US Patent 6,635,278: Scope, Claim Map, and US Landscape for the Claimed Alkaline-Excipient Formulation of 9-[2-[bis(pivaloyloxy)methyl]phosphonomethoxyl]ethyl]adenine

What is the core inventive scope of US 6,635,278?

US 6,635,278 claims a solid oral composition built around:

API: 9-[2-[bis(pivaloyloxy)methyl]phosphonomethoxyl]ethyl]adenine
(also appearing in dependent claim typography variants, including “9-[2-[[bis[(pivaloyloxy)methyl]phosphono]methoxy]ethyl]adenine”)
Alkaline excipient: an alkaline carbonate or alkaline hydroxide
Physicochemical constraints (claim 1):
- pKa of the conjugated acid of the excipient: at least about 4.0
- Ksp window: about 1×10−3 to about 1×10−15
Solid-state moisture spec:
- Loss on drying (LOD) at 75°C bounded in dependent claims
Dose/product forms:
- unit dose for tablet or capsule
- granules (dependent claim)

The claims are structured to capture both: 1) the API + alkaline excipient physicochemical relationship, and
2) the manufactured solid-state quality and formulation composition ranges likely aligned to commercial tablet manufacturing (granulation, compression and excipient selection).

How do the independent claim terms narrow the claim space? (Claim 1)

Claim 1 limitations (method-of-use is not required; it is composition scope)

Claim 1 recites a composition consisting essentially of:

API identity (fixed)
“An alkaline excipient” that must simultaneously satisfy:
- pKa (of conjugated acid): ≥ 4.0
- Ksp: ~1×10−3 to ~1×10−15
“Consisting essentially of” language:
- permits additional excipients but bars additional components that materially change the basic and novel characteristics (here, the alkaline excipient’s physicochemical buffering/ion association behavior and the resultant solid-state properties implied by LOD limits in dependents)

pKa and Ksp as functional gating criteria

The inclusion of pKa and Ksp operates as a filtration mechanism that excludes alkaline materials lacking the specified dissociation/solubility behavior. Practically, this targets excipients where the conjugated acid has pKa ≥ 4 and where the alkaline salt has Ksp in the claimed band.

What formulations are explicitly covered through dependent claims?

Which alkaline excipients are enumerated (claims 3–7, 9–12)?

The claim set specifies carbonate and hydroxide subsets.

Carbonates (claims 3–4, and also reused in later tablet excipient list):

calcium carbonate
magnesium carbonate
zinc carbonate
manganese carbonate
aluminum carbonate
ferrous carbonate
cobalt carbonate

Hydroxides (claims 2–3 and 5, 10–11):

magnesium hydroxide
calcium hydroxide
aluminum hydroxide
iron hydroxide

LOD at 75°C: moisture control as an enforceable parameter

Claim 2: LOD 75°C ≤ 5%
Claim 6: LOD 75°C ≤ 2%
Claim 7: LOD 75°C ≤ 1.5%

These are tight process-linked boundaries. They also create a common infringement posture: if a generic developer uses a similar alkaline excipient but produces higher moisture solids, they may exit dependents while still potentially staying within claim 1.

Alkaline excipient percent ranges (claims 8, 12, 16)

Claim 8: alkaline excipient ~1–20%
Claim 12: alkaline excipient ~2–6%
Claim 16: tablet/capsule alkaline excipient ~2–6% w/w

This narrows the most commercially plausible formulations (typical tablets land in the low single-digit w/w excipient fraction for functional excipients).

What dosage forms and quantitative tablet compositions are claimed?

Unit dose and tablet/capsule content ranges (claims 13–19)

Claim 13: composition is a unit dose
Claim 14: unit dose tablet has API ~1.0–300 mg
Claim 15: tablet/capsule has API ~5–30% w/w
Claim 16: alkaline excipient ~2–6% w/w

Additional tablet excipients tied to common oral solid manufacturing (claim 18)

lactose monohydrate / anhydrous lactose / microcrystalline cellulose in ~35–80% w/w

Carnitine co-formulation appears in claim 19

Claim 19 includes a more complex combination:

API: ~4–20% w/w
L-carnitine salts: L-carnitine-L-tartrate, L-carnitine-L-fumarate, or microencapsulated L-carnitine in ~20–50% w/w
alkaline excipient in ~1–6% w/w
Other excipient classes are not fully enumerated in claim 19, but the dependent claims 20–24 provide concrete example blends.

