Patent: 10,307,464

Summary for Patent: 10,307,464

Title:	Use of ultrarapid acting insulin
Abstract:	Disclosed herein are improved methods of treating hyperglycemia with a combination of an ultrarapid acting insulin and insulin glargine comprising prandial administration of the ultrarapid insulin, and administration of a first dose of insulin glargine within 6 hours of waking for a day.
Inventor(s):	Boss; Anders Hasager (Princeton, NJ), Petrucci; Richard (New Canaan, CT)
Assignee:	MannKind Corporation (Westlake Village, CA)
Application Number:	15/300,239
Patent Claims:	see list of patent claims

What does US Patent 10,307,464 claim, and where is the infringement and validity risk in the US insulin landscape?

US 10,307,464 claims methods that treat pre-meal hyperglycemia by giving ultra rapid acting insulin as a split dose around meals, with a timed secondary dose that is sized as a fraction of the initial mealtime dose and (in one claim family) titrated to a post-dose glucose target. The claims also narrow to a specific ultra-rapid insulin chemical class and, ultimately, to inhaled human insulin in dependent claim 12.

The core claim set is not a new molecule claim. It is a behavioral dosing regimen tied to pre-meal monitoring windows (10 days in claim 1) and glucose thresholds (120, 140, 150, 160 mg/dL). That structure matters for both infringement and validity because prior art and design-around arguments tend to be easiest when the debate is about (i) glucose targets and (ii) split-dose timing/fraction rather than about pharmaceutical composition novelty.

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What is the claim scope in plain dosing mechanics?

Claim 1: Split-dose for pre-meal hyperglycemia with a monitoring period

Claim 1 requires:

• Population/condition: patient “in need of treatment” monitored for pre-meal blood glucose levels for 10 days.
• Regimen: “regularly administering a split dose” of an ultra rapid acting insulin formulation:
  • Initial dose at mealtime
  • Second dose 30 to 150 minutes after beginning a meal
  • Second dose is 10% to 100% of the initial dosage
• Triggering glycemic criterion: “wherein when pre-meal blood glucose level for a next meal had been regularly greater than 120 mg/dl.”

This ties the split dosing to a learned patient pattern: after monitoring, the “next meal” uses the split-dose approach when the pre-meal levels repeatedly exceed 120 mg/dL.

Key scope levers

• “regularly greater than 120 mg/dl” is qualitative in claim 1, but dependent claim 4 supplies a quantitative interpretation for part of the family.
• Timing is broad: 30 to 150 minutes after meal start.
• Fraction is broad: 10% to 100% of initial.

Claims 2-6: Timing refinements and higher thresholds

• Claim 2: second dose at 60 to 150 minutes
• Claim 3: second dose at 90 to 150 minutes
• Claim 4: “regularly greater than 120 mg/dl comprises … greater than 140 mg/dl for a majority of the pre-meal blood glucose tests within a given time period.”
• Claim 5: regularly > 150 mg/dl
• Claim 6: regularly > 160 mg/dl

These dependent claims expand coverage upward in glucose thresholds and narrow the second-dose timing in steps.

Claim 7: Split dosing with post-dose median target

Claim 7 changes the operational test from “pre-meal threshold patterns” to a treatment goal tied to post-dose outcomes:

• Treat hyperglycemia where pre-meal blood glucose > 140 mg/dl
• Give:
  • Mealtime dose
  • Secondary dose 30 to 120 minutes after the mealtime dose
  • Secondary dose amount: 10% to 100% of initial dose
• Titration constraint:
  • “secondary dose is titrated so that median blood glucose 1 to 2 hours after the secondary dose is less than 180 mg/dl.”

This claim is broader in glucose threshold definition (pre-meal > 140) but narrower in the time window for the secondary dose (30-120 minutes) and adds a quantitative post-dose success criterion (median < 180).

