Patent: 6,221,893

Summary for Patent: 6,221,893

Title:	Administration of histamine for therapeutic purposes
Abstract:	Methods for obtaining beneficial stable levels of circulating histamine are disclosed for use in methods for enhancing natural killer cell cytotoxicity. In such methods, a beneficial level of circulating histamine is attained and an agent whose ability to enhance natural killer cell cytotoxicity is augmented by histamine is administered. Alternatively, stable beneficial levels of circulating histamine can be attained in subjects receiving chemotherapy or antiviral treatment. The invention may also be employed in treatments combining histamine, agents which enhance natural killer cell cytotoxicity, and chemotherapeutic agents. Optimization of the delivery of histamine and substances which induce the release of endogenous histamine are also disclosed.
Inventor(s):	Hellstrand; Kristoffer (Goeborg, SE), Hermodsson; Svante (Molndal, SE), Gehlsen; Kurt R. (Carlsbad, CA)
Assignee:	Maxim Pharmaceuticals, Inc. (N/A)
Application Number:	08/767,338
Patent Claims:	see list of patent claims

United States Patent 6,221,893: What the Claims Cover and How the Landscape Likely Works

US Patent 6,221,893 is built around a single therapeutic axis: raising systemic histamine exposure (blood/levels) in a controlled dosing window (1 to 30 minutes) to augment cytotoxicity of an effector arm, typically in oncology settings, and to do so in combination with a second agent (chemotherapeutic agent or another beneficial agent). The patent’s claim set also sweeps in broader histamine-related administration formats and, in dependent claims, downstream dosing parameters and administration mechanics.

What follows is a critical read of claim scope, likely infringement contours, and the patent landscape logic for both novelty/obviousness and design-around.

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1) What is claimed: the core invention pattern

What does Claim 1 actually require?

Claim 1 is the broadest method claim anchored to a mechanistic outcome: augmenting cytotoxic activity of cytotoxic effector cells via histamine.

It requires all of the following elements:

1. Administer histamine (pharmaceutically acceptable form)
2. Achieve stable blood histamine concentration
3. Delivery duration: not less than 1 minute and not greater than 30 minutes
4. Administer a beneficial agent whose cytotoxicity-enhancing effects are augmented by the histamine administration

Critical constraint: “stable blood histamine concentration sufficient to augment the cytotoxicity enhancing effect of said agent” ties histamine dosing not just to administration time, but to a physiologic target and clinical pharmacology effect.

Claim 2: shifts from effector-cell enhancement to “treating malignancy”

Claim 2 recasts the same histamine-plus-second-agent structure but adds:

• “Treating a subject having a malignancy”
• The second agent is the “second beneficial agent” whose activity is “augmented by histamine”
• Same 1 to 30 minute delivery window and “stable beneficial blood histamine level”

This makes Claim 2 a clinically framed version of Claim 1. The two claims differ mainly in who the patient is (malignancy context) and how the second agent is described.

Claim 3: adds a measurement-gated selection step

Claim 3 introduces a patient selection mechanic:

• Step (a): measure blood histamine levels
• If measurement indicates cytotoxic enhancement by increasing histamine is possible, then
• Step (b): administer histamine to reach stable beneficial blood histamine within 1 to 30 minutes
• Step (c): administer second agent to achieve enhanced cytotoxic activity

Critical legal effect: this claim narrows by requiring pre-treatment measurement and a condition precedent (“for whom said measuring step indicated…”). It can be harder to establish for enforcement, but it can also strengthen validity by adding a functional selection criterion.

Claim 4: couples histamine maintenance to chemotherapy

Claim 4 is a method of treating malignancy:

• Step (a): treat with chemotherapeutic agent
• Step (b): maintain “beneficial stable level of circulating blood histamine” by administering histamine
• Same delivery duration limitation: 1 to 30 minutes

This is important because it suggests the histamine dosing is not just a one-off adjunct but potentially a maintenance strategy to sustain circulating levels during treatment.

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2) Claim 5 through Claim 15: the patent’s dosing and formulation envelope

Claim 5: broad administration claim spanning multiple chemical classes

Claim 5 claims administering a therapeutically effective amount of a substance selected from:

• histamine
• histamine dihydrochloride
• histamine phosphate
• histamine salts
• histamine esters
• histamine congeners
• histamine prodrugs
• serotonin
• 5HT agonists
• H2 receptor agonists

…delivered over 1 to 30 minutes.

Critical scope: Claim 5 is not limited to oncology or cytotoxic effector cells. It is a general administration duration claim for a large group of pharmacologic entities, including serotonin and 5HT agonists, which are not histamine per se. That is a broad chemical and pharmacology sweep.

