US Patent 4,680,399 (Podophyllotoxin Purification): Claim Scope, Scope Limits, and Landscape

US Patent 4,680,399 claims a crystallization/complexation-driven purification route for podophyllotoxin (PPTX), using solid complexes between PPTX and an aromatic or heteroaromatic compound (explicitly excluding benzene as a complexing partner in the core improvement). The claims also cover a two-step purification architecture that can include (i) complex formation and separation and (ii) impurity removal from a PPTX-containing solution by contacting with an aqueous base in the presence of a water-immiscible organic solvent.

What do the independent claims actually cover?

Claim 1: What is the “improvement” the patent is anchored to?

Claim 1 is the central process claim. It requires all of the following in order:

Start with impure podophyllotoxin as a starting material.
Form a solution of the starting material.
Form a solid complex of:
- podophyllotoxin, and
- an aromatic or heteroaromatic compound other than benzene.
Separate the solid complex from the solution.

The “improvement” language makes the complex formation/separation step the key patentable differentiator over baseline dissolution and purification approaches.

Core scope elements (Claim 1):

Target: purified podophyllotoxin
Trigger: impure podophyllotoxin-containing starting material
Operating sequence: solution → solid complex formation → separation
Complex partner: aromatic or heteroaromatic compound ≠ benzene
Complex is solid and is separated from a solution

Claim 7: When does the claim move from a single pass to a multi-step regeneration cycle?

Claim 7 is a separate, more procedural and multi-step claim for purifying PPTX from a solution thereof, with a regeneration-like loop:

Form a solid complex of PPTX + aromatic/heteroaromatic compound + optionally water.
Separate the complex from solution.
Form a solution comprising PPTX from the separated complex.
Form a solid complex of PPTX from that solution + an aromatic/heteroaromatic compound + optionally water.
Separate the solid complex from the solution.
Isolate podophyllotoxin in free form from the separated complex.
Critical limitation: aromatic/heteroaromatic compounds used in steps (a) and (d) are different.

This claim explicitly enforces a two-stage complexing strategy where the complexing agent differs between stages, and it requires final conversion to free-form PPTX.

Core scope elements (Claim 7):

Solids-first, solids-second purification cycle
Includes conversion from complex back to PPTX solution (steps (b) and (c))
Includes a second complex formation cycle (steps (d) and (e))
Final isolation in free form (step (f))
Enforces different aromatic/heteroaromatic compounds across two complexation stages

Dependent claims: what narrows or expands real-world infringement risk

What additional limitations do Claims 2 to 6 impose?

Claim 2: Solid complex comprises PPTX + aromatic/heteroaromatic compound + water.
- Narrows scope to complexes that are explicitly water-including.
Claim 3: Solvent for the initial solution comprises ethanol.
- Narrows to processes using ethanol as (at least part of) the solvent for dissolution of the starting material.
Claim 4: Complex is formed by adding the aromatic/heteroaromatic compound and water to the solution of starting material.
- Narrows the operational method for complex formation to a dosing approach in the presence of water.
Claim 5: Dissolve the separated complex in a solvent to form a solution, then repeat solid complex formation and separation.
- Expands the claim concept to iterative cycles, not a single complex formation event.
Claim 6: Different aromatic/heteroaromatic compounds are used in at least two successive stages.
- Narrows to multi-stage purification with different complexing agents across successive stages.

Practical read: Claims 1 and 7 cover the architecture; Claims 2-6 specify how the complex is built (water content, solvents), how it is regenerated (dissolution of separated complex), and how the complexing agents vary between stages.

What does Claim 8 do to the “aromatic/heteroaromatic” bucket?

Claim 8 provides a specific list of selected aromatic/heteroaromatic compounds:

toluene
o-xylene, m-xylene, p-xylene
anisole
chlorobenzene
pyridine
phenol
nitrobenzene
quinoline
isoquinoline
furfuryl alcohol
naphthalene

This claim does not eliminate other aromatic/heteroaromatic compounds from Claim 1’s scope, but it creates a strong indicator of what the patentee considered workable “complexing compounds” and could influence claim construction for “selected from” limitations where Claim 8 is asserted.

