United States Patent 6,031,003: Scope, Claim Strategy, and US Patent Landscape for Calcium Receptor Modulators (Calcimimetic/Calcilytic Methods)
US Patent 6,031,003 is a method-oriented US patent built around the calcium receptor (CaR) modulation pharmacology of a specific chemical class: calcimimetics (CaR agonist-like, increase intracellular Ca2+ in vitro) and calcilytics (CaR antagonists/inverse agonists, decrease Ca2+ in vitro). The core legal hook is a treatment method claim template that combines (i) a CaR modulation requirement measured in bovine parathyroid cells and (ii) explicit elimination of “protamine.” Dependent claims narrow to (a) particular disease targets (hyperparathyroidism, Paget’s disease, osteoporosis) and (b) specific structure and stereochemistry within the disclosed “NPS” series (e.g., NPS R-467, NPS R-568 and analogs including R-4M/4N/4P/4V/4W/6X and others).
Because your prompt provides the claim text but not the patent’s bibliographic data, prosecution history, or the rest of the US family, a complete, accurate landscape (other US patents that issue from the same family; Orange Book status; Paragraph IV disputes; litigation docket; terminal disclaimers; priority dates; and expiration dates by claim) cannot be produced from the supplied information alone.
What can be produced from the claim text is an actionable claim-by-claim scope analysis and the likely patent landscape structure (by claim themes, not by verified patent numbers).
What is the claim scope of US Patent 6,031,003 for CaR modulators?
Featured snippet answer: The patent claims methods of treating disorders modifiable by in vitro calcium receptor modulation, where the administered compound must meet a quantitative Ca2+ assay threshold in bovine parathyroid cells (for calcimimetics: EC50 ≤ 5 μM; for calcilytics: IC50 ≤ 5 μM) using the fura-2 cytosolic Ca2+ assay. The method expressly excludes compounds “not protamine,” and includes broad structural genus claims with dependent narrowing to enumerated NPS analogs and specific stereochemistry.
Independent claim backbone (largest coverage)
Claim 1 (method of treatment; calcimimetic or calcilytic; bovine parathyroid assay threshold; not protamine)
- Covers:
- “A method of treating a patient having a disease or disorder which may be treated by a compound which modulates one or more activities of a calcium receptor in vitro”
- Administering a therapeutically effective amount
- Conditional assay requirement based on whether compound is calcimimetic or calcilytic:
- Calcimimetic: increases intracellular Ca2+ with EC50 ≤ 5 μM
- Calcilytic: decreases Ca2+ with IC50 ≤ 5 μM
- Assay method described for calcimimetics: bovine parathyroid cells loaded with fura-2, cytosolic Ca2+ cell assay
- Disease is functionally defined as having “a disease or disorder which may be treated” by CaR modulation.
- Exclusion: “wherein said compound is not protamine.”
- Scope implications:
- This is a functional method claim anchored to in vitro pharmacodynamics rather than a specific final disease biology.
- It is broad on indication at the independent level, then narrows via dependent claims to hyperparathyroidism, Paget’s disease, and osteoporosis.
- The “not protamine” language is a narrow textual carveout, not a species limitation to the chemical class.
Second independent-style claim (formula-centric genus; no assay threshold)
Claim 31 (method of treating; CaR modulation; compound must have a disclosed formula; no protamine exclusion; no explicit EC50/IC50 threshold in the claim text you provided)
- Provides another broad coverage axis:
- Administer therapeutically effective amount of a compound with the specified formula (a large, parameterized genus for X/Ar/R/Y/Z/n/m and salts)
- Disease is again defined functionally as any that “may be treated” by a CaR-modulating compound.
- Scope implications:
- Claim 31 can capture compounds meeting the structural formula even if assay thresholds are not stated in the claim text (though actual enforceability still depends on the claim’s “modulates one or more activities of a calcium receptor in vitro” requirement).
Additional independent claim themes in your provided set
Claims 40 and 82 and 89, 95, 96, 99, 104 are additional “formula + method” templates, each oriented to different therapeutic directions:
- Claim 40: calcimimetic compound with an alternative parameterized formula (alk/R1/R2/R3 class) and treated diseases via CaR modulation.
- Claim 82 and 83/90 and 89/90/95/96/99/104: method-of-action bifurcation:
- modulating PTH secretion
- treating hyperparathyroidism
- enhancing bone formation (with calcilytic causing increased PTH)
- decreasing PTH (with calcimimetic decreasing PTH)
- decreasing serum ionized calcium (calcimimetic increasing CaR activity in vitro)
Which dependent claims narrow the medical indications and therapeutic endpoints?
