United States Patent 8,623,868: Temozolomide Lyophilized Formulation Scope, Validity, and Patent Landscape

U.S. Patent No. 8,623,868 protects a narrowly defined lyophilized temozolomide formulation containing L-threonine. The independent claim requires both temozolomide and L-threonine. Dependent claims add mannitol, citrate buffer, hydrochloric acid, and polysorbate 80. The patent does not broadly cover temozolomide, all injectable formulations, or every lyophilized temozolomide product.

The principal commercial issue is formulation overlap. A competing product must contain L-threonine to create a strong literal infringement risk under claim 1. A temozolomide lyophilizate containing only mannitol, tromethamine, citrate, or another stabilizer would generally fall outside the literal scope of claim 1.

What does U.S. Patent 8,623,868 claim?

The supplied claims define a composition patent with a nested structure:

Claim	Required formulation elements	Scope
1	Temozolomide or pharmaceutically acceptable salt and L-threonine	Broadest claim
2	Claim 1 elements plus mannitol, citrate buffer, and hydrochloric acid	Narrower formulation
3	Claim 2 elements plus polysorbate 80	Narrowest formulation

Claim 1 is the controlling commercial claim because claims 2 and 3 cannot be infringed unless every limitation of claim 1 is also present.

Claim 1: temozolomide plus L-threonine

Claim 1 has two principal limitations:

A lyophilized powder.
The powder contains temozolomide, or a pharmaceutically acceptable salt, and L-threonine.

The claim does not expressly require:

A particular temozolomide concentration.
A specific vial size.
A particular reconstitution volume.
A specific pH.
Mannitol.
A citrate buffer.
Hydrochloric acid.
Polysorbate 80.
Intravenous administration.
A particular method of manufacturing.
A particular indication, such as glioblastoma or anaplastic astrocytoma.

The term "lyophilized powder" limits the claim to a freeze-dried solid formulation. A liquid solution, suspension, capsule, tablet, or non-lyophilized powder should not literally satisfy this limitation.

Claim 2: added excipient and pH limitations

Claim 2 requires all elements of claim 1 and adds:

Mannitol.
A citrate buffer.
Hydrochloric acid.

The claim does not state whether each component must be present in a specified concentration or ratio. Unless the specification or prosecution history supplies a narrower construction, the claim is directed to the presence of these components rather than to a particular quantitative formulation.

Hydrochloric acid is likely used as a pH-adjusting agent rather than as a principal therapeutic ingredient. Its presence may be difficult to establish from a finished-product label because pH adjusters can be present in small quantities and may not always be fully disclosed in public regulatory materials.

Claim 3: polysorbate 80

Claim 3 requires all elements of claims 1 and 2, plus polysorbate 80. It is the narrowest claim and provides the strongest formulation specificity but the smallest potential infringement population.

Polysorbate 80 may function as a surfactant, wetting agent, or aggregation-control excipient. A product that substitutes polysorbate 20, poloxamer, sodium lauryl sulfate, or another surfactant would not literally meet the polysorbate 80 limitation.

How broad is the patent protection?

The patent protects a formulation combination, not the temozolomide molecule itself.

Protected subject matter

The strongest reading of the claims covers:

Freeze-dried temozolomide compositions containing L-threonine.
Such compositions with mannitol, citrate buffer, and hydrochloric acid.
The narrower formulation also containing polysorbate 80.
Pharmaceutical products incorporating those compositions, subject to the claim language and applicable infringement principles.

Subject matter outside the literal claims

The following formulations generally fall outside the literal wording unless L-threonine is also present:

Temozolomide lyophilized with mannitol alone.
Temozolomide lyophilized with tromethamine.
Temozolomide lyophilized with lactose.
Temozolomide lyophilized with sucrose.
Temozolomide in a liquid injectable solution.
Oral temozolomide capsules.
Oral temozolomide tablets.
Temozolomide nanoparticles or liposomes without the claimed lyophilized composition.
A formulation using a different amino acid instead of L-threonine.

