US Patent 7,229,636: Scope, Claims, Expiration, and Patent Landscape for Intranasal Cyanocobalamin

US Patent 7,229,636 protects specific intranasal cyanocobalamin solutions and methods that achieve at least approximately 7% bioavailability relative to intramuscular cyanocobalamin. The broadest independent claims require a particular combination of cyanocobalamin, water, preservative, buffer, humectant, low viscosity, intranasal suitability, and a mercury-free formulation. The patent also claims a narrower commercial formulation containing 0.5% cyanocobalamin, citrate buffer, glycerin, and benzalkonium chloride.

The patent is associated with intranasal vitamin B12 products such as Nascobal. Its commercial importance was concentrated in the United States because the claims targeted the formulation and administration route used for prescription cyanocobalamin nasal products. Based on the patent’s priority and filing history, the patent’s ordinary statutory term has ended. Any current infringement analysis must therefore focus on related patents, regulatory exclusivity, later improvements, and unexpired family members rather than on US 7,229,636 itself.

What does US Patent 7,229,636 cover?

The patent covers four principal categories:

Stable aqueous cyanocobalamin compositions for intranasal administration.
Formulations using defined preservatives, buffers, and humectants.
A specific commercial formulation containing benzalkonium chloride and glycerin.
Methods of administering cyanocobalamin intranasally, including a method directed to increasing cerebrospinal-fluid vitamin B12 levels.

The patent does not claim every cyanocobalamin nasal formulation. The asserted product must satisfy the required formulation elements and the specified performance limitations.

Patent identification

Item	Description
Patent	US 7,229,636 B2
Subject matter	Intranasal delivery of vitamin B12
Active ingredient	Cyanocobalamin
Dosage form	Stable aqueous intranasal solution
Key route	Intranasal administration
Core performance limitation	At least about 7% bioavailability versus intramuscular administration
Key commercial formulation	0.5% cyanocobalamin, citrate buffer, 2.23% glycerin, 0.02% benzalkonium chloride
Key therapeutic method	Elevation of vitamin B12 levels in cerebrospinal fluid
Patent status	Ordinary US patent term has expired

How broad is independent claim 1?

Claim 1 is a composition claim with multiple mandatory limitations. A potentially covered formulation must contain:

Cyanocobalamin.
Water.
At least one listed preservative.
At least one listed buffer.
At least one listed humectant.
Viscosity below approximately 1,000 cPs.
Suitability for intranasal administration.
At least approximately 7% cyanocobalamin bioavailability relative to intramuscular injection.
No mercury or mercury-containing compound.

The preservative, buffer, and humectant limitations are written as Markush groups. The listed ingredients include the following:

Component	Claimed alternatives
Preservative	Benzyl alcohol, parabens, thimerosal, chlorobutanol, benzethonium chloride, benzalkonium chloride
Buffer	Citric acid, sodium citrate, monopotassium phosphate, disodium phosphate, potassium biphthalate, sodium hydroxide, sodium acetate, acetic acid
Humectant	Sorbitol, propylene glycol, glycerin

The claim is broad in ingredient selection but narrow in combination. A formulation containing cyanocobalamin and benzalkonium chloride alone would not necessarily infringe claim 1 because it would also need a qualifying buffer, humectant, viscosity, intranasal suitability, bioavailability, and mercury-free status.

The bioavailability limitation is commercially important

The requirement for at least about 7% bioavailability is a functional limitation. It narrows the claim beyond composition alone. A formulation that includes the listed ingredients but delivers less than the claimed relative bioavailability may fall outside the literal scope of claim 1.

The limitation also creates an evidentiary issue. In a patent dispute, the patentee would likely need pharmacokinetic evidence comparing intranasal delivery with intramuscular cyanocobalamin. The relevant testing could involve serum concentration, area under the curve, dose normalization, and study design. The patent language does not establish a universal test protocol in the claims supplied.

The 7% threshold is lower than the 12% threshold in claim 22. Claim 22 therefore has a narrower performance requirement but does not add a new ingredient limitation.

Which dependent claims protect the commercial formulation?

Claims 2 through 21 progressively narrow the formulation. They focus on a citrate buffer, pH around 5, particular humectants, and preservatives.

