH antagonist;
• D-asparagine-containing antagonist;
• Anionic polymer;
• Anionic polyalcohol derivative;
• Anionic polysaccharide derivative;
• Carboxymethylcellulose; and
• Listed alternatives such as alginate, xanthan gum, carrageenan derivatives, polygalacturonic acid derivatives, and sodium starch glycolate.

Claims 17 through 19 address the route of administration. Claims 20 through 23 identify diseases and reproductive uses.

These claims are broad in therapeutic language but narrow in formulation structure. The method claims require administration of a formulation containing the specified ionic complex. Treatment with an LHRH analogue alone would not fall within the claim.

Claims 24 and 25: core composition claims

Claim 24 covers:

A pharmaceutical composition comprising a solid ionic complex of a pharmaceutically active peptide and a carrier macromolecule, with peptide content of 57% to 80% by weight.

Claim 25 uses “consisting essentially of,” which ordinarily narrows the composition to the stated ionic complex and components that do not materially affect the claimed characteristics.

These are the most commercially important claims because they are not limited to LHRH analogues. They potentially reach other charged therapeutic peptides, subject to the solid-complex and loading limitations.

What technical limitations control infringement?

Solid ionic complex

The term “solid ionic complex” is the principal structural limitation. A simple solution, oil suspension, covalent conjugate, microsphere, biodegradable polymer matrix, or nonionic adsorption system would not necessarily qualify.

The complex must be formed through ionic association between charged species. For a cationic peptide, the preferred carrier is anionic. For an anionic peptide, the preferred carrier is cationic.

57% to 80% peptide content

The peptide-loading limitation is unusually important. A formulation below 57% or above 80% peptide by weight would fall outside the literal scope of the claims, assuming the stated range is measured on the same compositional basis used in the patent.

This limitation narrows the platform materially. Many controlled-release peptide systems rely on a high polymer fraction, encapsulation matrix, microsphere, or in situ gel. Those systems may not reach 57% peptide content and may not form an ionic complex.

Carrier macromolecule

Carboxymethylcellulose is the most specifically identified carrier. The claims also cover wider categories of anionic polymers and polysaccharide derivatives.

The listed carrier terminology includes apparent typographical errors, including “align” for algin, “xantham” for xanthan, “carageenan” for carrageenan, and “anonic” for anionic. Claim interpretation would ordinarily rely on the intrinsic patent record, specification, prosecution history, and technical meaning rather than the typographical error alone.

Sustained delivery

Claims 6 through 9 and 28 through 31 require sustained delivery for specified periods. The one-week limitation is the lowest threshold. The four-week limitation is narrower and requires evidence that the administered formulation provides delivery for at least four weeks.

A formulation that releases peptide slowly in vitro but does not provide the claimed in vivo delivery profile may face a factual dispute over this limitation. Release testing, pharmacokinetic data, dose interval, and claim-construction history would be material.

Which LHRH analogues are expressly covered?

The patent expressly identifies several LHRH analogues.

Peptide	Relevant claim	Claim significance
Specified D-Asn-containing LHRH antagonist	2, 4, 11, 46	Species-level coverage when combined with the claimed complex
General D-Asn-containing antagonist genus	44, 45	Genus and Markush-style coverage
Leuprolide	48	Expressly included LHRH agonist
Cetrorelix	49	Expressly included LHRH antagonist
Other LHRH analogues	1, 5, 43, 47	Covered if the ionic-complex and loading limitations are met

The sequence in claim 48 is leuprolide, an LHRH agonist. Claim 49 identifies cetrorelix, an LHRH antagonist. The presence of these names does not mean that every formulation of leuprolide or cetrorelix is covered. The formulation must also satisfy the solid ionic-complex and 57% to 80% peptide-content limitations.

How broad are claims 24 through 50?

Claims 24 through 50 create a layered platform:

1. Claims 24 and 25 establish the composition category.
2. Claims 26 and 27 define charge polarity.
3. Claims 28 through 31 define sustained delivery.
4. Claims 32 through 35 define peptide charge, valence, and length.
5. Claims 36 through 40 define carrier classes.
6. Claims 41 and 42 define solid, liquid-suspension, and semisolid forms.
7. Claims 43 through 50 identify LHRH analogues and other therapeutic peptides.

The composition claims are broader than the LHRH claims because they cover other peptide classes, including:

• Bradykinin analogues;
• Parathyroid hormone;
• Adrenocorticotrophic hormone;
• Calcitonin; and
• Vasopressin analogues.

The claim set therefore has two commercial layers. The first is a general peptide-complex platform. The second is an LHRH depot application.

What formulations are protected by US 6,180,608?

The patent potentially covers the following formulation types when the claimed loading and ionic-complex requirements are met:

Lyophilized solid complexes

Claim 41 covers a lyophilized solid. A development program could fall within this claim if the lyophilized product remains or contains the claimed solid ionic complex rather than merely being a dried mixture.

Liquid suspensions

Claims 3, 42, and related dependent claims reach liquid suspensions of the solid complex. This is significant for prefilled syringes and reconstituted injectable products.