How do Claims 9 to 11 broaden the purification method space beyond complexation?

Claims 9 to 11 add a separate purification mode centered on aqueous base contact to remove impurities from a solution.

Claim 9: Further purification step by contacting a solution of PPTX in a water-immiscible solvent with an aqueous base.
Claim 10: More directly, removing impurities from a solution comprising impure podophyllotoxin and a water-immiscible organic solvent by contacting with an aqueous base.
Claim 11: Base is an alkali metal hydroxide.

Practical read: Even if a competitor avoids the aromatic solid complex route, these dependent claims create potential coverage for the impurity-removal step if their process uses an aqueous base contact in a biphasic system with a water-immiscible organic solvent.

Claim coverage maps: “What’s in” vs “what’s out”

What is clearly “in scope”

Any process that includes all of the following is squarely within Claim 1 territory:

Dissolve impure PPTX starting material into a solution
Add an aromatic/heteroaromatic compound other than benzene
Form a solid complex of PPTX and that compound (optionally water is separately claimed, but the core Claim 1 does not require water)
Separate the complex solids from solution

For Claim 7, add these extra “in scope” requirements:

Build a PPTX solid complex from a PPTX-containing solution using one aromatic/heteroaromatic compound
Recover PPTX from the separated complex (forming a solution)
Re-complex using a different aromatic/heteroaromatic compound
Isolate PPTX in free form at the end
Ensure aromatic/heteroaromatic compounds used across stage (a) and (d) are different

For Claims 9-11:

Use an aqueous base contact on a PPTX-containing solution in a water-immiscible organic solvent
Where asserted against Claim 11, the base must be alkali metal hydroxide

What is clearly “out of scope”

If the complex partner is benzene, Claim 1’s “other than benzene” limitation blocks literal coverage for the core complex step.
If no solid complex is formed (for example, only liquid-phase extraction or adsorption without forming a solid complex), Claim 1 and Claim 7 lose their key element.
If the process does not include solid-liquid separation of the complex from the mother liquor (solution), Claim 1’s final required act is missing.

Patent landscape framing (what to test against when assessing freedom-to-operate)

How to position 4,680,399 in the purification technology space

US 4,680,399 sits in the intersection of:

solid-complex precipitation / crystallization methods for PPTX purification, and
base treatment of PPTX-containing solutions to remove impurities in a biphasic (water-immiscible solvent/aqueous base) setting.

It is not a broad “any PPTX purification method” patent. It is structurally focused on:

complex formation using aromatic/heteroaromatic agents (not benzene),
recovery of PPTX by dissolving/looping through complex formation, and
optional aqueous base impurity removal.

Key design-arounds implied by the claim language

These are the claim-sensitive variables a competitor can manipulate:

Complexing agent selection
- Avoid benzene. Use a different aromatic/heteroaromatic could still fall under Claim 1 if the agent forms a PPTX solid complex.
Whether a solid complex is actually formed
- If the process does not produce a separable solid complex with PPTX and the aromatic/heteroaromatic compound, the core claims are harder to map.
Process sequence and regeneration
- Claim 7 requires a two-stage complexing loop with different aromatic agents and isolation of free-form PPTX.
Role of water
- Claim 2 requires water in the complex. A process using no water in the complexation step may avoid Claim 2, but not necessarily Claim 1 or Claim 7.
Use of aqueous base and identity of base
- Claim 11 is limited to alkali metal hydroxides. Using a different aqueous base (if outside “alkali metal hydroxide”) changes mapping to Claim 11, but Claims 9 and 10 only require “aqueous base.”

Litigation and prosecution posture: what the claims suggest about enforcement leverage

The claim set indicates two distinct enforcement levers:

Primary lever: the solid complex route (Claims 1-8), where the claim terms are mechanistic and categorical (solution → solid complex → separation; optional water; specified aromatic list).
Secondary lever: aqueous base impurity removal in biphasic systems (Claims 9-11), which can be asserted even if a process differs on the complexation step.