The most commercially relevant limitations are:

Claim	Key limitation
2	Citric acid and sodium citrate; pH about 4 to 6
3	pH about 5
4	Propylene glycol
5	Sorbitol
6	Glycerin
7	Glycerin at approximately 2.23%
8	Benzyl alcohol, chlorobutanol, or benzalkonium chloride
9	Chlorobutanol
10	Benzalkonium chloride
11	Benzalkonium chloride at approximately 0.02%
12	0.5% cyanocobalamin, 0.12% citric acid, 0.32% sodium citrate
13	pH about 5
14-17	Sorbitol, propylene glycol, and glycerin combinations
18-21	Preservative limitations, including 0.02% benzalkonium chloride
22	At least approximately 12% bioavailability

Claims 12 through 21 describe a highly specific formulation family. Claim 23 then restates the principal commercial formulation as an independent composition claim:

0.5% cyanocobalamin.
0.12% citric acid.
0.32% sodium citrate.
2.23% glycerin.
0.02% benzalkonium chloride.
Water.
Viscosity below approximately 1,000 cPs.
Intranasal suitability.
At least approximately 7% relative bioavailability.
No mercury compounds.

This claim is narrower than claim 1 in ingredient concentrations but potentially easier to analyze against a marketed product because the formulation target is clearly defined.

What methods are protected by claims 24 through 31?

Claims 24 through 30 cover methods of administering cyanocobalamin by infusing the nose with the claimed aqueous solution. These claims are method-of-use claims rather than composition claims.

Claim 24 broadly tracks claim 1 but changes the claim category to administration. Claims 25 through 29 narrow the method by adding:

Citric acid and sodium citrate.
pH between approximately 4 and 6.
pH around 5.
Cyanocobalamin concentration between 0.5% and 1%.
Approximately 0.5% cyanocobalamin.
Approximately 0.12% citric acid.
Approximately 0.32% sodium citrate.

Claim 30 recites the specific glycerin and benzalkonium chloride formulation.

Claim 31 is the most technically distinctive method claim. It covers intranasal administration sufficient to increase the average ratio of vitamin B12 in cerebrospinal fluid to blood serum to at least approximately 1.1, expressed as:

[ \frac{\text{B12 in CSF}}{\text{B12 in serum}} \times 100 \geq 1.1 ]

The method also incorporates the detailed formulation limitations from claim 30. This creates a cumulative requirement: a potentially infringing product must use the specified formulation and achieve the CSF-to-serum result.

Why claim 31 is difficult to assert

Claim 31 is narrower than the composition claims and requires evidence involving cerebrospinal fluid. That can create practical obstacles:

CSF sampling is invasive.
The claim uses an average ratio, requiring a defined patient population or study design.
The ratio may depend on timing after administration.
The claim does not appear to cover every therapeutic use of intranasal cyanocobalamin.
A product may satisfy the formulation limitations without being used in a manner that meets the CSF limitation.

The claim may have been valuable during development because it supported central nervous system delivery. It is less likely to be the primary claim used against an ordinary intranasal vitamin B12 product unless clinical evidence directly addresses the claimed ratio.

What are the main claim-construction issues?

“About” concentration ranges

The claims use “about” for concentrations, pH, viscosity, bioavailability, and CSF ratios. Courts generally interpret “about” in view of the specification, technical meaning, precision of the measurement method, and prosecution history. The scope is not automatically unlimited.

A formulation containing 0.48% cyanocobalamin may present a different infringement question from one containing 0.20% or 1.0%. The analysis would depend on the patent specification, analytical tolerances, prosecution amendments, and equivalents doctrine.

Functional language

The terms “stable,” “suitable for intranasal administration,” and “bioavailability of at least about 7%” are potentially limiting. Stability may require support from storage data, degradation thresholds, or the specification’s definition. Intranasal suitability may be assessed through viscosity, tolerability, delivery-device compatibility, and actual administration characteristics.

“Infusing the nose”

The method claims use the phrase “infusing the nose.” The scope may turn on whether the term requires a particular administration technique or merely delivery of the solution into the nasal cavity. Device design, spray volume, dose placement, and administration instructions could affect the analysis.

Mercury exclusion

The mercury exclusion is an express limitation. A formulation containing thimerosal appears to create a tension within the claim set because thimerosal is listed among the permitted preservatives while the claims also require that the solution contain no mercury or mercury compounds. The mercury-free proviso controls. A thimerosal-containing formulation would likely fail that limitation even though thimerosal appears in the preservative Markush group.

When did US Patent 7,229,636 lose exclusivity?

The ordinary patent term has expired. The relevant term analysis should distinguish three dates:

Date type	Relevance
Priority date	Establishes the earliest claimed invention date and affects prior-art analysis
Nonprovisional filing date	Generally anchors the 20-year patent term for modern US applications
Patent expiration date	Determines whether ordinary infringement liability remains

US 7,229,636 was granted in 2007, but the grant date does not control expiration for a post-1995 US patent. The term generally runs 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and other statutory rules.[1] Public patent records identify the patent as expired after its ordinary term. The patent cannot now be treated as a live blocking right merely because it remains visible in patent databases.