Claim 6-8: narrows the duration and dose to specific numeric ranges

• Claim 6: 5 to 20 minutes
• Claim 7: 0.4 to 10 mg/day
• Claim 8: about 2.0 mg/day

This is the main numeric narrowing. In enforcement, numeric dependent claims help the patentee pin down specific dosing regimens.

Claim 9-11: frequency and infusion rate constraints

• Claim 9: once to four times per day
• Claim 10: twice per day
• Claim 11: delivery rate about 0.025 to 0.2 mg/minute

These can be meaningful for design-around because a competitor can adjust duration, frequency, or infusion rate (while still arguably using histamine and histamine-related entities).

Claim 12-13: route and transdermal specificity

• Claim 12 lists routes including subcutaneous, IV, intramuscular, intraocular, oral, transdermal.
• Claim 13 specifically claims transdermal via a patch.

This is a breadth enhancer. It captures multiple administration routes that competitors might choose for tolerability or pharmacokinetic shaping.

Claim 14-15: controlled-release mechanisms

• Claim 14: delivery via controlled release mechanism
• Claim 15: examples include polymers, gels, microspheres, liposomes, tablets, capsules, pumps, syringes, ocular inserts, transdermal formulations, hydrophilic gums, microcapsules, and colloidal drug delivery systems.

This is another breadth layer: it is hard to design around if the competitor uses any common controlled-release delivery form.

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3) Claim 16 through Claim 23: inducing endogenous histamine release (not giving histamine)

What changes in Claim 16?

Claim 16 is a different modality:

• Administer a substance that induces release of endogenous histamine
• That substance is delivered over 1 to 30 minutes
• Release yields an effective therapeutic amount of endogenous histamine within the same time window

So Claim 16 does not require direct histamine administration. It claims a histamine-release induction approach.

Dependent claims expand the inducers

• Claim 17: retinoic acid or retinoid
• Claim 18: IL-3
• Claim 19: ingestible allergen
• Claim 20: patient suffering from neoplastic disease
• Claim 21: routes oral, IV, IM, SC
• Claim 22: effective amount sufficient to induce release of about 0.05 to 0.2 mg/min endogenous histamine
• Claim 23: dosing frequency once to four times per day

Critical scope insight: this creates two infringement tracks:

1. Exogenous histamine delivery (Claims 1-15)
2. Endogenous release triggers (Claims 16-23)

Even if a competitor avoids direct histamine administration for safety reasons, Claim 16 gives a separate claim path using recognized histamine-release triggers (retinoids, IL-3, allergens).

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4) Critical claim-quality analysis: where the claims are strong vs. where they are vulnerable

Strong points (practical enforceability and commercial relevance)

1. Clear delivery window: “not less than 1 minute and not greater than 30 minutes” appears repeatedly. This is a bright-line feature for both claim construction and infringement mapping.
2. Outcome-tethered histamine target: multiple claims hinge on “stable beneficial” blood histamine concentration/levels sufficient to augment cytotoxicity. That links regimen to pharmacologic effect rather than mere co-administration.
3. Two modality tracks: direct histamine delivery and endogenous release inducers provide broader coverage than a single modality patent.

Vulnerable points (attack vectors for validity or avoidance)

1. “Stable beneficial blood histamine level” is functional and potentially indefinite. Functionality can be a novelty anchor, but it also creates claim-construction ambiguity if prior art or common practice used variable dosing without explicit “stable” definitions.
2. Breadth in Claim 5 extends beyond histamine: serotonin, 5HT agonists, and H2 receptor agonists are included within the same duration-delivery claim. If prior art exists for serotonin/5HT-related dosing windows or H2 agonist oncology combinations, the claim may face an obviousness challenge unless the specification supports a unified inventive concept across these classes.
3. “Cytotoxic effector cells” is not constrained. The claims do not define cell type (NK, T, macrophage, etc.) or mechanism. This can broaden infringement coverage but also weakens the specificity required to prove non-obviousness.
4. The combination partner is generic: “beneficial agent” and “chemotherapeutic agent” are not restricted to a specific list. That can increase enforceable scope, but it also invites obviousness arguments that histamine adjunctive immunomodulation plus standard chemotherapy is routine.

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5) Likely prior-art and novelty pressure points (landscape logic)

Because the claims rely on (i) histamine exposure and (ii) short-duration administration windows to augment cytotoxicity in malignancy, the key prior-art buckets that would pressure validity are:

• Histamine as an immune modulator in oncology or with cytotoxic therapies
• Combination therapy using histamine (or histamine analogs) with chemotherapy
• Use of histamine-releasing agents (retinoids, cytokines such as IL-3, allergens) to increase systemic histamine or mast-cell mediated responses
• H2 receptor agonist or 5HT agonist dosing regimens with oncology relevance
• Pharmacokinetic shaping of histamine exposure using infusion, controlled-release, or delivery duration constraints

A strong invalidity strategy would argue that the claim recites an already-known adjunctive immunostimulatory concept, then adds a dosing window and generic delivery forms that would have been obvious to optimize.