What are the specific example-like compositions claimed (claims 20–24)?

These claims function like composition exemplars with hard numeric ranges, tightening enforceability if a competitor’s formulation matches.

Claim 20 (example blend)

API: ~10 mg
alkaline carbonate: ~1–5 mg (magnesium carbonate or calcium carbonate)
croscarmellose sodium: ~4–8 mg
pregelatinized starch: ~5 mg
lactose: ~40–65 mg
microcrystalline cellulose: ~15–35 mg
talc: 0–6 mg
magnesium stearate: 0.5–2 mg

Claim 21

API: ~30 mg
magnesium carbonate: ~410 mg (notably high for a “~30 mg API” tablet; this appears to be a transcription-level anomaly in the excerpt you provided, but the numeric constraint is still a claim term as written)
lactose monohydrate or anhydrous lactose: ~61.5–75.25 mg
microcrystalline cellulose: ~22.5 mg
pregelatinized starch: ~7.5 mg
croscarmellose sodium: ~9 mg
talc: 0–9 mg
magnesium stearate: 0.75–1.5 mg

Claim 22

API: ~60 mg
magnesium carbonate: ~12 mg
lactose: ~73 mg
microcrystalline cellulose: ~30 mg
pregelatinized starch: ~10 mg
croscarmellose sodium: ~12 mg
silicon dioxide: ~1 mg
magnesium stearate: ~2 mg

Claim 23

API: ~120 mg
magnesium carbonate: ~12–24 mg
lactose: ~124–162 mg
microcrystalline cellulose: ~60 mg
pregelatinized starch: ~20 mg
croscarmellose sodium: ~24 mg
talc: 0–24 mg
magnesium stearate: ~2–4 mg

Claim 24 (high-level w/w composition)

API: ~4–8% w/w
magnesium carbonate: ~16% w/w
L-carnitine-L-tartrate: ~24–51% w/w
microcrystalline cellulose: ~20–36% w/w
pregelatinized starch: ~5% w/w
croscarmellose sodium: ~4% w/w
plus one of:
- sodium stearyl fumarate ~1% w/w, or
- talc ~2% w/w and type I hydrogenated vegetable oil ~1% w/w

Claim 24 drives a very specific formulation architecture likely tied to a particular product size.

What additional process/form scope exists beyond tablet blending?

Claim 25: composition is dried granules with LOD ≤ 2.0%
Claim 26: composition can include an additional excipient selected from:
- binder, disintegrant, diluent, lubricant, glidant, coloring agent, flavoring agent

Claim 26 reinforces that the claim set is not limited to the specific filler list in claim 20–24; it allows broad excipient categories as long as the alkaline excipient criteria and LOD windows are met (in dependents).

Where does the claim “consisting essentially of” sit relative to design-around strategies?

Within this claim set, the most relevant design-around logic is not changing the API identity but shifting one of the gate criteria:

Exit alkaline excipient category
- move away from carbonate/hydroxide list or use an alkaline species not meeting the pKa/Ksp windows
Exit pKa/Ksp gate
- even if the excipient is a carbonate/hydroxide, selecting a material outside the Ksp/pKa window avoids claim 1 and thus all dependents that depend from claim 1
Exit LOD windows
- keep the same alkaline excipient but manufacture solids outside LOD ≤ 5%, ≤ 2%, or ≤ 1.5% (depending on which dependent claim is targeted)
Exit alkaline excipient % windows
- particularly 1–20% (claim 8) and 2–6% (claim 12, 16)

The claim drafting also makes tablet size flexibility available: API ranges extend from 1 mg to 300 mg and w/w 5–30%, so competitors must manage numeric overlap at the product level.

How should investors and R&D teams read the landscape risk from this claim architecture?

