Details for Patent: 11,911,446

Which drugs does patent 11,911,446 protect, and when does it expire?

Patent 11,911,446 protects VOXZOGO and is included in one NDA.

This patent has forty-four patent family members in twenty-five countries.

Summary for Patent: 11,911,446

Title:	Use of C-type natriuretic peptide variants to treat skeletal dysplasia
Abstract:	The present disclosure provides for use of variants of C-type natriuretic peptide (CNP), and novel pharmaceutical compositions and formulations comprising CNP variant peptides for the treatment of skeletal dysplasias, one or more symptoms of skeletal dysplasias, such as long bone growth or growth velocity, and other disorders having a skeletal dysplasia and/or CNP-associated symptom or component.
Inventor(s):	Sherry Bullens, Stuart Bunting, Tianwei Chou, Augustus O. Okhamafe, Christopher P. Price, Daniel J. Wendt, Clarence Yap
Assignee:	Biomarin Pharmaceutical Inc
Application Number:	US16/837,905
Patent Claim Types: see list of patent claims	Use; Composition;

Patent 11,911,446 (US): Scope and claim coverage for CNP-variant peptides plus citric acid monohydrate/sodium citrate dihydrate/trehalose/mannitol/methionine/polysorbate 80 to treat achondroplasia via increased long-bone growth and growth velocity

US Drug Patent 11,911,446 claims a method-of-treatment centered on administering a CNP variant peptide (specific SEQ ID NOs tied to CNP-37 substitutions and CNP-38) at defined minimum doses together with a defined excipient/protectant/solubilizer composition. Independent claim 1 covers increasing long-bone growth; dependent claim 2 narrows to achondroplasia; dependent claims 3 to 8 define dosing schedule, treatment duration, subcutaneous administration, and dose ladders, plus quantified excipient concentration windows and specific “about” examples. Independent claim 9 mirrors claim 1 but pivots the clinical endpoint to growth velocity (annualized standing height), with additional outcome thresholds and safety/tolerability constraints in later dependent claims 23 to 27.

The patent landscape around this claim set is structurally important: it is a tight combination claim that simultaneously locks in (1) exact peptide sequence variants, (2) minimum systemic dose levels, (3) specific buffer/excipient system (citric acid/citrate salts, trehalose dihydrate, D-mannitol, L-methionine, polysorbate 80), and (4) route and regimen (subcutaneous; daily; at least 6 months; optional titration of dosing frequency). That structure tends to raise barriers to generic entry because design-around must avoid at least one of these claim pillars while still achieving the same clinical endpoints.

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What does US 11,911,446 claim, and what is the exact peptide and excipient scope?

Core protected activity: administering a composition containing a listed CNP variant peptide at specified minimum exposure (dose in μg/kg) plus a listed citric acid/citrate–trehalose–sugar alcohol–amino acid–surfactant formulation to increase long-bone growth or growth velocity in a subject.

Independent claim 1: long-bone growth endpoint + formulation excipient lock-in

Claim 1 requires, as a single method step:

1. CNP variant peptide in an amount of at least 7.5 μg/kg, where the peptide is limited to one of the listed sequences:

• CNP-37(M32N) (SEQ ID NO: 1)
  QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC
• Met-CNP-37 (SEQ ID NO: 2)
  MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
• Pro-CNP-37 (SEQ ID NO: 3)
  PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
• Gly-CNP-37(M32N) (SEQ ID NO: 4)
  GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC
• Pro-Gly-CNP-37 (SEQ ID NO: 5)
  PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
• Met-Gly-CNP-37 (SEQ ID NO: 6)
  MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
• Gly-CNP-37 or CNP-38 (SEQ ID NO: 7)
  GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC

2. Excipient/formulation system includes:

• citric acid monohydrate
• sodium citrate dihydrate
• trehalose dihydrate
• D-mannitol
• L-methionine
• polysorbate 80

3. The administration increases long bone growth in the subject.

Meaning for freedom-to-operate: A competitor using a different CNP variant sequence (outside these SEQ ID NOs) or substituting any excipient component outside the claimed set avoids the exact claim 1 structure. Substituting excipients while keeping the peptide may still avoid claim 1 because claim 1 requires the recited set of excipients, not “equivalents.”

Independent claim 9: growth velocity endpoint + same peptide/excipient lock-in

Claim 9 uses the same composition requirements as claim 1, but recites the clinical endpoint as increasing growth velocity.