The claim does not require that L-threonine perform a particular function. A formulation developer therefore cannot necessarily avoid claim 1 by asserting that L-threonine is present only as a stabilizer, bulking agent, or processing aid.

What infringement issues does U.S. Patent 8,623,868 create?

A product-by-product formulation comparison is required. The principal infringement questions are compositional.

Product characteristic	Claim 1 risk
Lyophilized temozolomide	No risk without L-threonine
L-threonine present	High literal risk
L-threonine only in process equipment or cleaning material	Usually no composition infringement
L-threonine present as a residual impurity	Fact-specific
Mannitol but no L-threonine	Generally outside claim 1
Citrate buffer and HCl but no L-threonine	Generally outside claim 1
Polysorbate 80 but no L-threonine	Generally outside claim 1
Liquid injectable product containing L-threonine	Potentially outside because of "lyophilized powder"
Reconstituted product after administration	Analysis depends on the accused act and claim construction

Literal infringement

Literal infringement requires every limitation to be present. For claim 1, the accused product must be a lyophilized powder containing temozolomide or a pharmaceutically acceptable salt and L-threonine.

Claims 2 and 3 require the additional excipients. A product containing L-threonine but omitting mannitol would potentially implicate claim 1 but not claim 2. A product containing claims 1 and 2 elements but using polysorbate 20 instead of polysorbate 80 would potentially implicate claim 2 but not claim 3.

Doctrine of equivalents

A patentee could argue that a chemically different excipient performs substantially the same function in substantially the same way to obtain substantially the same result. That theory is weaker where the patent claims a specific chemical compound, particularly polysorbate 80 or L-threonine.

Prosecution-history estoppel may also restrict equivalents if the applicant added L-threonine or the specific excipients to distinguish prior art. The amendment history is therefore material to any freedom-to-operate opinion.

Product-by-process and manufacturing issues

The claims supplied are composition claims, not process claims. A manufacturer does not avoid infringement merely by using a different freeze-drying cycle if the resulting product contains the claimed components.

Conversely, a manufacturer using the same process but producing a formulation without L-threonine should have a stronger non-infringement position, subject to evidence concerning residual or undisclosed formulation ingredients.

What patents historically protect temozolomide?

Temozolomide has been protected through several patent categories:

Patent category	Typical subject matter	Relevance to U.S. 8,623,868
Compound patents	Temozolomide and related imidazotetrazine compounds	Separate from the formulation patent
Oral pharmaceutical compositions	Capsules, tablets, excipient systems	Usually separate from a lyophilized injectable claim
Injectable formulations	Sterile solutions or lyophilized powders	Closest prior-art and competitive category
Manufacturing patents	Synthesis, purification, crystallization, and impurity control	Can create non-product barriers
Method-of-use patents	Cancer treatment regimens and combinations	Potentially relevant after composition-patent expiry
Formulation-stability patents	Stabilizers, buffers, surfactants, and shelf-life improvements	Directly relevant to validity and design-around analysis

The principal prior-art risks for U.S. 8,623,868 are earlier disclosures of:

Lyophilized temozolomide.
Temozolomide with amino acids.
Temozolomide with L-threonine.
Mannitol-containing temozolomide formulations.
Citrate-buffered temozolomide.
Freeze-drying cycles that produce the claimed composition.
Pharmaceutical excipient combinations used for related imidazotetrazines.

How strong are the claims against prior-art challenges?

The patent's strength depends on whether the prior art disclosed L-threonine as part of a lyophilized temozolomide formulation and whether the claimed combination produced an unexpected technical effect.

Anticipation risk

Claim 1 could be anticipated by a single prior-art reference disclosing:

Temozolomide or a pharmaceutically acceptable salt.
L-threonine.
A lyophilized powder form.

A reference that discloses only temozolomide and mannitol would not anticipate claim 1 unless it also discloses L-threonine.