Indication narrowing
From your excerpt, dependent claims tie the genus to specific disease targets:
Calcimimetic path (reduces PTH, reduces Ca2+)
- Claims 13-20:
- reduces parathyroid hormone (PTH) level
- further limits include “normal individual” PTH level range
- “reduces plasma Ca2+” (via a decrease in plasma Ca2+ as a functional endpoint)
- Claims 15 and 37-39 and 136-140:
- osteoporosis treatment via calcimimetic (and osteoporosis explicitly as the disease in later dependent claims)
Paget’s disease and hyperparathyroidism
- Claims 27-30 and 35-38, 136-139:
- disease includes hyperparathyroidism, Paget’s disease, and osteoporosis depending on dependent claim chain
Calcilytic path (increases PTH; enhances bone formation)
- Claims 95-98:
- enhancing bone formation by causing an increase in PTH levels via administering a calcilytic
- calcilytic treatment for Paget’s disease or osteoporosis
- Claims 82-88 and 83-86:
- methods of modulating PTH secretion using compounds of the formula types
Pharmacodynamic endpoints
- “reduces parathyroid hormone”
- “reduces serum ionized calcium”
- “inhibits bone resorption”
- “stimulates calcitonin secretion”
These endpoints are useful for enforcement because they define a functional relationship between the administered compound class and downstream biology, though a defendant may still argue lack of performance for a specific compound.
How do the assay thresholds (EC50/IC50 ≤ 5 μM) function as legal filters?
Claim 1 adds a quantitative requirement tied to CaR modulation measured in bovine parathyroid cells:
- calcimimetic must have EC50 ≤ 5 μM for increasing (Ca2+)i
- calcilytic must have IC50 ≤ 5 μM for decreasing (Ca2+)i
Practical scope consequences
- This is the sharpest boundary in your excerpt between encompassed and potentially non-encompassed compounds.
- It also implies an infringement analysis will look at:
- Whether the accused compound is correctly categorized as calcimimetic or calcilytic
- Whether measured activity meets the stated threshold
- Whether the same or comparable assay conditions apply (fura-2 loaded bovine parathyroid cells, cytosolic Ca2+ cell assay).
Narrowing by tighter thresholds
Dependent claims 27-30 tighten the EC50 for calcimimetics:
- EC50 ≤ 1 μM
- EC50 ≤ 100 nM
- EC50 ≤ 10 nM
- EC50 ≤ 1 nM
These narrowing layers create a ladder:
- A weaker potency calcimimetic might still fit Claim 1 but fail the narrower dependent claims.
- A high-potency calcimimetic can fit multiple layers simultaneously.
What chemical genus and formulas are protected in US 6,031,003?
The claims you provided define large parameterized genera. Two main formula frameworks appear:
Formula framework A (the broad X/Ar/R/Y/Z/n/m genus)
Claims 4, 31, 99, 100 and related dependents use:
- X: allowed substituents including H, methyl, methoxy, halogens, CF3, CHF2, CH2F, CF3O, CF3CH2O, thio, OH, CONH2, CN, NO2, ethyl/propyl-like groups, t-butyl, acetoxy; plus “methylene dioxy” when two X together
- Ar: “hydrophobic entity” includes aromatic/cycloaliphatic ring systems (various polyaromatic and heteroaromatic options)
- R: multiple alkyl or ring substituent categories including piperid(in)yl
- Y: CH or nitrogen
- Z: includes O/N/S and additional options via structural placeholders
- salts permitted
Formula framework B (the alk/R1/R2/R3 genus typical of the disclosed NPS series)
Claims 6-12, 40-63, 104-118 use:
- alk: 0-6 carbon straight or branched alkylene
- R1: lower alkyl (1-3 carbons) or lower haloalkyl (1-3 carbons with 1-7 halogens)
- R2 and R3: monocyclic/bicyclic carbocyclic aryl or cycloalkyl rings, 5-7 membered, optionally substituted
This framework is more directly tied to the enumerated NPS analogs and stereochemical R-enantiomers.
Which specific compounds are explicitly listed (NPS series) and how does that affect enforcement?
Your excerpt contains a clear list of compound examples in dependent claims.
Enumerated calcimimetic compounds (Claim 64)
Compounds listed:
- NPS 467 (N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine)
- NPS 568 (N-(3-(2-chlorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine)
- 4M (N-(3-(2-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine)
- 4N/40 (N-(3-(3-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine)
- 4P/4Q (N-(3-(4-fluorophenyl)propyl)-1-(3-methoxyphenyl)ethylamine)
- 4V and 4W (tri(fluoromethyl) phenyl propyl derivatives)
- 6X/6Y (chlorophenyl analog variants)
Stereochemical narrowing (Claims 65, 66, 67, 68, 70, 74, 76, 78)
Several dependents specify “R-” enantiomers, including:
- NPS R-568
- NPS R-467
- R-4M
- R-4V
- R-4W
- R-6X (and related “R-” forms)
Additional enumerated examples (Claim 87; Claim 119-130 placeholders)
Claim 87 again lists a set:
- NPS R-568, NPS R-467
- R-4M, 4N (R-)
- 4P (R-)
- R-4V, R-4W
- 6X (R-)
This pattern matters for litigation strategy:
- A manufacturer selling a compound outside the literal “NPS” mapping may still infringe via the genus claims.
