United States Patent 5,834,448: Hydroxocobalamin Formulation, Cyanide Antidote Scope, and Patent Landscape

US Patent 5,834,448 protects a specific freeze-dried hydroxocobalamin product and the manufacturing process used to produce it. Its central technical feature is hydroxocobalamin lyophilized from an acidic aqueous solution so that the resulting cake rapidly redissolves in neutral saline. The claims also cover pH-controlled manufacturing, selected fillers and buffers, concentration ranges, saline diluent presentations, cyanide-poisoning kits, and intravenous use.

The patent is no longer an active barrier to generic or competing hydroxocobalamin products. Its claims are directed to a formulation and presentation, not to hydroxocobalamin as a molecule. The most commercially important claim concepts are the acidic lyophilization medium, pH ranges of 3.5 to 5.5 and 4.0 to 5.0, hydroxocobalamin concentration of 1% to 5% w/v, and a kit combining a freeze-dried vial with 20 to 150 mL of saline.

What does US Patent 5,834,448 cover?

US 5,834,448 covers pharmaceutical compositions and processes involving freeze-dried hydroxocobalamin. The patent does not claim hydroxocobalamin generally, vitamin B12 chemistry generally, or every injectable hydroxocobalamin formulation.

Its claim architecture has four principal categories:

Claim category	Claims	Core subject matter
Freeze-dried composition	1-3, 16-17	Hydroxocobalamin lyophilized from an acidic medium and capable of rapid or stable redissolution
Manufacturing process	4-13	Acidification, optional excipients, pH control, concentration, lyophilization, and saline ampoules
First-aid kit	14	Freeze-dried hydroxocobalamin vial plus saline ampoule
Medical use	15	Intravenous administration for acute or chronic cyanide poisoning

The patent’s commercial focus is a ready-to-use cyanide antidote presentation rather than a general injectable vitamin product (U.S. Patent No. 5,834,448, 1998).

What is the independent claim scope?

Claim 1: acidic freeze-dried hydroxocobalamin composition

Claim 1 requires:

A pharmaceutical composition.
Hydroxocobalamin in freeze-dried form.
Freeze-drying in an acidic medium.
A product capable of rapid redissolution in neutral saline.

The claim is product-focused, but it contains functional language concerning redissolution speed. A product could fall within the claim even if its manufacturing records are unavailable if the product’s composition and performance demonstrate that it was lyophilized from an acidic medium and rapidly redissolves in neutral saline.

The claim does not expressly require a particular acid, buffer, excipient, vial size, hydroxocobalamin concentration, or freeze-drying cycle. Those limitations appear in dependent claims and related process claims.

Claim 3: acidic medium selected for solution stability

Claim 3 adds a stability requirement. The acidic medium must be selected so the reconstituted hydroxocobalamin solution is stable.

This limitation creates two technical questions in an infringement analysis:

What stability period and test conditions define a “stable solution”?
Must the accused product use the same acidification strategy, or is equivalent stability from another acidic formulation sufficient?

Because “stable” is relative to the patent’s disclosure and testing methods, prosecution history and specification data would be important in a claim-construction dispute. The supplied claim text does not identify a numerical stability threshold.

Claims 4-13: manufacturing processes

Claims 4 through 13 cover the production route. Common elements include:

Preparing hydroxocobalamin in water or an aqueous medium.
Adjusting the solution into an acidic pH range.
Optionally adding a filler or buffering agent.
Freeze-drying the product.
In some claims, filling and lyophilizing in the final container.
Preparing a saline ampoule for reconstitution.

These claims are narrower than a broad claim to any lyophilized hydroxocobalamin because they require specific process steps. A manufacturer using a materially different route may avoid infringement even if its final product has similar clinical performance, depending on the wording of the asserted claim and the doctrine of equivalents.

What pH and concentration ranges are protected?

The central process limitations are:

Claim	pH or concentration limitation
5	pH 3.5 to 5.5
6	pH 4.0 to 5.0
10	Hydroxocobalamin 1 to 5 g per 100 mL
11	Hydroxocobalamin 2 to 3 g per 100 mL
16	Composition concentration of 1 to 5 g per 100 mL

The ranges are material claim limitations. A process conducted at pH 4.2 would fall within both the 3.5-to-5.5 and 4.0-to-5.0 ranges. A process at pH 3.6 would fall within claim 5 but not claim 6. A formulation containing 5 g in 100 mL is at the literal upper boundary of the 1% to 5% w/v range.

