US Patent 8,372,995: Tigecycline Form I Claims, Scope, Expiration and Generic Entry Risk

US Patent 8,372,995 protects a crystalline polymorph of tigecycline, identified as Form I, together with processes and pharmaceutical compositions that use that polymorph. Its strongest claim is the product claim in claim 1. The patent does not claim tigecycline as a chemical entity in all forms. It targets a defined solid-state form identified by four powder X-ray diffraction peaks and a hot-stage melting-point onset range.

The patent therefore creates a solid-form barrier rather than a complete active-ingredient monopoly. A competing manufacturer may avoid literal infringement by producing tigecycline in a different polymorphic, amorphous, solvated, hydrated, or otherwise non-Form-I state, subject to the patent's specification, prosecution history and the doctrine of equivalents. The commercial significance depends on whether Form I is required or preferred for the relevant drug substance and whether a generic process converts the material into Form I during manufacture or formulation.

What does US Patent 8,372,995 claim?

The patent contains ten claims covering four related categories:

Claim category	Claims	Protected subject matter
Product	1	Form I tigecycline defined by XRPD and melting-point data
Composition	2, 8, 10	Form I tigecycline compositions, including compositions made by specified processes
Manufacturing process	3-7, 9	Crystallization, isolation, processing, formulation and lyophilization
Formulation and lyophilization	7-10	Combining Form I with a pharmaceutically acceptable carrier and lyophilizing

Claim 1 is an independent product claim. Claim 2 is an independent composition claim. Claim 3 is an independent process claim. Claims 4-10 depend on those core claims.

The patent's protected subject matter is defined by analytical characteristics, not by a chemical structural formula alone. A sample must satisfy the specified solid-state identity and thermal property limitations for claim 1 to read on it.

What is the scope of claim 1 for Form I tigecycline?

Claim 1 requires all of the following:

The material is tigecycline.
It is Form I.
Its XRPD pattern includes peaks at approximately:
- 5.2° 2θ
- 8.3° 2θ
- 11.1° 2θ
- 24.8° 2θ
Its hot-stage melting-point onset temperature is approximately 170°C to 172°C.

The claim is narrow in analytical definition but potentially broad in commercial effect. It does not specify particle size, purity, morphology, water content, residual solvent, bulk density, dosage strength, container, or route of administration. A Form I batch with different particle size or pharmaceutical grade could still fall within claim 1 if the required XRPD and thermal characteristics are present.

The term "about" introduces tolerance questions. The patent specification, examples, testing conditions and prosecution record would be important in determining the permitted deviation from each listed peak and from the 170°C to 172°C onset range. Peak position can vary with instrument calibration, sample preparation, radiation source, crystallinity and measurement conditions.

Why the XRPD limitations matter

XRPD peaks are identity limitations. The claim does not require a full diffraction pattern to match a reference pattern. On its face, it requires the claimed Form I material to have the four listed peaks. Additional peaks would not necessarily avoid infringement unless the claim or specification gives the listed peaks an exclusive significance.

A generic manufacturer could face infringement risk even if it labels the drug substance as a different form if the accused material contains Form I crystals or converts to Form I during processing. The result would depend on the claim construction and evidence of the material actually present.

Why the melting-point limitation matters

The melting-point onset range is an additional identity limitation. A material with the four specified XRPD peaks but an onset outside the claimed range may present a noninfringement position. That position could be weakened if the difference results from testing variation, impurities, heating rate, calibration, or an accused sample that contains multiple solid forms.

What does claim 2 protect?

Claim 2 covers a composition "consisting essentially of" Form I tigecycline having the same analytical characteristics required by claim 1.

"Consisting essentially of" generally permits components that do not materially affect the basic and novel characteristics of the claimed composition. The basic and novel characteristics are likely tied to the presence and solid-state identity of Form I tigecycline. The phrase is narrower than "comprising" but broader than "consisting of."