Expiration of US 7,229,636 does not automatically eliminate:

Related continuation patents.
Separate formulation patents.
Device patents.
Manufacturing patents.
Regulatory exclusivity.
Trade-secret protection.
Trademark rights in Nascobal.
Patents covering later formulations or delivery systems.

What is the Orange Book status of the intranasal cyanocobalamin product?

Nascobal is associated with FDA-approved cyanocobalamin nasal spray for treatment of vitamin B12 deficiency, particularly in patients requiring parenteral-level replacement or maintenance therapy.[2] The FDA product label identifies cyanocobalamin nasal spray as a prescription intranasal product with a 500 microgram dose delivered in a metered spray.[3]

The Orange Book analysis should be separated from the patent analysis:

An Orange Book-listed patent may create a notice and certification framework for an ANDA applicant.
Orange Book listing does not extend the patent term.
FDA approval does not establish patent validity.
FDA approval does not determine infringement.
A drug can remain approved after all listed patents expire.
Regulatory exclusivity and patent exclusivity are separate rights.

For an expired patent, any previous Orange Book listing has no continuing ability to block generic approval after the patent term ends. The practical question shifts to whether a generic applicant can obtain approval through the ANDA pathway and whether unexpired patents or product-specific regulatory barriers remain.[4]

Were there Paragraph IV challenges or patent litigation?

The patent claims supplied do not establish any Paragraph IV filing, litigation outcome, settlement, or validity decision. Publicly available regulatory and patent records should be reviewed separately for:

ANDA filings for cyanocobalamin nasal spray.
Paragraph IV notices.
Hatch-Waxman complaints.
Patent-listing disputes under 21 U.S.C. § 355(j).
Declaratory-judgment actions.
Settlements involving launch dates or licenses.

US 7,229,636’s expiration substantially reduces the commercial value of any historical Paragraph IV dispute concerning that patent alone. A generic entrant would focus on whether any later patent remains listed or whether the reference product has an approved product-specific exclusivity period.

Which companies have commercial exposure?

The primary commercial exposure historically belonged to the holder or licensee of the intranasal cyanocobalamin product, including Nastech-related development interests and later commercial participants associated with Nascobal. The exact exposure depends on ownership, licensing, distribution, and product-right transfers over time.

Stakeholder category	Exposure
Product sponsor or NDA holder	Revenue erosion from generic or alternative nasal B12 products
Patent owner	Loss of exclusionary value after expiration
Generic manufacturer	Development, bioequivalence, device, and formulation risk
Nasal-delivery technology provider	Potential licensing value for metered spray systems
Competing B12 suppliers	Substitution pressure from oral, sublingual, injectable, and nasal products
Pharmacies and distributors	Product availability and reimbursement changes

The revenue impact of patent expiry depends on product sales, reimbursement, patient persistence, physician preference, and whether a generic can match the nasal delivery device. A generic launch could face more than a simple active-ingredient challenge because the reference product uses a metered intranasal delivery system and a formulation with defined excipient concentrations.

How strong is the patent estate?

US 7,229,636 was technically meaningful but commercially concentrated. Its strengths were:

Coverage of a defined intranasal formulation platform.
Inclusion of performance-based bioavailability limitations.
Protection for a specific commercial formulation.
Method claims directed to nasal administration and CSF B12 elevation.
Coverage of multiple excipient alternatives.

Its limitations were:

Dependence on a narrow combination of ingredients.
Need to prove intranasal bioavailability.
Potential design-around options using different excipients or concentrations.
Potential difficulty proving the CSF ratio in claim 31.
Expiration of the principal patent term.
Limited applicability to nonaqueous, injectable, oral, sublingual, or materially different nasal formulations.

Likely design-around routes

A competitor could seek to avoid the claims by changing one or more of the following:

Use a preservative outside the listed groups.
Use a different buffer system.
Omit the claimed humectant.
Use a nonaqueous or powder-based nasal dosage form.
Alter concentrations outside the “about” ranges.
Develop a formulation that does not achieve the claimed bioavailability threshold.
Use a different cyanocobalamin delivery device or dose volume.
Use another vitamin B12 form, such as hydroxocobalamin or methylcobalamin, subject to regulatory and clinical requirements.
Develop an oral, sublingual, buccal, injectable, or transdermal product.