The concentration claims correspond closely to a 5 g hydroxocobalamin commercial vial that is reconstituted for intravenous administration. A product containing materially less than 1 g per 100 mL or more than 5 g per 100 mL would not literally satisfy the stated concentration limitation, although other claims could still be relevant.

What excipients and buffers are protected?

Claim 8 identifies four fillers:

Arginine hydrochloride
Lactose
Glycine
Sodium acetate

Claim 9 covers adding a buffering agent consisting of a sodium salt of an organic acid.

Claim 7 is broader regarding acid selection. It covers obtaining the acidic pH by adding a calculated amount of a strong inorganic acid or an organic acid. The claim does not confine the process to one named acid.

The excipient claims do not create ownership of these ingredients. They cover their use in the specified hydroxocobalamin lyophilization process. A competing manufacturer using mannitol, trehalose, sucrose, or another bulking agent would not literally meet claim 8, although it could still implicate claims 1, 3, 5, 6, 10, 12, 14, 15, 16, or 17 depending on the product and process.

What does claim 17 protect?

Claim 17 covers:

A pharmaceutical composition consisting essentially of freeze-dried hydroxocobalamin redissolved in a saline solution.

The claim is structurally different from claim 1 because it focuses on the reconstituted composition. “Consisting essentially of” generally permits components that do not materially alter the basic and novel characteristics of the composition, while excluding additional ingredients that materially change those characteristics.

The claim is potentially relevant to a reconstituted hydroxocobalamin injection containing saline and limited incidental excipients. It is less clearly applicable to a formulation containing substantial additional active agents, complex stabilizer systems, or a non-saline diluent.

How do the kit and method-of-use claims operate?

Claim 14: cyanide antidote kit

Claim 14 requires a first-aid kit consisting of:

A vial of freeze-dried hydroxocobalamin.
Between 1 and 5 g of hydroxocobalamin.
An ampoule containing 20 to 150 mL of saline.
A product obtained according to the process of claim 5.

The claim is narrower than a kit claim covering any hydroxocobalamin vial and any diluent. It incorporates the pH limitation of claim 5 through the phrase “obtained according to the process of claim 5.”

A kit with a 5 g vial and a 100 mL sodium chloride ampoule falls within the stated numerical ranges. A kit with a 10 g vial or a 200 mL ampoule would not literally satisfy those limitations.

Claim 15: intravenous treatment of cyanide poisoning

Claim 15 covers intravenous administration of the redissolved product for acute or chronic cyanide poisoning. It depends on the kit defined in claim 14.

The claim is narrower than a general method claim for treating cyanide poisoning with hydroxocobalamin. It requires use of the claimed first-aid kit and intravenous administration of the aqueous redissolved product.

When did US Patent 5,834,448 expire?

US 5,834,448 issued on November 10, 1998. It is an older patent whose enforceable term has elapsed. The patent therefore does not presently block commercial manufacture, sale, or use of a product that practices its formulation or process claims.

The controlling term calculation depends on the patent’s effective U.S. filing date, any applicable transition rules, patent-term adjustment, and any terminal disclaimer. The patent’s commercial exclusivity period nevertheless ended years ago, and no current patent-term extension under this patent is generally associated with the marketed hydroxocobalamin cyanide antidote.

Event	Date or status
U.S. patent issuance	November 10, 1998
Patent technology	Freeze-dried hydroxocobalamin and cyanide antidote presentation
Regulatory product associated with technology	Cyanokit, hydroxocobalamin for injection
Current enforceability	Expired
Current blocking value	None from US 5,834,448 itself

The patent’s expiration does not eliminate later-filed patents covering improvements, manufacturing controls, packaging, device integration, or new therapeutic uses. It removes only the exclusionary rights arising from this patent.

What was the FDA and Orange Book status?

Cyanokit, a 5 g hydroxocobalamin injection for intravenous infusion, received FDA approval in 2006 under NDA 022041. The FDA-approved indication is treatment of known or suspected cyanide poisoning (U.S. Food and Drug Administration, 2006).

The product’s regulatory presentation corresponds closely to the claimed technology:

Freeze-dried hydroxocobalamin in a vial.
Reconstitution before administration.
Intravenous use.
Use in acute cyanide exposure.
High-dose presentation, commonly 5 g per vial.

