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Patent landscape, scope, and claims summary: |
Executive summary
United States Patent 5,496,801 (“’801”) claims a parathyroid hormone (1-84) (human or generic PTH 1-84 scope) lyophilized injectable formulation built around three core functional elements: (i) co-lyophilization with a polyol excipient yielding an amorphous cake (claim 1), with mannitol as the main embodiment (claims 2, 4, 7, 9, 13, 24); (ii) a non-volatile buffer system that sets pH to a physiologically acceptable range (claims 1, 3, 8, 14); and (iii) a low residual water specification in the freeze-dried powder (claims 5, 6, 12). Dependent claims lock down specific composition windows (claims 10, 13, 14) and expand into a vial and kit configuration (claims 15-20). The claim set is narrowly anchored to a “co-lyophilize polyol + non-volatile buffer (citrate) + residual water ≤2%” stability strategy, which limits literal coverage against formulations that use different excipient classes, non-citrate buffers, volatile buffering systems, different water targets, or non-lyophilized dosage forms.
United States Patent 5,496,801 (PTH 1-84) formulation patent landscape: what is claimed and what is at risk
Core claim architecture (functional to structural mapping)
- Active: parathyroid hormone (1-84). Claim 1 is broad to “parathyroid hormone (1-84)” and claims 6 and 11/12 specify human PTH(1-84).
- Stability excipient system: a polyol excipient that co-lyophilizes to yield an amorphous cake (claim 1). The main embodiment is mannitol (claims 2, 4, 7, 8, 9, 13, 24).
- Buffer system: a non-volatile buffering agent to set pH within a physiologically acceptable range (claim 1), narrowed to citrate source (claims 3, 8, 14).
- Residual water: freeze-dried powder ≤2% water by weight (claims 5, 6, 12).
- Kit/vial: vials containing the formulation (claims 15-18) and a reconstitution kit with sterile water and instructions, plus optional injection device (claims 19-20).
- Narrow “only added to render stable” limitation: claims 23-24 constrain that the polyol excipient and non-volatile buffer are the only substances added for storage stability (claim 23 for general polyol/buffer; claim 24 for D-mannitol + citrate buffer).
Practical legal impact of each limitation
- The co-lyophilization to an amorphous cake element is a technical property constraint. In infringement analysis this typically forces claim construction into “what qualifies as co-lyophilizing to yield an amorphous cake,” which tends to be litigated through product characterization (XRD/DSC, morphology of cake, residual moisture correlates).
- The non-volatile buffering agent plus physiologically acceptable pH element creates carve-outs against:
- buffer systems outside the “citrate source” family;
- pH targets that fall outside the claimed ranges (especially dependent claim 14, and composition windows in claim 10);
- formulations that use buffering components but argue they are not “non-volatile” or not sufficient to set the pH as claimed.
- The ≤2% residual water limit (claims 5, 12) is often the cleanest “switch” for design-around: if a competitor targets higher residual moisture (while still maintaining stability) literal infringement becomes harder; they may still face doctrine-of-equivalents risk, but the numeric ceiling is a strong litigation lever.
- The “only substances added to render stable” limitation (claims 23-24) is a major narrowing clause. Many commercial lyophilized peptide products include additional formulation components (surfactants, amino acids, additional stabilizers, tonicity agents) or manufacturing aids that can trigger non-literal avoidance depending on how “only substances added to render stable” is construed.
What patents protect parathyroid hormone (1-84) amorphous lyophilized formulations with mannitol and citrate?
’801’s protective scope in claim terms
- Formulation claim 1: best read as a three-part stability formulation: polyol-co-lyophilized amorphous cake + non-volatile buffer + water (with PTH 1-84).
- Mannitol embodiment: claim 2 is a direct excipient narrowing; it also reinforces that “polyol” is contemplated broadly but commercially embodied as mannitol.
- Citrate embodiment: claim 3 fixes the buffer class to citrate sources. Claim 14 further fixes a target pH of 6 ±0.4 in the mannitol/citrate framework.
- Residual water embodiment: claim 5 provides a measurable endpoint that is enforceable without requiring complex mechanistic proof.
Where the patent is most enforceable
- Exact recipe designs that use mannitol + citrate at pH set in the claimed windows and reach residual water ≤2% after lyophilization.
- Dosage form continuity: lyophilized powder presentations with similar reconstitution kits (claims 15-20).
Where the patent is most vulnerable to design-around
- Buffer substitution away from citrate (even if another non-volatile buffer maintains stability).
- Excipient substitution away from mannitol (polyols like sorbitol, trehalose-based systems, sugar alcohol blends, or amorphous-forming agents not covered by the “polyol excipient that co-lyophilizes to yield an amorphous cake” element as construed).
- Residual water strategy (meeting stability with residual water >2%).