From a landscape standpoint, the strongest relevance for FTO analysis is to identify whether other PPTX processes:

use aromatic/heteroaromatic complexation (excluding benzene), and
form an isolable solid complex and separate it, and
use aqueous base contact for impurity removal.

Key claim chart (condensed)

Claim	What must happen (minimum steps/limitations)	Hard limiter(s)
1	Impure PPTX → form solution → form solid complex of PPTX + aromatic/heteroaromatic compound (≠ benzene) → separate solid complex	Aromatic/heteroaromatic must be ≠ benzene; solid complex formation and separation required
2	Same as Claim 1	Solid complex must include water
3	Same as Claim 1	Solution solvent comprises ethanol
4	Same as Claim 1	Complex formed by adding aromatic/heteroaromatic + water to PPTX solution
5	Same as Claim 1	Dissolve separated complex to form solution; repeat complex formation/separation
6	Same as Claim 5	Different aromatic/heteroaromatic compounds in at least two successive stages
7	Two-stage complexing purification from PPTX solution + different aromatic agents, then isolate free-form PPTX	Aromatic/heteroaromatic compounds in steps (a) and (d) must differ
8	Claim 1 route where aromatic/heteroaromatic is from the listed set	Compound selection limited to listed examples
9	Further purification: contact PPTX solution (in water-immiscible solvent) with aqueous base	Biphasic requirement: water-immiscible solvent + aqueous base
10	Impurity removal: contact impure PPTX + water-immiscible organic solvent with aqueous base	Includes “impure PPTX” and biphasic contact
11	Claim 10	Base must be alkali metal hydroxide

Key Takeaways

US 4,680,399 is a mechanistic solid-complex purification patent for podophyllotoxin using aromatic or heteroaromatic compounds other than benzene, with mandated solid complex formation and separation.
The highest-risk territory for implementation is processes that precipitate or crystallize a separable PPTX complex with an aromatic/heteroaromatic compound, followed by solid-liquid separation, and that can match the two-stage regeneration structure of Claim 7 (different aromatic agents across stages).
Independent coverage is complemented by aqueous base impurity removal claims (Claims 9-11) tied to water-immiscible solvent/aqueous base contact and, for Claim 11, alkali metal hydroxide specifically.
For landscape/FTO: map any competing PPTX purification route against four claim-sensitive variables: complex partner identity, solid complex formation, presence of ethanol/water depending on the asserted dependent claim, and aqueous base biphasic impurity removal.

FAQs

1) Does 4,680,399 cover only complexation-based purification?

No. It covers complexation-based purification (Claims 1-8) and also includes purification/impurity removal by aqueous base contact in the presence of a water-immiscible organic solvent (Claims 9-11).

2) Is benzene an allowed aromatic complexing partner under Claim 1?

No. Claim 1 requires an aromatic or heteroaromatic compound other than benzene.

3) What is the practical difference between Claim 1 and Claim 7?

Claim 1 covers a single complex formation and separation step. Claim 7 requires a two-stage cycle with regeneration from complex to PPTX solution and a second complex formation using a different aromatic/heteroaromatic compound, ending with isolation of free-form PPTX.

4) Do Claims 9-11 require forming a solid complex?

No. Those claims center on contacting a PPTX-containing solution in a water-immiscible solvent with aqueous base to remove impurities.

5) What dependent claim most directly narrows the complex composition to include water?

Claim 2. It specifies the solid complex comprises PPTX, the aromatic/heteroaromatic compound, and water.

References

[1] United States Patent 4,680,399, “Process for obtaining purified podophyllotoxin,” claims as provided in the prompt.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8424269	Sep 26, 1984

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	48427	⤷ Start Trial
Austria	63916	⤷ Start Trial
Canada	1268709	⤷ Start Trial
Canada	1276110	⤷ Start Trial
Germany	3574595	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,680,399

Summary for Patent: 4,680,399