US 5,834,448 was historically relevant to the Orange Book patent position for the product. Its expiration means that it no longer creates live Orange Book patent protection or a current statutory delay for an ANDA applicant.

Orange Book listing and patent expiry are separate questions. A patent can remain visible in historical regulatory records after its enforceable term has ended. A current ANDA applicant would evaluate the Orange Book entry, patent status codes, and any later-listed patents as of the relevant filing date (FDA, 2024).

Are Paragraph IV challenges relevant?

Paragraph IV certification is relevant only when an ANDA applicant challenges an unexpired listed patent. Because US 5,834,448 has expired, a Paragraph IV challenge directed solely to this patent would have no practical exclusivity consequence.

A generic hydroxocobalamin applicant could pursue an ANDA using an appropriate certification strategy for any remaining listed patents. The applicant would still need to address:

Drug substance identity and quality.
Sterility and endotoxin control.
Lyophilized cake performance.
Reconstitution time.
Stability after reconstitution.
Container-closure integrity.
Labeling and intravenous administration.
Bioequivalence or the FDA’s applicable waiver and clinical bridge requirements.

The patent itself should not prevent an ANDA or 505(b)(2) applicant from using an acidic lyophilization process, because expired patent claims are available for public use.

Which products and companies compete with the claimed technology?

Cyanokit

Cyanokit is the principal commercial product associated with high-dose hydroxocobalamin for cyanide poisoning. The product is a lyophilized 5 g presentation requiring reconstitution before intravenous infusion. Its commercial position is based on FDA approval, emergency-use protocols, manufacturing capability, and clinical familiarity, rather than continuing exclusivity under US 5,834,448.

Sodium nitrite and sodium thiosulfate products

Traditional cyanide antidote products use nitrite and thiosulfate combinations. These products are therapeutic alternatives to hydroxocobalamin but do not generally practice the freeze-dried hydroxocobalamin claims.

The competitive distinction is clinical:

Product class	Principal mechanism	Key commercial distinction
Hydroxocobalamin	Binds cyanide to form cyanocobalamin	Does not induce methemoglobinemia
Nitrite products	Induce methemoglobin to bind cyanide	May create oxygen-delivery concerns
Thiosulfate products	Provides sulfur for cyanide detoxification	Often used in combination regimens

Generic hydroxocobalamin

A generic or alternative manufacturer could design around narrower claims by using:

A non-acidic lyophilization medium.
A pH outside the claimed ranges.
A different concentration.
A different diluent or presentation.
A different filler system.
A preconstituted liquid formulation.
A manufacturing sequence that does not perform the claimed in-container lyophilization steps.

Because the patent is expired, design-around analysis is commercially useful for freedom-to-operate against later patents, but it is unnecessary for avoiding infringement of US 5,834,448.

How strong was the patent estate?

The patent was commercially strong when unexpired because it combined several layers of protection around one product:

Product claims to the lyophilized acidic formulation.
Process claims to pH adjustment and freeze-drying.
Concentration and excipient claims.
Kit claims to the vial and saline ampoule.
Method claims for intravenous cyanide treatment.

That layering would have increased litigation leverage against a product closely matching the marketed presentation. The strongest practical claims were likely the composition and kit claims because they could be assessed from the finished product and packaging. Process claims would require evidence concerning the accused manufacturer’s production method.

Its current strength is zero as an enforceable patent right. The patent remains relevant as:

Prior art against later patent applications.
Evidence of historical formulation technology.
A reference point for claim scope and product genealogy.
A potential source of prosecution-history estoppel or prior-art arguments in later disputes.

What manufacturing and intellectual-property barriers remain?

The expired patent does not remove the technical barriers to producing a commercial hydroxocobalamin antidote. The principal barriers are operational and regulatory:

Manufacturing barriers

Hydroxocobalamin formulations require control of:

Raw-material purity and cobalt-containing impurities.
Solution pH before lyophilization.
Color and degradation products.
Cake structure and residual moisture.
Reconstitution time.
Photostability.
Container-closure integrity.
Sterility assurance.
Large-volume intravenous handling.

A 5 g lyophilized dose also creates scale-up and fill-finish challenges. The product must reconstitute consistently despite its high active load and must remain suitable for emergency intravenous administration.

Regulatory barriers

An entrant must establish a legally adequate FDA pathway. A conventional ANDA may be difficult if the reference product’s formulation, reconstitution characteristics, or clinical bridge cannot be matched precisely. A 505(b)(2) application may be more practical where the applicant relies partly on published data or the FDA’s findings for the reference product but uses a materially different formulation or presentation (Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355).