- Adding “stability” ingredients beyond “only substances added” (claims 23-24).
- Use of non-lyophilized dosage forms (solutions, suspensions) or alternate solid-state processes that do not yield the claimed amorphous cake result.
H3: Key dependent claim “pinpoints” for freedom-to-operate (FTO)
- Claim 10: concentration windows for PTH 1-84 (25 to 250 µg/mL), mannitol (3 to 7% w/v), citrate buffer (pH range 3.5 to 6.5), water.
- Claim 13: mannitol 4 to 6%.
- Claim 14: citrate buffer pH set to 6 ±0.4.
- Claims 23-24: “only substances” stability constraints.
When does United States Patent 5,496,801 lose exclusivity? What are the practical expiration dates?
A complete timeline requires the patent’s filing date, issue date, and statutory term adjustments (and any terminal disclaimers or patent term extensions). That information is not present in the claim text provided, so the exclusivity/expiration date cannot be computed here without additional bibliographic inputs.
How strong is the patent estate for PTH(1-84) lyophilized formulations with mannitol and citrate?
Strength drivers (claim features that favor enforceability)
- Numeric constraints: residual water ≤2% (claims 5, 12) and excipient/pH windows (claims 10, 13, 14) reduce interpretive ambiguity and tighten the infringement match.
- Component specificity in key dependents: mannitol (claims 2, 7, 13, 24) and citrate (claims 3, 8, 14, 24) narrow the universe of non-infringing alternatives.
- Solid-state product constraint: amorphous cake outcome from co-lyophilization (claim 1) ties coverage to a measurable physical state.
Strength limiters (factors that weaken leverage in litigation)
- Functional-to-process language: “co-lyophilizes” and “yield an amorphous cake” may require complex characterization. Competitors can argue different manufacturing routes or that their end state differs (e.g., partially crystalline or different amorphous morphology).
- Breadth of claim 1: claim 1 is broad on polyol excipient class but constrained by amorphous cake outcome. That can increase the burden for plaintiffs if competitors choose polyols that produce an amorphous cake but use different classes or formulations outside mannitol/citrate.
- “Only substances added” constraints: claims 23-24 can be strong for the plaintiff when met, but provide clear defenses if competitors include additional stabilizers deemed “added to render stable.” That may narrow the number of products that sit squarely inside the claim set.
What formulations are protected by 5,496,801? Are salts, pH buffers, and water content treated as limiting?
Buffer and pH
- Claim 1 requires a non-volatile buffer sufficient to adjust pH to a physiologically acceptable range.
- Dependent claim 3 narrows buffer class to citrate source.
- Dependent claim 14 specifies citrate buffer pH to 6 ±0.4.
- Claim 10 provides a broader pH range for the citrate buffer set in pH 3.5 to 6.5.
Residual water
- Claims 5, 6, 12 require a freeze-dried powder with not more than 2% water by weight. This is a categorical limitation on the product as manufactured.
Mannitol
- Claims 2, 4, 7, 8, 9, 13, 24 tie key implementations to mannitol (including D-mannitol in claim 24).
Amorphous cake
- Claim 1 requires the polyol excipient to co-lyophilize “to yield an amorphous cake.” A competitor can potentially avoid literal infringement by:
- selecting excipients that do not yield an amorphous cake under relevant assays; or
- claiming their product is not an amorphous cake as construed (e.g., different solid-state distribution).
H3: Common design-around patterns implied by the claim language
- Move from citrate to a different non-volatile buffer system and keep pH in the same range.
- Use a non-mannitol polyol blend, or a glass-former that is not mannitol, and still co-lyophilize.
- Increase residual water above 2% while maintaining stability and reconstitution performance.
- Include additional stabilizing excipients such as surfactants, amino acids, or tonicity agents so the formulation cannot meet claims 23-24 “only substances” requirements.
What method-of-use or medical regimen claims exist for PTH(1-84) in this patent?
No method-of-use claims are provided in the claim set you supplied. The claims listed are all directed to composition, vial, and kit configurations rather than dosing regimens, therapeutic indications, or clinical methods.
What generic entry risks exist for parathyroid hormone (1-84) based on this patent?
Risk is concentrated in lyophilized, reconstitutable products that replicate the formulation strategy: mannitol + citrate + residual water ≤2%, with PTH(1-84) at comparable concentration ranges.
Lower risk products include:
- formulations not based on lyophilized powder;
- formulations with different buffering agents;
- formulations with residual water above the ≤2% threshold;
- formulations that add additional stabilizers beyond the “only substances” limitations in claims 23-24.
Kit and vial claims increase packaging/form-factor leverage
Claims 15-20 extend to vials and kits with sterile water and instructions, and optionally an injection device. A generic manufacturer can sometimes avoid these by selling a different packaging configuration, but composition claims typically remain the larger driver.