Claim 8: Non-proportionality / dosing response characterization

Claim 8 requires a patient where increasing the mealtime dose yields a lesser, non-proportional reduction in blood glucose compared with an unincreased mealtime dose. This is a clinical/phenomenological modifier that can be used either to distinguish prior art (if supported by evidence) or to complicate enforceability (if difficult to prove in real-world settings).

Claims 9-11: Ultra rapid insulin chemical class and formulation narrowing

• Claim 9: ultra rapid acting insulin formulation comprises a specific class: 3,6-di( … aminobutyl)-2,5-diketopiperazine derivatives including succinyl, maleyl, glutaryl, malonyl, oxalyl, fumaryl.
• Claim 10: narrows to 3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine
• Claim 11: narrows to human insulin

This is the key chemistry pivot: the method depends on a specific ultra rapid insulin chemical entity/class.

Claim 12: Administration by inhalation

Claim 12 further requires administration by inhalation.

Net effect: the claim set spans from broad behavioral dosing rules to narrow product/formulation constraints. That structure tends to create:

• a stronger infringement case if an accused regimen uses the same insulin technology and administration route, and
• a weaker infringement case if the accused product is an ultra rapid insulin with different chemistry or delivery mode.

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Where is the infringement most likely: timing and fraction, or the insulin chemistry?

The answer depends on what the accused product is. Patent enforcement will usually hinge on whether the accused method performs all claim elements.

If an accused therapy uses the same ultra-rapid chemistry and inhalation

Claims 9-12 become satisfied if the accused insulin is in the 3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine family, with human insulin, delivered by inhalation. In that scenario:

• the fight moves to dosing behavior (split dose timing/fraction; pre-meal patterns; median post-dose target).

If an accused therapy uses a different ultra-rapid insulin (different chemical formulation or delivery)

Then dependent claims 9-12 collapse quickly. In that scenario, claim 1-8 may still be asserted only if the “ultra rapid acting insulin formulation” is interpreted broadly enough to encompass the accused product. Because claim 1 and claim 7 do not recite the chemical class, they can be attacked for lack of enablement or indefiniteness if “ultra rapid acting” is contested. Conversely, they can be asserted broadly if the accused product is still “ultra rapid acting.”

Most material claim elements for infringement proof

From an evidentiary standpoint, the easiest elements to prove are:

• timing relative to meal start / mealtime dose
• fractional dose size (10%-100% of initial dose)
• monitoring logic (pre-meal monitoring over a period and decision triggers)
• measured glucose thresholds (120/140/150/160; median <180 at 1-2 hours)

The hardest to prove is often:

• claim 8’s non-proportional reduction phenomenon in an individual patient, and
• any dependency on a specific chemical formulation and inhalation, unless manufacturing and prescribing records align.

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How strong is the novelty story given typical prior-art insulin practice?

Split dosing around meals is a known clinical concept

Clinically, insulin regimens often use dose adjustments based on pre-meal glucose and post-dose response. Split dosing itself has long been part of insulin therapy strategies, including:

• partitioning bolus delivery to manage postprandial excursions,
• using earlier and later bolus components,
• titration to post-meal glucose targets.

This kind of art does not automatically anticipate the patent, but it raises obviousness pressure for:

• the general idea of a timed second bolus after the initial mealtime bolus, and
• using a glucose target to titrate the second dose.

What may differentiate the claims in prosecution

The claims add specificity in three places that may be argued as non-obvious combinations:

• ultra rapid acting insulin plus split dose fraction of 10%-100%
• timing relative to meal start (30-150 minutes in claim 1; 30-120 in claim 7; and dependent narrower windows)
• a “regularly” pre-meal threshold logic tied to repeated monitoring (claim 1 and claim 4), and a median post-dose <180 target (claim 7)

Critical vulnerability: “regularly greater than” and majority tests

Claim 1 uses “regularly greater than 120 mg/dl.” Dependent claim 4 interprets this as:

• “greater than 140 mg/dl for a majority of the pre-meal blood glucose tests within a given time period.”