Semisolid dispersions

Claim 42 covers dispersion of the solid ionic complex in a semisolid vehicle. The claim does not require a particular polymer depot mechanism beyond the claimed complex.

Oral formulations

Claim 18 recites oral administration. The broad platform claims do not depend exclusively on injection, although the LHRH analogues identified in the patent are more naturally associated with parenteral delivery.

Injectable formulations

Claims 17 and 19 expressly cover parenteral, intramuscular, subcutaneous, and intradermal delivery. A four-week injectable product would be the most commercially relevant implementation of this claim group.

When did US Patent 6,180,608 lose exclusivity?

US Patent 6,180,608 issued on January 30, 2001. U.S. utility patents filed after June 8, 1995 generally expire 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and statutory extensions under 35 U.S.C. §§ 154 and 156.

The patent’s enforceable term therefore ended no later than the late 2010s, with the ordinary term understood to have expired in approximately 2017-2018 based on its underlying filing chronology. The patent is not a current blocking patent for U.S. commercialization. The USPTO Patent Center record is the controlling source for any patent-term adjustment or terminal-disclaimer calculation.[1]

Event	Date or period
U.S. patent application and priority chain	1990s
Patent issued	January 30, 2001
Ordinary 20-year term	Approximately 2017-2018
Current enforceability	Expired by ordinary term
Current relevance	Prior art, formulation history, and freedom-to-operate background

Patent expiration does not eliminate the possibility of separate, later-expiring patents covering a particular LHRH active ingredient, dosage form, device, manufacturing process, polymorph, excipient combination, or clinical use.

What is the Orange Book status of US 6,180,608?

US 6,180,608 is not itself a reliable indicator of the Orange Book status of a marketed LHRH drug. The FDA Orange Book lists patents submitted by new drug application holders for approved products. A platform patent may be absent, expired, delisted, or listed against only one product depending on the NDA holder’s submission and the FDA’s administrative treatment.[2]

The principal marketed LHRH products have distinct regulatory and patent profiles:

Product	Active ingredient	Sponsor or major developer	Regulatory category
Lupron Depot	Leuprolide acetate	AbbVie and predecessors	NDA, injectable depot
Firmagon	Degarelix	Ferring	NDA, injectable antagonist
Orgovyx	Relugolix	Sumitomo Pharma and partners	NDA, oral antagonist
Cetrotide	Cetrorelix acetate	Merck Serono and predecessors	NDA, injectable antagonist
Ganirelix products	Ganirelix acetate	Multiple sponsors	NDA and generic-related pathways depending on product

The expiration of US 6,180,608 does not determine the loss of exclusivity for these products. Product-specific patents, regulatory exclusivity, pediatric extensions, and later formulation patents must be assessed separately.

How does the patent compare with competing LHRH formulation estates?

US 6,180,608 is a broad platform patent. It is different from patents directed to:

• Biodegradable microspheres;
• In situ forming gels;
• Polymeric implants;
• Osmotic delivery systems;
• Oral small-molecule GnRH antagonists;
• Specific salts or crystalline forms;
• Device configurations; and
• Manufacturing methods.

For leuprolide, commercial patent risk historically centered on depot formulations and delivery technologies rather than only on the active peptide. For degarelix, the relevant estate includes active-substance, formulation, manufacturing, and product-specific patents. For relugolix, the principal distinction is that it is an orally active small-molecule GnRH antagonist rather than a peptide, so the ionic-complex claims of US 6,180,608 do not directly map onto its active ingredient.

Patent characteristic	US 6,180,608	Typical product-specific LHRH patent
Claim focus	Peptide-carrier ionic complex	Active ingredient, formulation, device, or use
Active ingredient limitation	Broad, with LHRH species	Usually narrow
Peptide loading	57%-80%	Product-specific
Delivery duration	One to four weeks in dependent claims	Defined release profile or dosing interval
Patent term today	Expired	May remain in force depending on filing date
Litigation relevance	Historical and prior-art relevance	Direct freedom-to-operate relevance

Which companies could challenge related LHRH patents?

A generic or follow-on sponsor seeking approval for an LHRH product could use several pathways:

• An abbreviated new drug application under section 505(j);
• A section 505(b)(2) application for a modified formulation, route, or delivery system;
• A new drug application for a differentiated depot product; or
• A device or combination-product pathway where the delivery system is independently regulated.

For small-molecule or peptide products, “biosimilar” is generally not the principal U.S. pathway. Biosimilar applications under section 351(k) are designed for biological products. Many synthetic peptides and peptide drugs are handled through the 505(j) or 505(b)(2) framework, depending on FDA classification and product differences.[3]

Potential challengers would examine:

1. Whether any listed patent remains unexpired;
2. Whether the listed claims cover the approved dosage form;
3. Whether the proposed product uses an ionic complex;
4. Whether peptide content falls within 57% to 80%;
5. Whether the product uses the claimed carrier;
6. Whether the product provides the claimed release period;
7. Whether a design-around avoids the solid-complex limitation; and
8. Whether a Paragraph IV certification is required.