Claim 9 requires:

• CNP variant peptide at at least 7.5 μg/kg
• same set of citric acid/citrate, trehalose, D-mannitol, L-methionine, polysorbate 80
• outcome: increased growth velocity

Dependent claims then quantify how growth velocity must change and add safety constraints.

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What are the key dependent claim thresholds that narrow infringement risk?

Who is the target population (disease)?

• Claim 2 / 10: subject has achondroplasia.
  • This creates disease-specific exposure for a large portion of commercial relevance, since achondroplasia is the likely labeled use case for CNP-analog therapies.

Dosing schedule and treatment duration

• Claim 3: once daily.

• Claim 4: once daily for at least 6 months.

• Claim 14: once daily for at least 6 months.

• Claim 16: once daily for at least 12 months.

• Claim 17 (claim 9 lineage): daily, 3 times weekly, twice weekly, once weekly, or once every two weeks.

Practical reading: The patent covers both strict daily regimens (claims 3-4, 14-16) and broader frequency patterns (claim 17). A company altering dosing frequency may still fall within claim 17 if the schedule matches.

Route of administration

• Claim 5 / 18: subcutaneous.
• Claim 19 (claim 9 lineage): administered parenterally.

If a competitor switches to a non-parenteral route (unlikely for a peptide), they reduce risk. Between parenteral routes, subcutaneous is explicitly covered.

Minimum dose and high-dose variants

• Claim 6: administration includes CNP variant peptide at at least:
  • 15 μg/kg
  • 30 μg/kg
  • 60 μg/kg per day (the claim lists options).
• Claim 20 (claim 9 lineage): at least:
  • 15 μg/kg per day
  • 30 μg/kg per day
  • 60 μg/kg per day

Risk implication: If a competitor uses lower dosing than the asserted minimums in these dependent claims, they may avoid those dependent claims but still face independent claim 1/9 if they meet the minimum 7.5 μg/kg requirement.

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What excipient concentration ranges are claimed, and how do the “about” exemplars matter?

Claims 7-8 and 21-22 recite concentration windows and specific “about” values for each excipient component.

Concentration windows (claims 7 and 21)

For the claimed composition, the ranges are:

• Citric acid monohydrate: about 0.15 mg/mL to 0.40 mg/mL
• Sodium citrate dihydrate: about 0.5 mg/mL to 1.5 mg/mL
• Trehalose dihydrate: about 30 mg/mL to 70 mg/mL
• D-mannitol: about 10 mg/mL to 20 mg/mL
• L-methionine: about 0.5 mg/mL to 1.5 mg/mL
• Polysorbate 80: about 0.01 mg/mL to 0.1 mg/mL

Fixed “about” concentrations (claims 8 and 22)

The examples narrow to specific concentration setpoints:

• Citric acid monohydrate: about 0.28 mg/mL
• Sodium citrate dihydrate: about 1.08 mg/mL
• Trehalose dihydrate: about 58.01 mg/mL
• D-mannitol: about 15 mg/mL
• L-methionine: about 0.73 mg/mL
• Polysorbate 80: about 0.05 mg/mL

Design-around leverage: A competitor can attempt to leave the claimed excipient ranges or change one component concentration beyond the window. However, because claim 1/9 require the presence of the excipients (without limiting concentrations), avoiding dependent claims 7/21 and 8/22 does not necessarily remove claim 1/9 exposure unless the formulation also fails the broader “comprising” requirement (e.g., omits one excipient).

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What clinical response benchmarks are used for the growth-velocity claim set?

Claim 11 requires an annualized growth velocity change:

• Claim 11: at least 25% above baseline in standing height.

• Claim 12: at least 40% above baseline.

Claim 13 defines permitted measurement endpoints:

• standing height, sitting height, weight, head circumference, upper arm length, lower arm length, hand length, foot length, plus limb lengths (upper/lower leg).

Interpretation: A method that achieves growth velocity but uses different statistical endpoints could still fall under claim 9 if it is shown to “increase growth velocity” and then the dependent claim measurement thresholds are not met. For infringement analysis, plaintiffs often use the strongest dependent benchmarks because they tie the efficacy to objective criteria.

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What safety/tolerability constraints appear in the later dependent claims?

Adverse-event exclusion

• Claim 23: method “does not cause an adverse event of grade two or higher.”

