United States Patent 6,440,392: Calcitonin Nasal Formulation Claims, Patent Scope and Generic-Entry Landscape

U.S. Patent No. 6,440,392 protects a narrow calcitonin nasal formulation centered on citric acid at 10 to approximately 50 mM. The broadest independent composition claim requires four elements: calcitonin or an acid-addition salt, citric acid or a citrate salt, the specified concentration range, and a form suitable for nasal administration. The patent also claims nasal sprays, saline carriers, low viscosity, salmon calcitonin, defined dose ranges, acidic pH, near-isotonic osmotic pressure, surfactant and preservative combinations, administration methods, stability enhancement, and improved nasal bioavailability.

The patent’s practical value was concentrated in the pre-generic period for salmon-calcitonin nasal products, particularly Miacalcin nasal spray. The patent term has ended, eliminating ordinary U.S. patent exclusivity under the patent. Its historical importance remains relevant because the claim structure illustrates how formulation patents can protect a marketed product without claiming the active ingredient itself.

What does U.S. Patent 6,440,392 cover?

The patent covers liquid nasal compositions in which citric acid or a citrate salt is used with calcitonin at a concentration from 10 to approximately 50 mM.

Claim 1 is the central composition claim:

Required limitation	Claim 1 requirement
Active ingredient	Calcitonin or an acid-addition salt
Stabilizing or formulation agent	Citric acid and/or a salt thereof
Citric acid concentration	10 to about 50 mM
Dosage form	Suitable for nasal administration

The claim does not require salmon calcitonin, a nasal spray device, a specific pH, a preservative, a surfactant, saline, or a particular calcitonin dose. Those limitations appear in dependent claims or separate claims.

The patent therefore has a layered claim structure:

A broad composition claim based on calcitonin plus citric acid or citrate.
Dependent composition claims narrowing the carrier, dosage form, viscosity, species of calcitonin, concentration, pH, osmotic pressure, surfactant, and preservative.
Two specific formulation claims.
A nasal-administration method claim.
Stability and bioavailability method claims.

How broad is claim 1 of Patent 6,440,392?

Claim 1 is materially broader than the detailed formulation claims. A product may infringe claim 1 without having the precise commercial formulation recited in claims 18 or 19.

A composition would potentially fall within claim 1 if it contains:

Salmon, human, porcine, eel, or another form of calcitonin;
Citric acid or a citrate salt at 10 to about 50 mM;
A liquid formulation;
A presentation suitable for nasal administration.

The claim does not expressly require:

A saline carrier;
A spray pump;
A particular preservative;
Polysorbate or another surfactant;
A pH between 3 and 5;
A specific osmotic pressure;
A defined calcitonin potency;
A particular container or device.

The principal scope issue is whether the formulation is “in a form suitable for nasal administration.” That language is functional and may cover more than a marketed spray. A liquid nasal drop, atomized formulation, or other nasal delivery presentation could potentially satisfy the limitation if the product is suitable for administration through the nose.

The claim is narrower than a claim to calcitonin nasal delivery generally. It requires the citric acid or citrate concentration. A formulation using another stabilizer, buffer, or absorption enhancer without citric acid would not satisfy the literal composition requirement of claim 1.

What do claims 2 through 17 add?

Claims 2 through 17 create narrower fall-back positions.

Claim	Additional limitation	Commercial significance
2	Pharmaceutically acceptable aqueous liquid nasal carrier	Captures conventional aqueous nasal formulations
3	Aqueous saline carrier	Narrows the carrier to saline
4	Nasal spray	Targets the principal commercial dosage form
5	Viscosity below 0.98 cP	Narrows the spray formulation by flow properties
6	Salmon, human, porcine, or 1,7-Asu-eel calcitonin	Defines species or analog scope
7	Salmon calcitonin	Aligns with Miacalcin-type products
8	100 to 8,000 MRC units/mL	Broad potency range
9	500 to 4,000 MRC units/mL	Intermediate potency range
10	500 to 3,000 MRC units/mL	Narrower potency range
11	1,000 to 2,500 MRC units/mL	Commercially focused potency range
12	pH 3 to 5	Acidic formulation
13	pH 3.5 to 3.9	Narrow acidic range
14	pH about 3.7	Specific target pH
15	Osmotic pressure 250 to 350 mOsm/L	Near-isotonic formulation
16	At least 0.1% polyoxyethylene(20) sorbitan monooleate	Surfactant limitation, commonly associated with polysorbate 80
17	Listed preservatives	Preservative-specific narrowing

Because the claims depend from claim 1, each dependent claim incorporates the citric-acid concentration requirement. A product with a pH of 3.7 but no citric acid in the claimed concentration range would not meet claim 14 as written.