Design-around analysis must account for the doctrine of equivalents. A formulation that avoids literal wording may still present risk if the substituted component performs substantially the same function in substantially the same way to achieve substantially the same result.

How does this patent compare with other vitamin B12 products?

Product type	Route	Relationship to US 7,229,636
Nascobal-type cyanocobalamin spray	Intranasal	Closest commercial subject matter
Cyanocobalamin injection	Intramuscular or subcutaneous	Outside the claimed intranasal route
Oral cyanocobalamin	Oral	Generally outside the claimed formulation and method scope
Sublingual B12	Sublingual	Generally outside the claimed intranasal route
Hydroxocobalamin injection	Injectable	Different active ingredient and route
Methylcobalamin products	Oral or injectable	Different active ingredient
Nasal B12 powder or gel	Intranasal	Requires separate element-by-element analysis

The patent is therefore more relevant to nasal cyanocobalamin competitors than to the broader vitamin B12 market.

What manufacturing and intellectual-property barriers remain?

After expiration, manufacturing barriers are primarily regulatory and technical rather than exclusionary patent barriers. A competitor may still need to address:

Cyanocobalamin stability in aqueous solution.
Light sensitivity and degradation control.
Preservative compatibility.
pH control.
Nasal mucosal tolerability.
Spray-device dose uniformity.
Microbial limits and container-closure integrity.
Manufacturing reproducibility at low excipient concentrations.
Bioequivalence or comparative clinical requirements.
FDA requirements for the nasal delivery device.

The formulation’s simplicity does not eliminate development risk. A product can match the nominal composition and still fail to reproduce spray performance, delivered dose, stability, or clinical exposure.

Key Takeaways

US 7,229,636 covers stable aqueous intranasal cyanocobalamin solutions with defined preservatives, buffers, humectants, viscosity, bioavailability, and mercury-free requirements.
Claim 23 is the principal narrow composition claim for the commercial formulation containing 0.5% cyanocobalamin, citrate buffer, 2.23% glycerin, and 0.02% benzalkonium chloride.
Claims 24 through 30 cover intranasal administration methods using the claimed formulations.
Claim 31 targets elevation of CSF vitamin B12 relative to serum and is narrower and more difficult to enforce.
The patent’s ordinary US term has expired, so it is not presently a standalone blocking patent.
Orange Book status, later continuation patents, product-specific exclusivity, and device patents must be analyzed separately.
The principal remaining competitive barriers are regulatory approval, nasal-device performance, stability, bioequivalence, and commercial adoption.
Generic risk is highest for a product that reproduces the original Nascobal-type formulation and delivery profile, although expired patent claims no longer independently prevent launch.

FAQs About US Patent 7,229,636

Does US 7,229,636 cover all nasal vitamin B12 products?

No. It covers formulations and methods meeting the claim limitations. A nasal product using different excipients, a different active B12 form, a nonaqueous dosage form, or materially different performance characteristics may fall outside the claims.

Does the patent cover hydroxocobalamin nasal spray?

Not literally based on the claims supplied. The claims require cyanocobalamin. Hydroxocobalamin is a different chemical form of vitamin B12.

Is 0.5% cyanocobalamin the only concentration covered?

No. The broad claims do not require only 0.5%. Dependent claims identify 0.5%, while other claims use broader or different concentration language.

Can a generic use the same citrate, glycerin, and benzalkonium chloride formulation?

The formulation would have to be assessed against every claim limitation. Because US 7,229,636 has expired, the patent itself does not ordinarily block launch, but later patents, regulatory requirements, device rights, and other intellectual-property rights may remain relevant.

Does the CSF claim create a separate patent barrier for nasal cyanocobalamin?

No current barrier arises from an expired claim. Historically, claim 31 created a narrower method claim requiring both the specified formulation and a defined CSF-to-serum vitamin B12 ratio.

References

United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation guidance. https://www.uspto.gov/patents/laws/patent-term-adjustment
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book
U.S. Food and Drug Administration. (n.d.). Nascobal cyanocobalamin nasal spray prescribing information. FDA labeling database. https://www.accessdata.fda.gov/scripts/cder/daf/
U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application process and patent certifications. https://www.fda.gov/drugs/types-applications/abbreviated-new-drug-application-anda
United States Patent and Trademark Office. (2007). Intranasal delivery of vitamin B12, U.S. Patent No. 7,229,636. https://patents.google.com/patent/US7229636B2 en

Details for Patent: 7,229,636

Summary for Patent: 7,229,636