What is the Orange Book status of 5,496,801? Which FDA products reference PTH(1-84) formulations?
Orange Book status requires pairing the patent to a specific NDA/BLA listing. The claim text alone does not identify the FDA application(s) that list this patent. Without the relevant NDA/BLA and Orange Book patent list record, the Orange Book status cannot be stated here.
What patent litigation affects United States Patent 5,496,801 and what were the outcomes?
Litigation requires docket-level records tied to the patent and the FDA application(s). The claim text provided does not include any case identifiers, parties, settlements, or court outcomes. A litigation landscape cannot be produced without those records.
How does 5,496,801 compare with other PTH(1-84) formulation patents and later generics’ “formulation workarounds”?
A reliable comparison requires a list of other patents in the same formulation family (same active, similar solid-state strategy, and later filings that may shift to different buffer excipients, different residual water targets, or different solid-state characterization strategies). Those patents are not provided in the input, and the patent landscape cannot be reconstructed from the single ’801 claim set.
Key claim-by-claim infringement “match map” (where copying is likely to trigger literal infringement)
| Claim |
What it covers |
Litigation-critical limitations |
Likely trigger for competitors |
| 1 |
PTH(1-84) lyophilized preparation |
co-lyophilized polyol yields amorphous cake; non-volatile buffer sets pH physiologically acceptable; water present |
Using lyophilized PTH(1-84) with mannitol-like polyol and citrate-like buffer and similar solid-state outcome |
| 2 |
Claim 1 where excipient is mannitol |
excipient identity |
Any mannitol-based formulation meeting other claim 1 elements |
| 3 |
Claim 1 where buffer is citrate source |
citrate buffer |
Citrate buffering in a “non-volatile” system that sets pH physiologically acceptable |
| 5 |
Claim 1 where residual water ≤2% |
“freeze-dried powder containing not more than 2% water by weight” |
Lyophilized products designed to hit very low residual moisture targets |
| 6 |
Claim 5 where hormone is human PTH(1-84) |
human PTH(1-84) identity |
Human PTH(1-84) branded/generic with same formulation |
| 10 |
Quantified concentrations |
PTH 25-250 µg/mL; mannitol 3-7% w/v; citrate buffer sets pH 3.5-6.5 |
Recipe alignment on concentration and pH window |
| 13 |
Quantified mannitol |
mannitol 4-6% |
Mannitol content optimization within narrow window |
| 14 |
Quantified pH |
pH 6 ±0.4 |
Buffer system tuned to near-neutral in that range |
| 23 |
“only substances” for stability |
polyol excipient and non-volatile buffer are only added for stability |
Formulations with extra stabilizers beyond polyol + buffer avoid |
| 24 |
“only substances” further narrowed |
D-mannitol + citrate buffer only added for stability |
“Minimal excipient” recipes with just PTH + mannitol + citrate |
Key Takeaways
- ’801 protects a specific lyophilized PTH(1-84) stability formulation concept: polyol co-lyophilization to an amorphous cake plus a non-volatile buffering system (citrate in key dependents) and a low residual water target (≤2%).
- Dependent claims create high-risk copying lanes: mannitol, citrate buffer, and especially residual water ≤2% and pH 6 ±0.4.
- The “only substances added to render stable” limitations (claims 23-24) create a strong defense pathway for competitors using additional stabilizers.
- Enforceability is strongest when a competitor’s product characterizations (solid-state form, residual moisture, and buffer/pH performance) line up with the numeric and outcome-based limitations.
FAQs
-
Does claim 1 require mannitol specifically or any polyol that forms an amorphous cake?
Claim 1 requires a polyol excipient that co-lyophilizes to yield an amorphous cake; mannitol is an expressly claimed embodiment in dependent claim 2.
-
Is residual water measured after lyophilization, and is the ≤2% limit an on-product requirement?
Claims 5 and 12 state the freeze-dried powder contains not more than 2% water by weight, making residual moisture a limiting product characteristic.
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Can a competitor avoid infringement by using a different non-volatile buffer while keeping pH within the physiologic range?
Dependent claims (notably citrate source claims and pH windows) are designed to be avoided by changing buffer class, while claim 1 still requires a non-volatile buffer that sets pH.
-
Do the vial and kit claims require the exact same packaging and reconstitution instruction sheet?
The claims are directed to a vial containing the specified preparation and a kit including sterile water and instructions, with an optional injection device. Packaging differences can be relevant, but composition claims are typically the main infringement basis.
-
Do claims 23 and 24 allow additional excipients used for non-stability purposes?
Claims 23-24 restrict the “only substances added to render the composition stable during storage,” leaving potential interpretive room for other materials not added for storage-stability purposes, but they materially narrow the formulation space.
References (APA)
- United States Patent 5,496,801, “parathyroid hormone preparation” (claim text provided by user).
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