Lab parameter stability

• Claim 24: no clinically significant change in listed blood parameters:
  • hemoglobin
  • blood platelet number
  • electrolytes
  • blood urea nitrogen
  • creatinine
  • alkaline phosphatase
  • ALT (alanine amino transferase)
  • AST (aspartate amino transferase)

Body proportions ratio constraints

• Claim 25: change in upper body length to lower body length ratio between -0.05 and 0.05
• Claim 26: upper arm length to forearm length ratio between -0.05 and 0.05
• Claim 27: upper leg length to lower leg length ratio between -0.05 and 0.05

Risk implication: These dependent claims narrow to a favorable safety and anthropometric profile. A competitor could argue that even if growth velocity is achieved, grade ≥2 adverse events or lab changes may occur, undermining those dependent claim theories. Independent claim 9 still only requires “increases growth velocity,” so safety-profile-dependent constraints are mostly relevant to selecting which causes of action and which dependent claim theories are strongest.

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How do claims 1 and 9 compare, and what does that mean for claim strategy?

Shared backbone: both claims require:

• administration of a listed CNP variant peptide at ≥ 7.5 μg/kg
• plus the same six excipients (citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine, polysorbate 80)
• with a parenteral route implied by the later dependent claim structure

Different clinical endpoint:

• Claim 1: “increasing long bone growth”
• Claim 9: “increasing growth velocity,” with dependent claims quantifying standing height-based annualized growth velocity thresholds.

Strategic impact: If evidence in litigation or regulatory dossiers supports standing-height annualized growth velocity, claim 9’s dependent thresholds can be easier to map. If evidence includes radiographic or longitudinal long-bone growth measures, claim 1 can be leveraged. The portfolio likely uses both to cover different readouts.

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Where are the most actionable design-around levers?

1. Peptide variant substitution

   • The peptide list is limited to SEQ ID NO 1 to 7. A variant outside these sequences may avoid independent claims 1/9.

2. Excipient system omission

   • Independent claims require the presence of the cited excipients. Removing one excipient component is a direct structural design-around.

3. Excipient concentration range engineering

   • Dependent claims 7/8 and 21/22 can be avoided by moving outside the concentration ranges or changing the specific “about” exemplars.

4. Dose minimization

   • Dependent claims 6 and 20 set higher daily dose thresholds. But the floor in independent claims remains 7.5 μg/kg, so dose reduction has limited value unless it also drops below the independent claim minimum.

5. Dosing frequency and route

   • Subcutaneous and frequency patterns have explicit dependent coverage. Non-subcutaneous parenteral alternatives or schedules not matching claim 17 may reduce coverage.

6. Clinical outcome selectivity

   • For claim 9, the strong dependent thresholds are ≥25% and ≥40% annualized standing height increases. If a competitor targets a different efficacy profile (or claims differ in measure design), they may avoid those dependent claims but still risk claim 9’s independent “increase growth velocity” allegation.

7. Safety and anthropometric profile

   • Claims 23 to 27 are objective constraints. If clinical data show adverse events or ratio shifts outside the defined bounds, infringement of those dependent claims can be contested.

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What does the claim scope imply for a US generics/Paragraph IV and biosimilar-style risk analysis?

This patent is a method-of-treatment claim with a defined peptide sequence set and a defined formulation excipient system. In a US entry scenario, the risk is less about “generic peptide identicality” alone and more about whether the proposed product is used to perform the protected method.

Key points for entry planning:

• If an applicant’s proposed label and instructions mirror the patented method (peptide variant, excipient set, dosing regimen, subcutaneous administration, and results consistent with “increasing growth velocity/long bone growth”), litigation exposure rises.
• If an applicant can credibly offer a different dosing endpoint framing, different regimen, or a different formulation excipient system, they may reduce method infringement while still delivering a similar pharmacological effect.
• Even if a product avoids dependent claims 7/8 and 21/22 (concentration windows), it can still infringe independent claims if it includes the claimed excipient set and peptide variants at or above the independent minimum.

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Patent landscape mapping: how US 11,911,446 fits into a broader CNP-variant competitive estate

A complete landscape requires bibliographic linking to related US applications, family members, and the specific branded product to which the CNP variants map. That bibliographic linkage is not provided in the prompt, so a full estate-wide comparison across specific family members cannot be completed from claim text alone.

What can be concluded from the claim text alone is the patent’s likely “estate role” within a CNP program:

• It is a late-stage, clinical-efficacy and formulation-coupled claim, because it recites:
  • therapeutic indications (achondroplasia via dependent claim 2/10),
  • objective efficacy thresholds (annualized standing height change),
  • and explicit formulation composition with protective excipients (citric acid/citrate, trehalose, mannitol, methionine, polysorbate 80).
• This profile is typical of patents intended to guard the commercial dosing product and clinical claims, not merely the peptide sequence itself.