What formulations are specifically protected by claims 18 and 19?

Claims 18 and 19 recite highly specific formulations:

Component	Claim 18	Claim 19
Salmon calcitonin	About 2,200 MRC units	About 2,200 MRC units
Citric acid	About 10 mM	About 20 mM
Phenylethyl alcohol	About 0.2%	About 0.2%
Benzyl alcohol	About 0.5%	About 0.5%
Polyoxyethylene(20) sorbitan monooleate	About 0.1%	About 0.1%

These claims are narrower than claim 1 because they require a defined combination of active ingredient, acid concentration, preservatives, and surfactant.

Their infringement value depends on how “about” is construed. Courts generally interpret “about” in view of the specification, technical context, prosecution history, and the precision ordinarily used in the relevant pharmaceutical field. A formulation with materially different preservative or surfactant concentrations could argue that it falls outside the literal scope, although the doctrine of equivalents could have been relevant while the patent was enforceable.

Claims 18 and 19 are useful as product-specific claims but less useful against a deliberate design-around that changes one or more excipients. Claim 1, by contrast, may capture a wider range of products so long as the citric acid concentration remains within the claimed range.

What do claims 20 through 23 protect?

Nasal administration method

Claim 20 covers administering a claim 1 composition through the nasal route to a subject requiring calcitonin treatment. Claim 21 narrows the administered amount to approximately 200 to 600 MRC units.

These claims are method-of-treatment claims. They do not cover every calcitonin nasal treatment. The administered composition must still satisfy claim 1, including the citric acid or citrate concentration.

Stability method

Claim 22 covers improving the stability of a liquid calcitonin pharmaceutical composition by adding citric acid or a citrate salt at 10 to approximately 50 mM.

This claim is broader in operational form than the composition claims because it is directed to a method of improving stability. It still requires a liquid calcitonin composition and the specified citric-acid concentration. Potential enforcement issues would include whether the accused formulation actually demonstrates the claimed stability improvement and whether the added acid is within the claimed concentration range.

Bioavailability and plasma concentration method

Claim 23 covers improving calcitonin bioavailability or plasma concentration after nasal administration by adding citric acid or a citrate salt at 10 to approximately 50 mM before administration.

This claim targets the functional effect attributed to the citric acid. Proof would likely require formulation analysis and pharmacokinetic or bioavailability evidence. A formulation could present greater enforcement complexity than a composition claim because the claim includes an outcome-oriented limitation.

What is the likely claim construction of “citric acid and/or salt thereof”?

The phrase covers citric acid, citrate salts, or combinations of the two. Depending on the specification and prosecution history, the relevant concentration may be assessed as a molar concentration of the citrate system rather than solely as undissociated citric acid.

Potentially relevant materials include:

Citric acid;
Sodium citrate;
Potassium citrate;
Other pharmaceutically acceptable citrate salts;
Mixtures of citric acid and citrate.

A formulation buffered with phosphate, acetate, lactate, or another acid system would generally fall outside the literal citric-acid limitation unless it also contains citric acid or citrate within the claimed concentration.

The phrase “10 to about 50 mM” creates a concentration boundary. The lower endpoint is 10 mM. The upper endpoint is qualified by “about,” which can introduce a limited tolerance depending on the technical evidence and patent specification.

When did Patent 6,440,392 lose exclusivity?

U.S. Patent 6,440,392 is an expired patent. Its enforceable term ended before the present date, subject to any patent-term-adjustment or terminal-disclaimer details recorded in the official patent file.

The patent issued on August 27, 2002. The relevant patent family priority and filing history place the ordinary 20-year patent term in the late 2010s. Public patent databases and FDA product-patent records associate the patent with the historical exclusivity period for calcitonin nasal formulations marketed in the United States.[1][2]

Event	Date or period
U.S. patent application	Late 1990s
U.S. Patent No. 6,440,392 issued	August 27, 2002
Patent term	Approximately 20 years from the applicable nonprovisional filing date, subject to adjustments
Practical U.S. patent expiry	Late 2010s
Current status	Expired; no current ordinary patent exclusion

The patent cannot now support a new U.S. infringement action for conduct occurring after expiration. Historical infringement disputes, damages periods, prosecution history, and claim-construction issues remain relevant for diligence involving legacy products or litigation records.