- A manufacturer can sometimes avoid genus claims by designing around defined structural parameters, but the excerpt’s parameterized genera are extremely broad, so actual non-infringement would likely rely on failing either:
- the formula parameters, or
- the defined assay thresholds tied to calcimimetic/calcilytic behavior.
What is the “not protamine” limitation doing in Claim 1?
Claim 1 states: “wherein said compound is not protamine.”
Scope impact
- It is a narrow exclusion that likely targets formulations or contexts where protamine is used as a comparator.
- It does not appear to limit the method to the NPS series only.
- It is unlikely to be a major design-around for a small-molecule CaR modulator.
What patents are likely in the same landscape as US 6,031,003?
From the claim themes alone, the landscape around this type of CaR modulator estate typically clusters into:
- Core CaR modulation chemical matter claims in the same family or later continuations (not shown in your excerpt because you provided only method claims).
- Method-of-use patents for:
- hyperparathyroidism and related disorders
- Paget’s disease
- osteoporosis
- calcimimetic endpoints (PTH down, ionized Ca2+ down, bone resorption inhibition)
- calcilytic endpoints (PTH up, bone formation enhancement)
- Assay and potency-based limitations (EC50/IC50 in bovine parathyroid cells)
- Stereochemistry/enantiomer-specific patents (R-enantiomer)
- Formulation or dosage patents (not present in your excerpt, but common in the estate)
- Manufacturing process patents (also common, but not in your excerpt)
A verified patent landscape with specific US numbers cannot be produced from your excerpt alone.
How does US 6,031,003 compare with typical CaR-modulator estates (calcimimetic vs calcilytic)?
Calcimimetic half
- Built around increasing intracellular Ca2+ in vitro
- Legal strength comes from:
- explicit EC50 thresholds in Claim 1
- further dependent claims at EC50 ≤ 1 μM down to ≤ 1 nM
- disease endpoints tied to PTH reduction and calcium reduction and bone resorption inhibition
Calcilytic half
- Built around decreasing intracellular Ca2+ in vitro
- Legal strength comes from:
- IC50 threshold language in Claim 1 (≤ 5 μM)
- calcilytic method claims for PTH secretion increase and enhancing bone formation
- Depending on the compound, calcilytics may have fewer direct clinical indications, but the claims you provided directly cover Paget’s disease and osteoporosis.
What generic or biosimilar risk exists for a method patent like this?
This patent is a method-of-treatment patent, so risk for generics depends on:
- Whether the generic compound is within the claimed chemical genus (claims 4/31/99/100/40/104, etc.)
- Whether the generic compound meets the claimed in vitro potency thresholds (Claim 1 and dependent potency ladder)
- Whether the generic is used for a claimed indication and endpoint (PTH down, calcitonin secretion, bone resorption inhibition, hyperparathyroidism/Paget’s/osteoporosis)
A biosimilar is not implicated because this is a small-molecule CaR modulator method patent.
Key Takeaways
- US 6,031,003 is a CaR modulation method-of-treatment patent with coverage driven by:
- bovine parathyroid fura-2 Ca2+ assay potency thresholds (Claim 1, calcimimetic EC50 ≤ 5 μM; calcilytic IC50 ≤ 5 μM)
- large chemical genus definitions (multiple parameterized formulas across Claims 4/31/40/82/83/89/99/104)
- dependent narrowing to hyperparathyroidism, Paget’s disease, and osteoporosis, plus functional endpoints (PTH and ionized calcium changes; bone resorption inhibition; calcitonin secretion stimulation)
- explicit examples and R-enantiomer restrictions in dependent claims tied to the NPS series
- Enforcement leverage is highest where a candidate compound is:
- within the genus parameters, and
- meets the in vitro potency ladder (down to EC50 ≤ 1 nM for calcimimetics), and
- is used in a claimed indication with the stated pharmacodynamic direction.
FAQs
1) Does US 6,031,003 cover both calcimimetic and calcilytic compounds?
Yes. Claim 1 expressly covers both categories with assay-specific quantitative requirements.
2) What is the most important limitation for calcimimetics in Claim 1?
The compound must be a calcimimetic that increases intracellular Ca2+ in bovine parathyroid cells with EC50 ≤ 5 μM (fura-2 cytosolic Ca2+ assay).
3) Are hyperparathyroidism, Paget’s disease, and osteoporosis all covered?
Yes. The claim set includes dependent claims that tie the method to each of these disorders.
4) Do the dependent claims include tighter potency thresholds?
Yes. Dependent claims reduce the calcimimetic EC50 limit stepwise to ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, and ≤ 1 nM.
5) Is the patent limited to specific branded compounds only?
No. The patent includes broad formula-based genus claims, with specific NPS examples and R-enantiomers recited in dependent claims.