Even without seeing the full specification text in your prompt, the claim suite itself indicates that infringement risk concentrates around:

using the exact API
using a carbonate/hydroxide alkaline excipient that matches pKa ≥ 4 and Ksp 10−3 to 10−15
achieving low moisture at 75°C and aligning with LOD thresholds
matching API loading and excipient fraction if the competitor product targets similar dosing strength or the same co-formulation with L-carnitine salts

This is a classic “formulation gate” patent where the API identity is fixed and the exclusivity leans on:

physicochemical excipient properties
manufactured solid-state quality
quantitative tablet composition ranges

US patent landscape mapping: what can be inferred from the claim set itself?

Your prompt includes only the claims, not the family tree, assignee, priority, prosecution history, or citing/cited relationships. Under that constraint, the landscape can be mapped only at the level of claim-defined competitive zones, not at the level of other numbered US patents.

Competitive infringement zones created by numeric constraints

API + alkaline excipient combinations meeting pKa and Ksp:
- any carbonate/hydroxide within the enumerated lists that fits Ksp/pKa
Low LOD manufacturing
- LOD ≤ 5%, ≤ 2%, ≤ 1.5% at 75°C
Alkaline excipient loading
- 1–20% or 2–6% w/w
Tablet strength and w/w
- API 5–30% w/w
Co-formulation with L-carnitine salts
- ~20–50% w/w L-carnitine-L-tartrate/L-fumarate or microencapsulated L-carnitine
Example-like full formulations
- compositions in claims 20–24 create “high-likelihood overlap” if competitors adopt similar blending recipes

Practical assessment posture for freedom-to-operate

For a generic or reformulation program, the dominant question is whether the company can:

choose an alkaline excipient outside Ksp/pKa gate,
or tolerate a higher LOD and accept product stability differences,
or adjust alkaline excipient percentage outside the claimed windows while still meeting dissolution and stability.

Those are the claim-critical levers.

Key Takeaways

US 6,635,278 is a formulation patent centered on 9-[2-[bis(pivaloyloxy)methyl]phosphonomethoxyl]ethyl]adenine plus an alkaline carbonate/hydroxide excipient.
Claim 1 is gated by two physicochemical parameters of the excipient: pKa(conjugated acid) ≥ 4.0 and Ksp ~1×10−3 to ~1×10−15.
Dependent claims add enforceable product attributes: LOD at 75°C capped at 5%, 2%, and 1.5%, and alkaline excipient loading capped at 2–6% in the tablet/capsule subset.
The claim set explicitly covers carbonate/hydroxide members (Ca/Mg Zn Mn Al Fe/Co carbonates; Mg/Ca/Al/Fe hydroxides) and provides tight quantitative example blends (claims 20–24).
Co-formulation with L-carnitine salts is explicitly claimed in dependent claim structure (notably claim 19 and claim 24), raising the risk for combination-product developers.

FAQs

Does US 6,635,278 cover methods of treatment or only compositions?
It is drafted to cover a composition (including unit dose tablets/capsules and dried granules), not a method-of-treatment.
Which excipients are explicitly allowed for the alkaline component?
The claims list alkaline carbonates (including calcium, magnesium, zinc, manganese, aluminum, ferrous, cobalt carbonates) and alkaline hydroxides (including magnesium, calcium, aluminum, iron hydroxides).
What are the key physicochemical gates in the broadest claim?
The alkaline excipient must have pKa (conjugated acid) ≥ 4.0 and Ksp between about 1×10−3 and about 1×10−15.
What moisture limit is used as a dependent claim hook?
LOD at 75°C: ≤ 5% (claim 2), with tighter limits at ≤ 2% (claim 6) and ≤ 1.5% (claim 7).
Do the claims include detailed tablet recipes or only ranges?
Both: the claims include general range claims and multiple numeric composition claims (claims 20–24) with specific mg and w/w boundaries.

References

No external sources were provided in the prompt, and the request requires analysis of US 6,635,278 with citations.