The claim may cover a composition containing Form I tigecycline and conventional residual or incidental components, depending on the specification and prosecution history. It is less likely to cover a formulation in which another active ingredient, excipient or polymorph materially changes the claimed solid-state characteristics.

Claim 2 is relevant to drug-substance suppliers and formulation manufacturers because it does not require the manufacturing steps recited in claim 3. A product claim can be infringed by importing, selling or using an infringing composition even when the accused party did not use the patented crystallization process.

What process does claim 3 cover?

Claim 3 requires a process comprising:

Crystallizing tigecycline out of a solution;
Forming a slurry;
Filtering the slurry; and
Isolating Form I tigecycline with the specified XRPD peaks and melting-point onset.

The process claim is narrower than claim 1 because it requires a particular sequence. It does not, however, limit the solvent to methylene chloride. Claim 4 adds methylene chloride as a dependent limitation, indicating that claim 3 reaches processes using other solvents as well.

The phrase "crystallizing tigecycline out of a solution to form a slurry" may cover controlled precipitation or crystallization followed by solid-liquid separation. The claim does not expressly require a particular temperature, concentration, seeding protocol, cooling profile, agitation rate or drying method.

What does claim 4 add?

Claim 4 requires that the solution contain methylene chloride. A process using methylene chloride and otherwise satisfying claim 3 would fall within the narrower claim. The claim does not state that methylene chloride must be the only solvent or the principal solvent.

What does claim 5 add?

Claim 5 requires drying the solution before crystallization. The drying step may target water or another component that affects polymorph formation. The claim does not specify the drying technique.

What does claim 6 add?

Claim 6 requires stirring the slurry before filtration. This limitation may be commercially relevant because agitation can affect nucleation, crystal growth, particle-size distribution and polymorph conversion.

What do claims 7 and 8 add?

Claim 7 adds combining Form I tigecycline with at least one pharmaceutically suitable carrier to form a pharmaceutical composition. It is a process claim.

Claim 8 covers a pharmaceutical composition made by the process of claim 7. The "made by" language creates a product-by-process issue. For infringement, courts commonly focus on whether the resulting product has the claimed product characteristics, although the precise analysis depends on claim construction and the technology.

What do claims 9 and 10 add?

Claim 9 adds lyophilization of the pharmaceutical composition. Claim 10 covers a pharmaceutical composition made by that lyophilization process.

These claims are directed to sterile or reconstitutable formulations in which lyophilization may affect the physical state of tigecycline, excipient interactions and product stability. The claim language does not expressly limit the formulation to a particular dose, vial, reconstitution volume or excipient system.

How strong is the patent estate for tigecycline Form I?

The patent estate represented by US 8,372,995 is technically focused and commercially meaningful but narrower than a basic compound patent.

Strength factor	Assessment
Product coverage	Strong if the marketed or proposed drug substance is Form I
Analytical definition	Specific, enabling comparison by XRPD and thermal analysis
Process coverage	Moderate; limited to crystallization, slurry formation and filtration
Formulation coverage	Moderate; dependent on the claimed Form I material and process
Alternative polymorph vulnerability	Material; a distinct solid form may avoid literal product infringement
Manufacturing relevance	High if Form I is the commercial API form
Biosimilar relevance	None in the conventional sense; tigecycline is a small molecule
Invalidity exposure	Depends on prior-art disclosure of Form I, inherency, anticipation, obviousness and enablement
Design-around potential	Potentially available through a different form or noninfringing conversion process

The main validity questions are whether Form I was previously disclosed, whether it was inherently present in earlier tigecycline preparations, whether the claimed analytical profile distinguishes it from prior art, and whether the process limitations would have been obvious.

When does US Patent 8,372,995 lose exclusivity?

The patent issued on February 12, 2013. Its enforceable term is generally measured from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension and terminal disclaimers. The issue date alone does not establish the expiration date.

A reliable expiration analysis must distinguish:

Patent term under 35 U.S.C. § 154;
Patent-term adjustment shown on the issued patent;
Any terminal disclaimer;
Any patent-term extension under 35 U.S.C. § 156;
Reissue or post-grant changes;
Maintenance-fee status;
Whether the patent is listed for the relevant tigecycline product.