A strong patentee counter would focus on the specific combination of:

• achieving “stable blood histamine levels,”
• within a defined 1 to 30 minute administration duration,
• correlated to augmentation of cytotoxic effector cell activity,
• including measurement-gated selection (Claim 3),
• and/or the endogenous histamine release timing (Claims 16-23).

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6) Where infringement risk is highest (and how competitors can design around)

Highest-risk claim targets

1. Direct histamine adjunct in oncology where the regimen explicitly aims to elevate systemic histamine quickly (1-30 minutes) and the protocol uses a defined dosing window.
2. Protocols claiming or measuring “blood histamine levels” prior to escalation (Claim 3).
3. Use of histamine-releasing inducers that are administered with timing constraints to induce endogenous histamine release in the 1 to 30 minute window (Claims 16-23).
4. Controlled-release formulations used to deliver histamine-related agents within the claimed duration.

Common design-around levers

• Adjust administration duration outside 1-30 minutes or eliminate any protocol aspect that can be mapped to a stable target within that window.
• Avoid “stable blood histamine concentration/beneficial levels” as an explicit objective, and do not measure blood histamine to guide dosing escalation (to avoid Claim 3’s gating).
• Use exogenous agents that are not within the Claim 5 chemical set, or avoid routes and mechanisms that fit dependent claims (though Claim 5 is broad on routes and mechanisms).
• For endogenous release approaches, move away from the specific inducers enumerated in dependent claims (retinoids, IL-3, ingestible allergens), or shift the timing and dosing strategy so that effective endogenous release does not occur within the claimed window.

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7) Patent landscape map: how this patent likely sits relative to product development

A practical landscape view for investment or R&D planning:

A) If you are developing an oncology regimen with histamine

You should assume this patent is designed to cover:

• histamine dosing co-administered with chemotherapy or “beneficial agents”
• infusion or administration protocols that can be characterized as 1-30 minutes delivery
• controlled-release and transdermal forms

B) If you are developing histamine-mobilizing or histamine-releasing approaches

Assume coverage extends to substances that induce endogenous histamine release, including:

• retinoic acid or retinoids
• IL-3
• ingestible allergens …and require that effective release occurs within 1-30 minutes.

C) If you are using serotonin/5HT agonists or H2 receptor agonists

Claim 5 pulls these into the same duration-delivery concept. A developer should treat these as higher-risk if they deliver such agents within 1-30 minutes as part of a therapeutic method that could be argued to meet the claim’s definition of “therapeutically effective amount” delivered over that window.

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Key Takeaways

• US 6,221,893 claims histamine-driven augmentation of cytotoxic activity using a repeatable regimen feature: delivery over 1 to 30 minutes to achieve stable beneficial blood histamine levels.
• The patent is built as two parallel coverage tracks: exogenous histamine/histamine-related agents (Claims 1-15) and endogenous histamine release inducers (Claims 16-23).
• Claim 5 is structurally broad and includes serotonin, 5HT agonists, and H2 receptor agonists, not only histamine.
• Design-around space centers on shifting out of the 1-30 minute window, avoiding measurement-gated protocols (Claim 3), and avoiding timing/dosing that yields the claimed “stable” blood histamine target.
• The patent’s enforcement strength likely increases where development programs explicitly quantify blood histamine and tune dosing to a stable target during oncology combination therapy.

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FAQs

1) Does this patent require a specific cancer type?
No. Oncology is referenced, but the claims do not confine malignancy to a defined tumor type.

2) Is measurement of histamine levels required?
Only Claim 3 includes a measurement step. Claims 1, 2, and 4 focus on administering histamine to reach stable beneficial levels within the time window.

3) Can infringement occur without directly administering histamine?
Yes. Claims 16-23 cover administering substances that induce release of endogenous histamine with release occurring within 1-30 minutes.

4) What time window is central to the claims?
The repeated constraint is not less than 1 minute and not greater than 30 minutes for delivery that produces stable beneficial blood histamine levels or effective endogenous histamine release.

5) What dosing details are claimed in dependent claims?
Dependent claims specify examples including about 2.0 mg/day, a range of 0.4 to 10 mg/day, rate about 0.025 to 0.2 mg/minute, and administration frequency once to four times per day (with a separate dependent claim for twice per day).

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References

[1] United States Patent 6,221,893. Claims excerpt as provided by user.

Details for Patent 6,221,893

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Alk-abello, Inc.	HISTATROL	positive skin test control-histamine	Injection	103754	September 29, 1950		2016-12-16
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	March 13, 1924		2016-12-16