Title:	Pharmaceutical formulations
Abstract:	The invention provides compositions comprising the nucleotide analog 9-[2-[[bis[(pivaloyloxy)methyl]phosphono]methoxy]ethyl]adenine and an alkaline excipient with or without L-carnitine-L-tartrate. The compositions are more stable those previously described. The invention also provides methods to make the compositions and their intermediates.
Inventor(s):	Terrence C. Dahl, Lung-Chi J. Yuan
Assignee:	HENSLEY MAX D , Gilead Sciences Inc
Application Number:	US09/211,613
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Dosage form;
Patent landscape, scope, and claims:	US Patent 6,635,278: Scope, Claim Map, and US Landscape for the Claimed Alkaline-Excipient Formulation of 9-[2-[bis(pivaloyloxy)methyl]phosphonomethoxyl]ethyl]adenine What is the core inventive scope of US 6,635,278? US 6,635,278 claims a solid oral composition built around: API: 9-[2-[bis(pivaloyloxy)methyl]phosphonomethoxyl]ethyl]adenine (also appearing in dependent claim typography variants, including “9-[2-[[bis[(pivaloyloxy)methyl]phosphono]methoxy]ethyl]adenine”) Alkaline excipient: an alkaline carbonate or alkaline hydroxide Physicochemical constraints (claim 1): pKa of the conjugated acid of the excipient: at least about 4.0 Ksp window: about 1×10−3 to about 1×10−15 Solid-state moisture spec: Loss on drying (LOD) at 75°C bounded in dependent claims Dose/product forms: unit dose for tablet or capsule granules (dependent claim) The claims are structured to capture both: 1) the API + alkaline excipient physicochemical relationship, and 2) the manufactured solid-state quality and formulation composition ranges likely aligned to commercial tablet manufacturing (granulation, compression and excipient selection). How do the independent claim terms narrow the claim space? (Claim 1) Claim 1 limitations (method-of-use is not required; it is composition scope) Claim 1 recites a composition consisting essentially of: API identity (fixed) “An alkaline excipient” that must simultaneously satisfy: pKa (of conjugated acid): ≥ 4.0 Ksp: ~1×10−3 to ~1×10−15 “Consisting essentially of” language: permits additional excipients but bars additional components that materially change the basic and novel characteristics (here, the alkaline excipient’s physicochemical buffering/ion association behavior and the resultant solid-state properties implied by LOD limits in dependents) pKa and Ksp as functional gating criteria The inclusion of pKa and Ksp operates as a filtration mechanism that excludes alkaline materials lacking the specified dissociation/solubility behavior. Practically, this targets excipients where the conjugated acid has pKa ≥ 4 and where the alkaline salt has Ksp in the claimed band. What formulations are explicitly covered through dependent claims? Which alkaline excipients are enumerated (claims 3–7, 9–12)? The claim set specifies carbonate and hydroxide subsets. Carbonates (claims 3–4, and also reused in later tablet excipient list): calcium carbonate magnesium carbonate zinc carbonate manganese carbonate aluminum carbonate ferrous carbonate cobalt carbonate Hydroxides (claims 2–3 and 5, 10–11): magnesium hydroxide calcium hydroxide aluminum hydroxide iron hydroxide LOD at 75°C: moisture control as an enforceable parameter Claim 2: LOD 75°C ≤ 5% Claim 6: LOD 75°C ≤ 2% Claim 7: LOD 75°C ≤ 1.5% These are tight process-linked boundaries. They also create a common infringement posture: if a generic developer uses a similar alkaline excipient but produces higher moisture solids, they may exit dependents while still potentially staying within claim 1. Alkaline excipient percent ranges (claims 8, 12, 16) Claim 8: alkaline excipient ~1–20% Claim 12: alkaline excipient ~2–6% Claim 16: tablet/capsule alkaline excipient ~2–6% w/w This narrows the most commercially plausible formulations (typical tablets land in the low single-digit w/w excipient fraction for functional excipients). What dosage forms and quantitative tablet compositions are claimed? Unit dose and tablet/capsule content ranges (claims 13–19) Claim 13: composition is a unit dose Claim 14: unit dose tablet has API ~1.0–300 mg Claim 15: tablet/capsule has API ~5–30% w/w Claim 16: alkaline excipient ~2–6% w/w Additional tablet excipients tied to common oral solid manufacturing (claim 18) lactose monohydrate / anhydrous lactose / microcrystalline cellulose in ~35–80% w/w Carnitine co-formulation appears in claim 19 Claim 19 includes a more complex combination: API: ~4–20% w/w L-carnitine salts: L-carnitine-L-tartrate, L-carnitine-L-fumarate, or microencapsulated L-carnitine in ~20–50% w/w alkaline excipient in ~1–6% w/w Other excipient classes are not fully enumerated in claim 19, but the dependent claims 20–24 provide concrete example blends. What are the specific example-like compositions claimed (claims 20–24)? These claims function like composition exemplars with hard numeric ranges, tightening enforceability if a competitor’s formulation matches. Claim 20 (example blend) API: ~10 mg alkaline carbonate: ~1–5 mg (magnesium carbonate or calcium carbonate) croscarmellose sodium: ~4–8 mg pregelatinized starch: ~5 mg lactose: ~40–65 mg microcrystalline cellulose: ~15–35 mg talc: 0–6 mg magnesium stearate: 0.5–2 mg Claim 21 API: ~30 mg magnesium carbonate: ~410 mg (notably high for a “~30 mg API” tablet; this appears to be a transcription-level anomaly in the excerpt you provided, but the numeric constraint is still a claim term as written) lactose monohydrate or anhydrous lactose: ~61.5–75.25 mg microcrystalline cellulose: ~22.5 mg pregelatinized starch: ~7.5 mg croscarmellose sodium: ~9 mg talc: 0–9 mg magnesium stearate: 0.75–1.5 mg Claim 22 API: ~60 mg magnesium carbonate: ~12 mg lactose: ~73 mg microcrystalline cellulose: ~30 mg pregelatinized starch: ~10 mg croscarmellose sodium: ~12 mg silicon dioxide: ~1 mg magnesium stearate: ~2 mg Claim 23 API: ~120 mg magnesium carbonate: ~12–24 mg lactose: ~124–162 mg microcrystalline cellulose: ~60 mg pregelatinized starch: ~20 mg croscarmellose sodium: ~24 mg talc: 0–24 mg magnesium stearate: ~2–4 mg Claim 24 (high-level w/w composition) API: ~4–8% w/w magnesium carbonate: ~16% w/w L-carnitine-L-tartrate: ~24–51% w/w microcrystalline cellulose: ~20–36% w/w pregelatinized starch: ~5% w/w croscarmellose sodium: ~4% w/w plus one of: sodium stearyl fumarate ~1% w/w, or talc ~2% w/w and type I hydrogenated vegetable oil ~1% w/w Claim 24 drives a very specific formulation architecture likely tied to a particular product size. What additional process/form scope exists beyond tablet blending? Claim 25: composition is dried granules with LOD ≤ 2.0% Claim 26: composition can include an additional excipient selected from: binder, disintegrant, diluent, lubricant, glidant, coloring agent, flavoring agent Claim 26 reinforces that the claim set is not limited to the specific filler list in claim 20–24; it allows broad excipient categories as long as the alkaline excipient criteria and LOD windows are met (in dependents). Where does the claim “consisting essentially of” sit relative to design-around strategies? Within this claim set, the most relevant design-around logic is not changing the API identity but shifting one of the gate criteria: Exit alkaline excipient category move away from carbonate/hydroxide list or use an alkaline species not meeting the pKa/Ksp windows Exit pKa/Ksp gate even if the excipient is a carbonate/hydroxide, selecting a material outside the Ksp/pKa window avoids claim 1 and thus all dependents that depend from claim 1 Exit LOD windows keep the same alkaline excipient but manufacture solids outside LOD ≤ 5%, ≤ 2%, or ≤ 1.5% (depending on which dependent claim is targeted) Exit alkaline excipient % windows particularly 1–20% (claim 8) and 2–6% (claim 12, 16) The claim drafting also makes tablet size flexibility available: API ranges extend from 1 mg to 300 mg and w/w 5–30%, so competitors must manage numeric overlap at the product level. How should investors and R&D teams read the landscape risk from this claim architecture? Even without seeing the full specification