What was the Orange Book status of Patent 6,440,392?

The patent was associated with calcitonin nasal spray product protection in the FDA’s Orange Book framework. The relevant branded product was Miacalcin nasal spray, a salmon calcitonin product historically marketed by Novartis.[3][4]

Orange Book listing does not itself establish that every claim of a listed patent is valid or infringed. It identifies patents submitted by the NDA holder as required by the Hatch-Waxman framework. A listed formulation patent can generate a Paragraph IV certification if a generic applicant asserts that the patent is invalid, unenforceable, or not infringed.

Because Patent 6,440,392 has expired, it no longer creates a current Orange Book block to approval or launch. Any historical listing should be distinguished from current regulatory exclusivity.

Were there Paragraph IV challenges to the patent?

A Paragraph IV certification would have been the relevant Hatch-Waxman mechanism for a generic applicant seeking approval before expiration while challenging the listed patent. The standard certification asserts that the patent is invalid, unenforceable, or will not be infringed by the proposed product.[5]

The existence of an Orange Book listing does not, by itself, establish that a Paragraph IV lawsuit was filed. Public records concerning calcitonin nasal products include broader product and regulatory disputes, but a complete statement of specific Paragraph IV litigation against Patent 6,440,392 requires matching the patent number to FDA listing records, ANDA filings, district-court complaints, and docket outcomes.

No current Paragraph IV barrier remains because the patent term has ended.

Which products and companies were exposed to the patent?

The principal historical commercial exposure was the salmon-calcitonin nasal spray market.

Entity or product	Relevance
Novartis	Historical marketer of Miacalcin and associated NDA rights
Miacalcin nasal spray	Commercial product most closely aligned with the claimed salmon-calcitonin nasal formulation
Generic ANDA applicants	Potentially exposed if their products used citric acid or citrate within the claimed concentration
Other calcitonin manufacturers	Could avoid the composition claims through non-citrate formulations, nonnasal dosage forms, or different concentration ranges

The patent did not claim the calcitonin molecule itself. It therefore did not block:

Injectable calcitonin formulations;
Oral products;
Buccal or pulmonary formulations;
Nasal calcitonin formulations lacking the claimed citric-acid concentration;
Formulations using different buffering or stabilizing systems, subject to other patent rights.

How strong was the patent estate?

The estate was moderately strong against close copies of the commercial formulation but weaker against deliberate formulation redesign.

Strengths

Claim 1 captured a broad citric-acid concentration range.
The claims covered both compositions and methods.
Dependent claims tracked commercially relevant attributes, including salmon calcitonin, nasal spray, pH, viscosity, potency, preservatives, and surfactant.
Claims 18 and 19 targeted recognizable formulation combinations.
Citric acid was positioned as both a stability component and a bioavailability-related component.

Weaknesses

The active ingredient, calcitonin, was not monopolized.
The patent did not cover nasal calcitonin formulations lacking citric acid or citrate.
A competitor could potentially alter buffer chemistry, excipients, pH, concentration, or delivery format.
Functional claims 22 and 23 could require technical proof of stability or pharmacokinetic improvement.
Narrow claims 18 and 19 were vulnerable to changes in one required excipient or concentration.
The patent is now expired.

The strongest historical enforcement position likely involved a product substantially matching the claimed citric-acid, salmon-calcitonin, preservative, and surfactant profile. The weakest position involved a non-citrate formulation or an alternative delivery system.

What design-around strategies were available?

Potential design-around pathways included:

Replacing citric acid or citrate with another buffer or stabilizer.
Using citrate below 10 mM or materially above approximately 50 mM, subject to claim construction and other patent rights.
Changing the nasal formulation to a nonliquid dosage form.
Using a different active peptide or calcitonin analog.
Altering the surfactant or preservatives to avoid claims 16 through 19.
Changing the formulation pH or viscosity to avoid narrower dependent claims.
Using a nonnasal route.
Developing an injectable calcitonin product.

These routes would not necessarily avoid every claim in the patent family or every patent covering calcitonin delivery. They address the specific limitations recited in the supplied claims.

How does Patent 6,440,392 compare with broader calcitonin patent protection?

Patent 6,440,392 is a formulation and use patent, not a basic compound patent.