Claim 2 requires the additional combination of mannitol, citrate buffer, and hydrochloric acid. Claim 3 requires polysorbate 80 as well. Their narrower scope makes single-reference anticipation more difficult, but the claims also cover a smaller commercial formulation space.

Obviousness risk

Obviousness is likely the central validity issue. A challenger could combine:

Earlier temozolomide lyophilization disclosures.
Pharmaceutical formulation references describing L-threonine as a stabilizer or bulking agent.
References using mannitol, citrate, hydrochloric acid, and polysorbate 80 in injectable products.
Routine freeze-drying and pH-adjustment knowledge.

The patentee's strongest response would be evidence of an unexpected result, such as improved:

Chemical stability.
Reconstitution time.
Cake structure.
Resistance to degradation.
Particulate control.
Shelf life.
Compatibility with intravenous administration.

Without comparative data, the combination of familiar excipients may face a meaningful obviousness challenge.

Enablement and written-description considerations

The claims are composition claims with limited quantitative detail. Potential challenges could focus on whether the specification supports the full scope of:

All amounts of L-threonine.
All pharmaceutically acceptable temozolomide salts.
Every possible lyophilized cake structure.
All citrate-buffer concentrations.
All combinations of mannitol, hydrochloric acid, and polysorbate 80.

These challenges are stronger if the patent discloses only one narrow example but claims a broad range of compositions.

When does U.S. Patent 8,623,868 lose exclusivity?

The patent's enforceable expiration depends on its earliest effective nonprovisional priority date, patent-term adjustment, terminal disclaimers, and any applicable patent-term extension. The issue date alone does not determine expiration.

For a utility patent filed under the modern 20-year patent-term regime, the baseline term is generally 20 years from the earliest effective U.S. nonprovisional filing date, subject to adjustments under 35 U.S.C. § 154 and possible terminal disclaimers [3].

Exclusivity component	Effect
Patent term	Normally measured from earliest effective nonprovisional filing date
Patent-term adjustment	May extend the term for qualifying USPTO delays
Patent-term extension	May apply for regulatory review, but only if statutory requirements are met
Terminal disclaimer	Can shorten the term to the expiration of another patent
Claim cancellation or invalidity	Can reduce enforceable scope before nominal expiration
Disclaimer or lapse	Can eliminate enforceability in particular circumstances

The precise expiration date should be taken from the USPTO patent record and validated against any terminal disclaimer or adjustment data. A patent-number-only expiration estimate is not reliable.

What is the Orange Book status of the patent?

The Orange Book lists patents submitted by an NDA holder for approved drug products. Listing is product-specific and does not automatically follow from patent issuance.

For temozolomide, the relevant regulatory products include:

TEMODAR capsules.
TEMODAR for injection.
Generic temozolomide capsules.
Any approved generic or follow-on injectable product.

A formulation patent may be listed against the injectable product if the NDA holder submitted it as a drug-substance, drug-product, or method-of-use patent meeting FDA listing requirements. It may not be listed against oral capsules if the claimed formulation is limited to a lyophilized injectable powder.

The commercial consequences are different:

Status	Consequence
Listed in Orange Book	A Paragraph IV certification can trigger patent litigation and potentially a 30-month stay
Not listed	A Paragraph IV challenge to that patent does not create the same Orange Book stay mechanism
Listed only against injection	Oral generic applicants may have no certification obligation for that patent
Expired listing	No continuing Orange Book barrier to approval, although other claims may remain relevant

An Orange Book entry must be checked by product and patent number. FDA's Approved Drug Products with Therapeutic Equivalence Evaluations is the controlling public source for listed patents and exclusivity [1].

Are Paragraph IV challenges likely?

A Paragraph IV challenge would be commercially relevant only if:

The patent is listed for the reference product identified in the abbreviated new drug application.
The generic applicant seeks approval for a product within the listed scope.
The applicant certifies that the patent is invalid, unenforceable, or will not be infringed.