That helps, but it also means the broader claim 1 may be attacked as indefinite or as leaving too much discretion to users/clinicians. For enforceability, “regularly” can become a factual and definitional battleground: how many tests count, what “given time period” means, and whether real-world adherence satisfies the claim.

Critical vulnerability: “titrated” and outcome-based median

Claim 7 defines “titrated” by an outcome:

• median glucose 1-2 hours after secondary dose must be <180 mg/dL.

Outcome-based limitations can be strong if prior art cannot meet the specific median constraint, but can also be attacked if:

• median is not a routine clinical metric in prior art,
• the median threshold is likely to be met in many regimens through titration, or
• the measurement and population are undefined.

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Patent landscape analysis: where competitors can align or diverge

Because you requested a “patent landscape” for US 10,307,464, the operative question is: what other patent families exist around (i) ultra rapid inhaled insulin, and (ii) dosing strategies with split boluses? Without external bibliographic confirmation of the patent’s full contents and priority chain in the record you provided, the landscape can only be analyzed at the claim-logic level.

Landscape cluster A: Ultra rapid inhaled insulin products

If the market is using an ultra rapid inhaled insulin with high pharmacodynamic speed, it is likely that competitors already have method claims around:

• administration timing relative to meals,
• dose titration,
• algorithmic adjustments,
• post-prandial glucose targets.

Impact on 10,307,464

• Claims 9-12 are most resilient if the accused product’s chemistry differs from the specific diketopiperazine derivative and delivery is oral/injectable rather than inhaled.
• If the accused product is within the same chemistry/delivery class, the landscape’s main differentiator becomes the split dosing timing/fraction and median/threshold logic, which tend to be fertile grounds for overlap in existing dosing-algorithm patents.

Landscape cluster B: Closed-loop and decision-support dosing algorithms

Many method patents cover “monitoring and adjusting insulin doses” using CGM or SMBG patterns.

• Claim 1 resembles a decision-support rule: monitor for 10 days, then use split dosing on subsequent meals when pre-meal glucose is regularly above threshold.
• Claim 7 resembles a titration-to-outcome rule.

Impact

• If competitors have algorithm patents that already prescribe a two-stage bolus response based on pre-meal readings, 10,307,464 risks obviousness overlap unless the second dose fraction/timing and ultra-rapid-inhaled insulin context are locked down.

Landscape cluster C: Fractionated bolus and post-dose metrics

Fractionated dosing and post-dose metrics like AUC, 1-2 hour response, or threshold-based control are common.

• Claim 7’s median <180 at 1-2 hours after secondary dose is a specific metric.
• Claim 4’s majority-based “regularly” threshold is another specific metric.

Impact

• Competitors can design around by choosing different metrics (mean vs median), different windows, or different glucose targets (for example, targeting 2-3 hour glucose, or using peak-only constraints).

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Critical review of the claim set from a enforceability perspective

1) Breadth vs narrow chemistry creates layered validity and infringement risks

• Broad method claims (1 and 7) do not recite the chemical structure or inhalation route.
• Narrow dependent claims (9-12) do.

That layering is strategically useful for claim coverage, but it creates a tradeoff:

• If prior art is strong on split-dose strategies with ultra-rapid insulin generally, then claim 1/7 can be vulnerable.
• If prior art is mostly on different insulin formulations or delivery routes, then claims 9-12 can be the enforcement anchor.

2) The “meal beginning” timing can be ambiguous in real use

Claim 1 measures the second dose from “beginning a meal,” and claim 7 measures from “mealtime dose.” Meal start identification can vary (start of eating vs bolus administration vs documented entry). This can be used to argue non-infringement if an accused regimen defines different reference points.

3) “Split dose” might be argued to include multiple bolus schemes

If an accused system delivers a series of small boluses, the question becomes whether it is truly “split dose” with one initial and one secondary dose, and whether delivery beyond the defined first/second dose counts. Claim language in your excerpt appears to require two doses, not multiple fractions.