Patent category	Typical subject matter	Relationship to 6,440,392
Compound patent	Calcitonin molecule or analog	Not the focus of this patent
Sequence patent	Peptide sequence or variant	Not the focus of this patent
Formulation patent	Excipients, pH, stability, viscosity	Core subject of 6,440,392
Device patent	Nasal pump, actuator, container	Not recited in the supplied claims
Method-of-use patent	Disease treatment or dosing regimen	Claims 20 and 21 provide limited treatment-method coverage
Manufacturing patent	Peptide synthesis, purification, filling	Not recited in the supplied claims

The patent’s value depended on the interaction between formulation design and regulatory product matching. It did not independently prevent all generic calcitonin competition.

What is the current generic-entry risk?

Current U.S. generic-entry risk from this patent is unrestricted because the patent has expired. A generic or follow-on product does not need to design around Patent 6,440,392 as a live exclusion right.

Commercial barriers may still arise from:

FDA approval requirements for calcitonin nasal spray;
Reference-product availability;
Bioequivalence or comparative clinical requirements;
Device performance and dose-delivery testing;
Product discontinuation or limited market demand;
Other unexpired patents not covered by the supplied claims;
Regulatory exclusivity or labeling constraints unrelated to this patent.

The patent remains relevant to historical freedom-to-operate analysis, legacy litigation, patent-family mapping, and assessment of why the branded product used its particular excipient system.

What is the geographic coverage?

U.S. Patent 6,440,392 provides rights only in the United States. Corresponding international or foreign family members would require separate analysis by jurisdiction.

The claim concepts could have been pursued in Europe, Canada, Japan, and other markets through national or regional filings. Expiration dates, claim scope, opposition history, supplementary protection certificates, and maintenance status would differ by country. A U.S. expiration does not establish that every foreign counterpart has expired on the same date.

Key Takeaways

Patent 6,440,392 is directed to liquid nasal calcitonin compositions containing 10 to approximately 50 mM citric acid or citrate.
Claim 1 is the principal broad composition claim.
Claims 2 through 17 narrow the invention by carrier, spray format, viscosity, calcitonin species, potency, pH, osmotic pressure, surfactant, and preservatives.
Claims 18 and 19 cover specific salmon-calcitonin formulations with citric acid, benzyl alcohol, phenylethyl alcohol, and polyoxyethylene(20) sorbitan monooleate.
Claims 20 through 23 cover nasal administration, dosing, stability improvement, and bioavailability or plasma-concentration improvement.
The patent was historically relevant to Miacalcin nasal spray and the salmon-calcitonin nasal market.
The patent is expired and does not create a current U.S. patent barrier to generic entry.
The historical estate was strongest against close copies using the claimed citrate concentration and commercial excipient combination.
The patent did not cover calcitonin as a molecule, all nasal calcitonin products, or non-citrate formulations.

FAQs About U.S. Patent 6,440,392

Does Patent 6,440,392 cover all salmon calcitonin nasal sprays?

No. It covers salmon calcitonin nasal formulations that also satisfy the citric-acid or citrate concentration and other claim limitations. A nasal spray using a different buffer may fall outside claim 1.

Does the patent cover injectable calcitonin?

No. The supplied claims require a form suitable for nasal administration or a nasal administration method. Injectable calcitonin is outside those limitations.

Is citric acid required at exactly 10 mM?

No. The claim covers a range from 10 to about 50 mM. Claims 18 and 19 separately identify approximately 10 mM and 20 mM formulations.

Can a generic company launch a product using the claimed formulation today?

The patent is expired, so it does not independently prevent launch. The product must still satisfy FDA requirements and avoid any other unexpired patent rights.

Does an Orange Book listing prove that the patent was valid?

No. An Orange Book listing identifies a patent submitted for an approved drug product. Validity, enforceability, infringement, and claim scope are separate legal questions.

References

United States Patent and Trademark Office. (2002). U.S. Patent No. 6,440,392, pharmaceutical compositions containing calcitonin.
United States Patent and Trademark Office. (n.d.). Patent Center: U.S. Patent No. 6,440,392.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. Orange Book.
Novartis Pharmaceuticals Corporation. (n.d.). Miacalcin (calcitonin salmon) nasal spray prescribing information.
U.S. Food and Drug Administration. (2019). Approved drug products with therapeutic equivalence evaluations: Book 2, 39th edition. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	3660401	⤷ Start Trial
Australia	783952	⤷ Start Trial
Canada	2399505	⤷ Start Trial
China	1183965	⤷ Start Trial
China	1422160	⤷ Start Trial
European Patent Office	1251867	⤷ Start Trial
World Intellectual Property Organization (WIPO)	0156594	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,440,392

Summary for Patent: 6,440,392