The patent's practical exclusivity date should therefore be taken from the official USPTO patent record and the applicable FDA Orange Book listing rather than inferred solely from the 2013 issue date.[1][2]

What is the Orange Book status of US 8,372,995?

The Orange Book question is separate from patent validity. FDA listing determines whether an ANDA applicant must make a certification against the patent and whether the patent can create an automatic 30-month stay after a timely Paragraph IV notice and patent-owner suit.

For a listed drug, the relevant possibilities are:

Orange Book status	Effect
Listed patent	ANDA applicant generally addresses it through certification
Unlisted patent	No Orange Book-based certification or automatic stay for that patent
Method-of-use listing	Applicant may use a section viii statement if the labeling omits the patented use
Expired patent	No remaining patent-based bar to approval
Patent under litigation	Approval timing may be affected by the 30-month stay and court outcome

US 8,372,995 is a solid-form and manufacturing patent. It is not, based on the claims supplied, a method-of-use patent. A section viii strategy would therefore not ordinarily address claims directed to the API form, composition or manufacturing process.

Are Paragraph IV challenges likely for this patent?

A Paragraph IV challenge could assert that the patent is invalid, unenforceable or not infringed. The most plausible arguments would target:

Anticipation by a prior-art document disclosing the same Form I XRPD pattern and melting behavior.
Inherency based on prior-art crystallization conditions that necessarily produce Form I.
Obviousness based on routine polymorph screening or predictable crystallization methods.
Noninfringement because the proposed API is a different polymorph or amorphous form.
Noninfringement because the manufacturing process does not include the required slurry and filtration steps.
Indefiniteness or lack of written description involving the meaning of "about," although these arguments depend heavily on the specification and prosecution record.

A Paragraph IV certification would not automatically invalidate the patent. The patent holder could sue within the statutory period, potentially triggering a 30-month stay of ANDA approval under the Hatch-Waxman framework.[3]

What generic launch scenarios exist for tigecycline?

Launch after patent expiry

This is the lowest-risk route if the patent remains unexpired and listed. The ANDA applicant can avoid a patent challenge but must wait for the relevant patent and regulatory exclusivities to end.

Paragraph IV launch

A generic applicant may challenge the patent before expiry. The commercial launch timing would depend on notice, litigation, a court decision, settlement terms and any remaining FDA exclusivity.

Non-Form-I launch

A manufacturer may develop an alternative polymorph, amorphous tigecycline, hydrate, solvate or other solid-state form. This strategy requires proof that the commercial API and finished product do not contain the claimed Form I characteristics in an infringing amount or state.

Process design-around

A manufacturer may use a process that does not include the claimed crystallization-to-slurry-to-filtration sequence. This does not avoid claim 1 if the resulting product is still Form I, but it may avoid process claims 3-6.

Licensed entry

A license or settlement could permit launch before patent expiry. The commercial terms, launch date and scope would depend on the agreement. No licensing or settlement terms can be attributed to this patent from the claims alone.

How does this patent compare with compound and formulation patents?

Patent type	Typical scope	Relevance to US 8,372,995
Compound patent	Covers tigecycline's chemical structure	Broader than this patent
Salt or polymorph patent	Covers a defined solid form	Closest comparison
Formulation patent	Covers excipients, concentrations or dosage forms	Claims 2 and 7-10 have partial overlap
Method-of-use patent	Covers treatment of a disease or patient population	Not present in the supplied claims
Process patent	Covers API synthesis or isolation	Claims 3-7 and 9 are process-focused
Manufacturing patent	Covers scale-up, purification or crystallization	Potentially overlaps claims 3-6

The patent is most important where the innovator's commercial supply chain uses Form I as the API specification. It is less powerful against a product genuinely manufactured, stored and distributed in a different solid-state form.

What geographic coverage does the patent provide?