text in your prompt, the claim suite itself indicates that infringement risk concentrates around: using the exact API using a carbonate/hydroxide alkaline excipient that matches pKa ≥ 4 and Ksp 10−3 to 10−15 achieving low moisture at 75°C and aligning with LOD thresholds matching API loading and excipient fraction if the competitor product targets similar dosing strength or the same co-formulation with L-carnitine salts This is a classic “formulation gate” patent where the API identity is fixed and the exclusivity leans on: physicochemical excipient properties manufactured solid-state quality quantitative tablet composition ranges US patent landscape mapping: what can be inferred from the claim set itself? Your prompt includes only the claims, not the family tree, assignee, priority, prosecution history, or citing/cited relationships. Under that constraint, the landscape can be mapped only at the level of claim-defined competitive zones, not at the level of other numbered US patents. Competitive infringement zones created by numeric constraints API + alkaline excipient combinations meeting pKa and Ksp: any carbonate/hydroxide within the enumerated lists that fits Ksp/pKa Low LOD manufacturing LOD ≤ 5%, ≤ 2%, ≤ 1.5% at 75°C Alkaline excipient loading 1–20% or 2–6% w/w Tablet strength and w/w API 5–30% w/w Co-formulation with L-carnitine salts ~20–50% w/w L-carnitine-L-tartrate/L-fumarate or microencapsulated L-carnitine Example-like full formulations compositions in claims 20–24 create “high-likelihood overlap” if competitors adopt similar blending recipes Practical assessment posture for freedom-to-operate For a generic or reformulation program, the dominant question is whether the company can: choose an alkaline excipient outside Ksp/pKa gate, or tolerate a higher LOD and accept product stability differences, or adjust alkaline excipient percentage outside the claimed windows while still meeting dissolution and stability. Those are the claim-critical levers. Key Takeaways US 6,635,278 is a formulation patent centered on 9-[2-[bis(pivaloyloxy)methyl]phosphonomethoxyl]ethyl]adenine plus an alkaline carbonate/hydroxide excipient. Claim 1 is gated by two physicochemical parameters of the excipient: pKa(conjugated acid) ≥ 4.0 and Ksp ~1×10−3 to ~1×10−15. Dependent claims add enforceable product attributes: LOD at 75°C capped at 5%, 2%, and 1.5%, and alkaline excipient loading capped at 2–6% in the tablet/capsule subset. The claim set explicitly covers carbonate/hydroxide members (Ca/Mg Zn Mn Al Fe/Co carbonates; Mg/Ca/Al/Fe hydroxides) and provides tight quantitative example blends (claims 20–24). Co-formulation with L-carnitine salts is explicitly claimed in dependent claim structure (notably claim 19 and claim 24), raising the risk for combination-product developers. FAQs Does US 6,635,278 cover methods of treatment or only compositions? It is drafted to cover a composition (including unit dose tablets/capsules and dried granules), not a method-of-treatment. Which excipients are explicitly allowed for the alkaline component? The claims list alkaline carbonates (including calcium, magnesium, zinc, manganese, aluminum, ferrous, cobalt carbonates) and alkaline hydroxides (including magnesium, calcium, aluminum, iron hydroxides). What are the key physicochemical gates in the broadest claim? The alkaline excipient must have pKa (conjugated acid) ≥ 4.0 and Ksp between about 1×10−3 and about 1×10−15. What moisture limit is used as a dependent claim hook? LOD at 75°C: ≤ 5% (claim 2), with tighter limits at ≤ 2% (claim 6) and ≤ 1.5% (claim 7). Do the claims include detailed tablet recipes or only ranges? Both: the claims include general range claims and multiple numeric composition claims (claims 20–24) with specific mg and w/w boundaries. References No external sources were provided in the prompt, and the request requires analysis of US 6,635,278 with citations. More… ↓ ⤷ Start Trial

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Details for Patent: 6,635,278

Summary for Patent: 6,635,278