For a lyophilized injectable temozolomide product, the applicant would likely compare its formulation against claims 1 through 3. The strongest design-around would omit L-threonine. If the proposed product uses L-threonine, the applicant would need a non-infringement theory based on the meaning of "lyophilized powder," the amount or form of L-threonine, the identity of the temozolomide component, or prosecution history.

A Paragraph IV case would likely focus on:

Whether L-threonine was disclosed or suggested in the prior art.
Whether the claimed excipient combination was routine.
Whether the patent's examples support the full claim scope.
Whether the listed patent covers the proposed dosage form.
Whether claim construction limits the term "lyophilized powder."

What generic entry risks exist for temozolomide?

Oral temozolomide

The patent presents limited risk to oral generic temozolomide because the claims require a lyophilized powder. Oral capsules and tablets ordinarily do not meet that limitation.

The principal barriers for oral products have historically been compound, formulation, method-of-use, regulatory, and manufacturing patents rather than this specific lyophilized composition.

Injectable temozolomide

Injectable products face greater formulation risk, but the risk is highly dependent on L-threonine content.

Proposed injectable formulation	Risk under claim 1
Temozolomide plus L-threonine, lyophilized	High
Temozolomide plus mannitol, no L-threonine	Low under literal claim 1
Temozolomide plus mannitol and citrate, no L-threonine	Low under literal claim 1
Temozolomide plus L-threonine and mannitol	High under claim 1; possible claim 2 risk
Temozolomide plus all claim 3 excipients	Highest
Liquid temozolomide injection with L-threonine	Possible non-infringement based on lyophilization limitation
Alternative amino acid replacing L-threonine	Lower, subject to equivalents analysis

The patent therefore creates a formulation-selection issue rather than a universal injectable-entry prohibition.

What manufacturing and intellectual-property barriers remain?

A generic or follow-on manufacturer must separate three questions:

Can it manufacture temozolomide at the required purity?
Can it produce a stable injectable dosage form?
Can it commercialize that product without infringing formulation or use patents?

Manufacturing barriers may include:

Control of temozolomide degradation products.
Reproducible freeze-drying.
Sterility assurance.
Reconstitution performance.
Container-closure compatibility.
Control of particulate matter.
Stability after reconstitution.
Scale-up of the lyophilization cycle.
Protection of process know-how that is not disclosed in the patent.

A formulation design-around may avoid the patent but create a new regulatory burden if the alternative excipient system changes stability, safety, or clinical comparability.

How does this patent compare with broader temozolomide patents?

Issue	U.S. 8,623,868	Compound patent	Oral formulation patent	Method-of-use patent
Protected subject matter	Lyophilized formulation	Active molecule	Capsule or tablet composition	Treatment regimen
Requires L-threonine	Yes, claim 1	No	Usually no	No
Covers oral capsules	Generally no	Potentially, subject to term	Potentially	Potentially
Covers injectable powder	Yes, if L-threonine is present	May cover active ingredient broadly	Usually no	Depends on use
Design-around potential	Relatively high	Low after compound expiry	Moderate	Depends on indication and regimen
Main validity issue	Obviousness and written description	Novelty and term	Obviousness and enablement	Written description and obviousness

The patent is narrower than a compound patent but potentially more valuable against a specific injectable formulation. Its commercial value depends on whether the reference product and proposed generic products use L-threonine.

What litigation and settlement issues should be reviewed?

The relevant litigation review should cover:

Federal district-court cases naming the patent.
Paragraph IV notices involving temozolomide injection.
ANDA litigation against the NDA holder.
Inter partes review or post-grant review petitions.
Reexamination or certificate proceedings.
Terminal disclaimers and ownership changes.
License agreements affecting the patent.
Covenants not to sue.
Settlement agreements with generic manufacturers.
Authorized-generic arrangements.