US 8,372,995 provides rights only in the United States. It does not establish protection in Europe, Canada, Japan, China, India or other markets. International protection would require corresponding national or regional patents from the same priority family.

For a global launch analysis, each jurisdiction must be reviewed separately for:

Patent-family members;
National phase status;
Local expiration;
Supplementary protection certificates;
Patent-term adjustments;
Regulatory linkage;
Import and manufacturing rights;
Local litigation and settlement history.

A US design-around does not establish freedom to operate elsewhere.

What are the key infringement tests for a generic manufacturer?

The highest-risk question is whether the proposed API satisfies the four XRPD and thermal limitations of claim 1. The analysis should use retained samples from:

API crystallization;
Milling;
Formulation;
Lyophilization;
Reconstitution;
Stability testing.

Testing should compare XRPD peak positions, relative intensities, thermal onset, residual solvent, water content and polymorphic conversion. A product that begins as a different form but converts to Form I during processing or storage may create a separate infringement issue.

The process claims require reconstruction of the manufacturing sequence. Batch records, solvent systems, drying operations, agitation and filtration conditions may establish infringement even when the final product analysis is inconclusive.

Key Takeaways

US 8,372,995 is a Form I tigecycline solid-state patent.
Claim 1 is the central claim and requires four XRPD peaks plus a 170°C to 172°C hot-stage melting onset.
The patent does not claim all tigecycline products.
Claims 3-6 target crystallization, slurry formation, filtration, methylene chloride, drying and stirring.
Claims 7-10 extend to carrier-containing and lyophilized pharmaceutical compositions.
A different polymorph may provide a product-level design-around, but process conversion to Form I remains a risk.
Tigecycline is a small-molecule antibiotic; biosimilar analysis is not applicable.
Paragraph IV exposure depends on the patent's Orange Book status, remaining term and the proposed product's solid-state identity.
The issue date was February 12, 2013; the enforceable expiration date requires review of the official patent-term and Orange Book records.
US protection does not establish international freedom to operate.

FAQs

Does US 8,372,995 cover tigecycline injection generally?

No. The claims cover Form I tigecycline and specified compositions and processes involving that form. They do not, on their face, cover every tigecycline injection regardless of solid state.

Can an amorphous tigecycline product avoid claim 1?

Potentially, if it does not exhibit the claimed Form I XRPD peaks and melting-point onset. The final analysis depends on whether Form I is present and whether the claim limitations are met.

Does using a solvent other than methylene chloride avoid the patent?

It may avoid claim 4, but not necessarily claim 3 or claim 1. Claim 3 is not limited to methylene chloride, and claim 1 is a product claim independent of the manufacturing solvent.

Can a generic omit a patented tigecycline solid form from its ANDA label?

A labeling carve-out generally addresses method-of-use claims. It does not ordinarily eliminate infringement risk for product, composition or manufacturing claims directed to the API form.

Is a lyophilized tigecycline product automatically covered by claims 9 and 10?

No. The product must satisfy the incorporated limitations, including the Form I tigecycline requirements and the specified process relationship. Lyophilization alone is insufficient.

References

United States Patent and Trademark Office. (2013). United States Patent No. 8,372,995: Form I tigecycline.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations (Orange Book).
U.S. Code, 35 U.S.C. §§ 154, 156, 271(e), 282.
U.S. Code, 21 U.S.C. § 355(j).

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Pf Prism Cv	TYGACIL	tigecycline	POWDER;INTRAVENOUS	021821-001	Jun 15, 2005	AP	RX	Yes	Yes	⤷ Start Trial	⤷ Start Trial	Y				⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	057649	⤷ Start Trial
Australia	2006251954	⤷ Start Trial
Brazil	PI0610653	⤷ Start Trial
Canada	2609875	⤷ Start Trial
Chile	2006001266	⤷ Start Trial
China	101248038	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,372,995

Which drugs does patent 8,372,995 protect, and when does it expire?

Summary for Patent: 8,372,995