What Paragraph IV risks arise from this patent?

US 6,180,608 no longer presents a live Paragraph IV barrier because an expired patent cannot support a current Hatch-Waxman infringement stay. Paragraph IV risk may still arise from later-expiring patents covering a marketed LHRH product.

For a generic leuprolide or cetrorelix product, the relevant analysis would separate:

• Expired platform patents;
• Unexpired formulation patents;
• Unexpired device patents;
• Method-of-use patents;
• Manufacturing patents;
• Patent-term extensions; and
• Regulatory exclusivity.

A generic applicant may also avoid infringement through a non-infringing formulation that does not contain a solid ionic complex or that falls outside the 57% to 80% peptide-content range.

What manufacturing and IP barriers remain?

The patent’s expiration removes the principal legal barrier created by its claims, but technical barriers remain. A commercial product must still address:

• Reproducible ionic-complex formation;
• Control of peptide loading;
• Particle-size distribution;
• Suspension stability;
• Syringeability and needle compatibility;
• Sterility and endotoxin control;
• Peptide aggregation and degradation;
• In vivo release kinetics;
• Dose uniformity;
• Storage stability; and
• Scale-up of the drying or complexation process.

Manufacturing know-how may retain commercial value even after patent expiration. Trade secrets, validated process parameters, supplier controls, and analytical methods can limit practical competition without creating patent exclusivity.

Is there evidence of a license or settlement tied to US 6,180,608?

The supplied claim set does not establish a license, settlement, assignment history, or litigation outcome. A patent assignment is not equivalent to a commercial license, and a product’s use of a similar formulation does not establish that it practiced the claims.

The relevant public records for ownership, assignments, and litigation are the USPTO assignment database, PACER, and district-court docket records. No current enforceable restriction should be inferred solely from the patent’s historical association with an LHRH formulation platform.

How strong is the patent estate today?

The patent estate is legally weak as a current exclusionary position because US 6,180,608 has expired. Its historical claim breadth was moderate to strong at the platform level but constrained by three elements:

1. The requirement for a solid ionic complex;
2. The 57% to 80% peptide-content range; and
3. The need to establish the claimed formulation or delivery characteristics.

Its strongest historical coverage was likely directed to high-loading injectable peptide complexes using carboxymethylcellulose or related anionic polymers. Its weakest area was any product using a different delivery mechanism, a nonionic carrier, a substantially different peptide loading, or a polymer matrix without the claimed ionic complex.

Key Takeaways

• US 6,180,608 is a platform patent for solid ionic complexes of charged peptides and carrier macromolecules.
• The central numerical limitation is 57% to 80% peptide content by weight.
• The patent expressly reaches LHRH analogues, including leuprolide, cetrorelix, and D-Asn-containing LHRH antagonists.
• Carboxymethylcellulose is the principal specifically named carrier.
• Claims cover packaged products, syringes, pharmaceutical compositions, sustained delivery, and treatment methods.
• The patent’s ordinary U.S. term expired approximately in 2017-2018.
• It is not a current blocking patent for U.S. LHRH product development.
• Later product, formulation, device, manufacturing, and method-of-use patents must be analyzed separately.
• Synthetic LHRH peptides generally raise 505(j) or 505(b)(2) issues rather than conventional biosimilar issues.
• The most credible design-arounds avoid the claimed solid ionic complex, the 57% to 80% loading range, or the specified carrier architecture.

FAQs

Does US 6,180,608 cover all leuprolide depot injections?

No. It covers only leuprolide formulations that satisfy the claimed solid ionic-complex and peptide-loading limitations. A leuprolide microsphere, in situ gel, implant, or other depot system may use a different architecture.

Can a company launch a product using carboxymethylcellulose now?

Potentially, yes, because the patent has expired. The product still requires evaluation against later-expiring patents, FDA requirements, formulation performance standards, and any applicable product-specific exclusivity.

Is cetrorelix covered by the patent?

Claim 49 expressly identifies cetrorelix, but only as a dependent composition claim requiring the claimed ionic complex, carrier, and peptide-content limitations inherited from the parent claims.

Does the patent cover oral GnRH antagonists such as relugolix?

Not directly based on the claimed subject matter. Relugolix is a small molecule, while the patent claims pharmaceutically active peptides and LHRH analogues formulated as ionic complexes.

Does expiration of US 6,180,608 eliminate all patent risk for LHRH depots?

No. It eliminates the risk created by this patent, but not by later patents covering specific active ingredients, release systems, devices, manufacturing processes, salts, formulations, or approved methods of use.

References

1. United States Patent and Trademark Office. (2001). U.S. Patent No. 6,180,608: Pharmaceutical compositions comprising ionic complexes of active peptides and carrier macromolecules. U.S. Department of Commerce.

2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

3. U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application process and biosimilar biological product development. Center for Drug Evaluation and Research.

Drugs Protected by US Patent 6,180,608

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 6,180,608

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	010351
Austria	378059
Austria	383165
Austria	516812
Australia	5699198