A patent litigation search should use the patent number, family members, title, assignee names, TEMODAR, temozolomide, and the relevant NDA number. Public patent databases identify prosecution and family data, while PACER and PTAB records identify litigation and administrative challenges [2][4][5].

No reliable conclusion about a license, settlement, or active case should be drawn from the patent number alone. Patent ownership and litigation status may have changed after issuance.

What is the commercial exposure?

The patent's revenue exposure is concentrated in injectable temozolomide rather than the overall temozolomide market.

Potential exposure is highest where:

The originator's injectable product uses L-threonine.
The patent is listed for the injectable reference product.
The patent remains unexpired.
No design-around formulation has been approved.
The injectable product has material hospital or oncology-center sales.
Generic applicants need the same excipient system for stability or regulatory comparability.

Exposure is lower where:

Sales are dominated by oral capsules.
The marketed injectable formulation omits L-threonine.
The patent is not Orange Book-listed.
The patent term has expired.
A generic can use mannitol or another excipient without L-threonine.
The claims have been invalidated, disclaimed, or narrowed.

Revenue analysis should distinguish total temozolomide sales from sales attributable to the particular injectable presentation. Using total product sales to value this formulation patent would overstate the relevant market.

Key Takeaways

U.S. Patent 8,623,868 is a formulation patent directed to a lyophilized temozolomide powder containing L-threonine.
Claim 1 is the principal commercial claim.
Claims 2 and 3 add mannitol, citrate buffer, hydrochloric acid, and polysorbate 80.
The patent does not broadly cover temozolomide, oral capsules, or every injectable formulation.
A lyophilized injectable product without L-threonine has a strong literal non-infringement position.
The main validity risks are obviousness, anticipation by earlier lyophilized temozolomide disclosures, and the adequacy of written-description support.
Orange Book relevance depends on product-specific listing, particularly whether the patent was listed against an injectable temozolomide NDA.
Generic risk is concentrated in injectable products that reproduce the L-threonine formulation.
The enforceable expiration date requires review of the patent's priority chain, patent-term adjustment, terminal disclaimers, and any extension.
Commercial valuation should focus on injectable temozolomide revenue, not the entire oral and injectable temozolomide market.

FAQs

Does U.S. Patent 8,623,868 cover Temodar capsules?

Generally no. The supplied claims require a lyophilized powder. Conventional temozolomide capsules do not satisfy that dosage-form limitation.

Can a generic use mannitol and avoid the patent?

Possibly. Mannitol alone does not satisfy claim 1. The formulation must also contain L-threonine and be lyophilized to create the clearest literal infringement risk.

Does claim 3 cover any polysorbate?

No. Claim 3 specifically recites polysorbate 80. Other surfactants are not literal substitutes, although a doctrine-of-equivalents analysis may depend on the patent's prosecution history.

Can a liquid temozolomide injection infringe the patent?

A liquid product has a potential non-infringement position because the claims require a lyophilized powder. The analysis depends on the accused product, the claim construction, and whether infringement is alleged based on manufacture, sale, or use of the formulation.

Is the patent automatically enforceable until 2034?

No. Patent term depends on the earliest effective nonprovisional filing date, patent-term adjustment, terminal disclaimers, and any statutory extension. The issue date does not establish the expiration date.

References

U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files
U.S. Patent and Trademark Office. (n.d.). Patent Center. https://patentcenter.uspto.gov/
U.S. Patent and Trademark Office. (n.d.). Patent term adjustment. https://www.uspto.gov/patents/laws/patent-term-adjustment
U.S. Patent and Trademark Office. (n.d.). Patent Trial and Appeal Board End-to-End system. https://ptabdata.blob.core.windows.net/
U.S. Courts. (n.d.). PACER: Public Access to Court Electronic Records. https://pacer.uscourts.gov/

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	038535	⤷ Start Trial
Argentina	064722	⤷ Start Trial
Argentina	084868	⤷ Start Trial
Austria	397440	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,623,868

Summary for Patent: 8,623,868