As a result, in competitive freedom-to-operate terms, US 11,911,446 functions as a barrier patent for:

• substitution of peptide sequence variants without changing excipient system or dosing outcomes,
• and for non-identical formulations that still include the required excipient set.

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Actionable claim chart for infringement analysis (high-level)

Claim element	Requirement in US 11,911,446	Design-around route
Therapeutic method	Increases long bone growth (claim 1) or growth velocity (claim 9)	Avoid protected endpoint usage (difficult if label requires growth outcomes)
CNP variant peptide	Specific SEQ ID NOs 1 to 7 only	Use peptide variants not in list
Dose floor	≥ 7.5 μg/kg	Dose below 7.5 μg/kg (if clinically feasible)
Excipient set	Citric acid monohydrate + sodium citrate dihydrate + trehalose dihydrate + D-mannitol + L-methionine + polysorbate 80	Omit at least one excipient component
Dose regimen (dependent)	Once daily; ≥6 months; optional ≥12 months	Switch regimen outside covered patterns
Route (dependent)	Subcutaneous; parenteral	Use non-covered route
Efficacy benchmarks (dependent)	≥25% or ≥40% annualized standing height change	Different efficacy framing/outcome targets
Safety/ratios (dependent)	No grade ≥2 AEs; no clinically significant labs; ratio bounds	Show different safety profile or measurements

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Key Takeaways

• US 11,911,446 protects a specific, coupled method: administering listed CNP variant peptide sequences at ≥7.5 μg/kg with a defined excipient set (citric acid/citrate, trehalose, mannitol, L-methionine, polysorbate 80) to achieve long-bone growth or increased growth velocity.
• Independent claims (1 and 9) require the peptide list and the excipient set; dependent claims narrow to achondroplasia, subcutaneous once-daily regimens, ≥6- and ≥12-month treatment durations, and dose ladders.
• Dependent claims 7/8 and 21/22 lock in excipient concentration ranges and specific “about” exemplars, enabling targeted formulation design-around, but not necessarily avoiding independent claim exposure unless an excipient component is omitted.
• The later dependent claims 23 to 27 impose objective safety and anthropometric proportion constraints, which can be used to contest infringement of those dependent theories based on clinical data, while independent “increase growth velocity/long bone growth” theories remain broader.

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FAQs

1) Does US 11,911,446 require exact matching of excipient concentrations to infringe?
Independent claims require the presence of the excipients set; specific concentration ranges appear in dependent claims (7/8 and 21/22).

2) If a competitor uses a different CNP variant peptide, is infringement still possible?
Independent claims are limited to the listed SEQ ID NO peptides; using a variant outside the listed sequences avoids those independent elements.

3) What clinical endpoint is most directly tied to quantified success criteria?
Claim 9’s dependent claims quantify growth velocity as annualized standing height changes of ≥25% or ≥40% above baseline.

4) Are subcutaneous injections covered even if dosing is less frequent than daily?
Yes. Subcutaneous is explicitly covered (claim 5/18), and dosing frequency alternatives are covered in dependent claim 17 (daily through once every two weeks).

5) Can a competitor avoid the patent by showing adverse events or lab changes occur?
Safety-related dependent claims (23 and 24) can be contested with clinical data, but independent claim 9 only requires “increases growth velocity,” so safety contests do not necessarily remove independent risk.

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References

1. US 11,911,446 patent application/patent document (claim text provided).

Drugs Protected by US Patent 11,911,446

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Biomarin Pharm	VOXZOGO	vosoritide	POWDER;SUBCUTANEOUS	214938-001	Nov 19, 2021		RX	Yes	Yes	11,911,446					USE TO INCREASE LINEAR GROWTH IN PEDIATRIC PATIENTS WITH ACHONDROPLASIA WITH OPEN EPIPHYSES
Biomarin Pharm	VOXZOGO	vosoritide	POWDER;SUBCUTANEOUS	214938-002	Nov 19, 2021		RX	Yes	Yes	11,911,446					USE TO INCREASE LINEAR GROWTH IN PEDIATRIC PATIENTS WITH ACHONDROPLASIA WITH OPEN EPIPHYSES
Biomarin Pharm	VOXZOGO	vosoritide	POWDER;SUBCUTANEOUS	214938-003	Nov 19, 2021		RX	Yes	Yes	11,911,446					USE TO INCREASE LINEAR GROWTH IN PEDIATRIC PATIENTS WITH ACHONDROPLASIA WITH OPEN EPIPHYSES

International Family Members for US Patent 11,911,446

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	105563
Australia	2016298425
Australia	2023200669