Later patent barriers

Potential later rights may cover:

Improved hydroxocobalamin stability.
Alternative lyophilization cycles.
Reconstitution devices.
Closed-system transfer components.
Preassembled emergency kits.
Packaging and light protection.
Combination antidote regimens.
New cyanide-poisoning treatment protocols.

Those rights must be assessed separately from US 5,834,448.

What litigation or settlement risk is associated with this patent?

US 5,834,448 does not create a current litigation risk because its patent term has ended. Any historic Paragraph IV litigation or settlement involving the patent would not restore exclusivity after expiration.

The principal current risks are regulatory and commercial:

FDA refusal to approve a product that does not adequately match the reference presentation.
Manufacturing failure during high-dose lyophilization.
Supply constraints for emergency stockpiling.
Trade-secret disputes concerning production parameters.
Later-patent infringement claims concerning devices, packaging, or improved formulations.
Trademark and labeling disputes involving Cyanokit or successor products.

No live settlement restriction can be inferred from the expired patent alone.

What are the generic launch scenarios?

Launch scenario	Effect of US 5,834,448
Generic 5 g lyophilized hydroxocobalamin with saline	Patent does not block launch
505(b)(2) product with modified excipients	Patent does not block launch
Preconstituted hydroxocobalamin solution	Outside the core lyophilized presentation claims
Alternative cyanide antidote	No relevance to this patent’s claims
Product using the same pH and excipients	Still not blocked because the patent is expired
Product with later patented device or packaging	Requires separate freedom-to-operate review

Market entry would depend more on FDA approval, manufacturing validation, supply reliability, emergency procurement contracts, and product liability management than on US 5,834,448.

Key Takeaways

US 5,834,448 covers acidic-medium lyophilization of hydroxocobalamin for rapid or stable saline reconstitution.
The most specific technical limitations are pH 3.5 to 5.5, preferably 4.0 to 5.0, and hydroxocobalamin concentration of 1 to 5 g per 100 mL.
The patent also covers selected fillers, sodium-organic-acid buffers, in-container lyophilization, saline ampoules, cyanide-poisoning kits, and intravenous administration.
The claims are formulation, process, kit, and use claims. They do not claim hydroxocobalamin as a molecule.
Cyanokit is the principal FDA-approved product associated with the claimed presentation.
The patent’s term has expired and it does not create a current barrier to generic or competing hydroxocobalamin products.
Paragraph IV activity directed only to this patent would have no current exclusivity impact.
Remaining commercial barriers are FDA approval, high-dose sterile lyophilization, reconstitution performance, supply capacity, and later patents covering improvements or delivery systems.

FAQs

Does US 5,834,448 cover all hydroxocobalamin injections?

No. It targets freeze-dried hydroxocobalamin produced from an acidic medium, with related claims covering saline reconstitution, process conditions, kits, and cyanide-poisoning use.

Can a company use the same pH range disclosed in US 5,834,448?

Yes, because the patent has expired. The company must still assess later patents and satisfy FDA manufacturing and approval requirements.

Is hydroxocobalamin a biologic requiring a biosimilar application?

No. Hydroxocobalamin is a chemically defined small-molecule drug. A biosimilar pathway under section 351(k) is not the normal regulatory route. An ANDA or 505(b)(2) pathway is more relevant.

Does the patent cover the saline ampoule by itself?

No. The saline ampoule is claimed as part of specified hydroxocobalamin production processes and the first-aid kit. Saline as a standalone product is outside the patent’s central scope.

What is the principal freedom-to-operate issue for a new Cyanokit competitor?

The principal issue is not US 5,834,448. The relevant analysis is whether later patents cover the proposed hydroxocobalamin formulation, lyophilization process, vial and diluent configuration, reconstitution system, packaging, or method of use.

References

Food and Drug Administration. (2006). Cyanokit: Hydroxocobalamin for injection, prescribing information. U.S. Department of Health and Human Services.

Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.

Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355.

U.S. Patent No. 5,834,448. (1998). Pharmaceutical composition and process comprising freeze-dried hydroxocobalamin. United States Patent and Trademark Office.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
France	95 13512	Nov 15, 1995

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	7172096	⤷ Start Trial
Australia	720219	⤷ Start Trial
Germany	69619767	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,834,448

Summary for Patent: 5,834,448