4) “regularly greater than” can be contested

Claim 1 and 4 depend on repeated patterns over time. If the accused protocol uses fewer measurements, different thresholds, or thresholds that fluctuate around the cutoff, it can avoid “regularly greater than” definitions.

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Key design-arounds competitors can pursue (based on claim elements alone)

These are claim-logic deviations that typically avoid meeting limitations:

1. Change the second-dose timing window

   • Claim 1: 30 to 150 minutes after meal beginning.
   • Claim 7: 30 to 120 minutes after mealtime dose. Shifting outside both windows can reduce literal infringement risk.

2. Change the secondary dose fraction

   • Claim 1 and 7: 10% to 100% of initial dose. Moving to <10% or using a fixed minimum bolus strategy may avoid the fraction range.

3. Avoid the “regularly above threshold” rule

   • Claim 1: regularly >120 mg/dL.
   • Claim 4: majority of tests >140 mg/dL. Protocols that use single measurements, moving averages, or alternative threshold rules can avoid the “regularly” requirement.

4. Avoid median <180 at 1-2 hours

   • Claim 7 ties titration to a median outcome. Algorithms that optimize to a different statistical descriptor (mean) or different time interval can be positioned away from literal compliance.

5. Use a non-covered ultra rapid insulin formulation or non-inhaled route

   • Claims 9-12 narrow to a specific diketopiperazine derivative, human insulin, inhalation. If an accused product differs, dependent claims 9-12 do not read on the therapy.

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Key Takeaways

• US 10,307,464 is a dosing-regimen patent focused on split dosing of ultra rapid acting insulin around meals, triggered by pre-meal glucose monitoring and controlled by timing and dose fraction.
• The claim set spans from broad behavioral rules (claims 1 and 7) to narrow chemistry and route limitations (claims 9-12).
• The infringement and validity risk will pivot on two axes: 1) whether an accused protocol matches the split-dose timing/fraction and the glucose logic (threshold patterns; median <180), and
  2) whether the accused insulin product matches the specific ultra-rapid inhaled insulin chemistry in dependent claims.
• Practical design-around options exist by moving outside the timing windows, dose fraction range, threshold definitions, or by using different post-dose targets/statistics.

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FAQs

1) Which claims are the primary enforcement anchors?
Claims 9-12 can be strong anchors if the accused therapy uses the same ultra rapid inhaled human insulin chemical class; otherwise, claims 1-8 carry the burden but face broader obviousness overlap risks.

2) What feature most strongly distinguishes the regimen from generic bolus titration patents?
The combination of a two-part bolus with a secondary dose fraction (10%-100%) and meal-timed delay windows, paired with explicit glucose decision logic (regular pre-meal thresholds and/or median <180 at 1-2 hours).

3) Can a competitor avoid infringement by changing the reference point for “time after meal”?
Yes. Claim 1 uses “beginning a meal,” and claim 7 uses “after the mealtime dose.” Using different reference definitions can help with non-infringement arguments.

4) How does claim 8 affect enforceability?
Claim 8 adds a patient-specific response characterization (non-proportional reduction when increasing mealtime dose), which can be difficult to prove across real-world patients.

5) What is the most plausible chemical/product design-around?
Switching away from the covered ultra rapid insulin chemistry and/or from inhalation can avoid dependent claim coverage and force reliance on broader claims that may be more vulnerable to prior art.

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References

No sources were provided in the prompt for US 10,307,464 text, prosecution history, priority documents, or cited prior art; therefore, no external citations are included.

Details for Patent 10,307,464

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	October 28, 1982		2035-03-27
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	December 29, 2015		2035-03-27
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	August 06, 1998		2035-03-27
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	March 31, 1994		2035-03-27
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	May 25, 2018		2035-03-27
Novo Nordisk Inc.	NOVOLIN R	insulin human	Injection	019938	June 25, 1991		2035-03-27