Details for Patent: 9,387,266

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Which drugs does patent 9,387,266 protect, and when does it expire?

Patent 9,387,266 protects AXUMIN and is included in one NDA.

This patent has thirty patent family members in sixteen countries.

Summary for Patent: 9,387,266

Title:	Precursor compound of radioactive halogen-labeled organic compound
Abstract:	It is intended to provide a novel amino acid organic compound which can be used as a labeling precursor compound for radioactive halogen-labeled amino acid compounds including [18F]FACBC, and which prevents methanol from remaining in the radioactive halogen-labeled amino acid compounds produced therefrom. The novel amino acid organic compound is a compound represented by the following formula: wherein n is an integer of 0 or of 1 to 4; R1 is an ethyl, 1-propyl or isopropyl substituent; X is a halogen substituent or a group represented by —OR2; R2 is a straight-chain or branched-chain haloalkylsulfonic acid substituent with one to 10 carbon atoms, trialkylstannyl substituent with 3 to 12 carbon atoms, fluorosulfonic acid substituent or aromatic sulfonic acid substituent; and R3 is a protective group.
Inventor(s):	Osamu Ito, Akio Hayashi, Fumie Kurosaki, Masahito Toyama, Toshiyuki Shinmura, Arinori Harano
Assignee:	Nihon Medi Physics Co Ltd
Application Number:	US14/814,185
Patent Claim Types: see list of patent claims	Use;

United States Patent 9,387,266: Scope, Claims, Exclusivity, and Fluciclovine Patent Landscape

U.S. Patent No. 9,387,266 protects a specific manufacturing-and-use sequence for producing fluciclovine F 18, also known as 1-amino-3-[18F]fluorocyclobutanecarboxylic acid, for PET tumor imaging. Its practical scope is narrower than a broad composition patent because infringement requires performance of the claimed radiochemical process, including use of acetonitrile, acid-mediated deprotection, and production conditions that substantially avoid methanol.

The patent was granted on July 12, 2016. Its expected U.S. patent-term endpoint is in late 2032, subject to any patent-term adjustment or regulatory extension recorded by the USPTO. The patent is commercially relevant to Axumin, the FDA-approved fluciclovine F 18 PET imaging agent.

What does U.S. Patent 9,387,266 protect?

The patent protects a process for manufacturing fluciclovine F 18 and then administering the resulting radiotracer for PET diagnosis of tumors.

The core process has these elements:

Claim element	Required limitation
Product	1-amino-3-[18F]fluorocyclobutanecarboxylic acid
Precursor	An ethyl-substituted, trifluoromethanesulfonate-substituted, Boc-protected cyclobutane precursor
Radiofluorination	Addition of radioactive fluoride
Solvent	Acetonitrile
Deprotection	Acid-mediated removal of protecting groups
Product-quality limitation	Production substantially does not give methanol
Clinical step	Administration to a subject for tumor PET

The claims do not broadly cover every method of making fluciclovine F 18. They focus on a defined precursor and a defined process intended to avoid methanol formation during radiotracer production.

The patent therefore has two linked components:

1. A radiochemical manufacturing process.
2. Use of the manufactured fluciclovine F 18 for PET tumor diagnosis.

A process that makes fluciclovine F 18 but does not perform the claimed diagnostic administration step may not satisfy the complete method claims as written. Conversely, a party that administers fluciclovine F 18 for tumor PET but obtains it through a process outside the claimed precursor and reaction conditions may avoid literal infringement of these claims.

What are the independent claims in U.S. Patent 9,387,266?

Claims 1, 3, 4 and 5 are independent method claims based on the supplied claim text. Claim 2 depends on claim 1.

Claim 1

Claim 1 requires:

• the specific formula (1) precursor;
• n equal to zero;
• an ethyl R1 substituent;
• a trifluoromethanesulfonate X substituent;
• a tert-butoxycarbonyl R3 protecting group;
• radioactive fluoride addition;
• acetonitrile as the fluorination reaction medium;
• acid-mediated deprotection;
• substantial absence of methanol in production;
• administration of the resulting fluciclovine F 18 for tumor PET.

The claim is cumulative. Omitting one required process feature can defeat literal infringement.

Claim 2

Claim 2 narrows claim 1 by requiring hydrochloric acid as the deprotection acid.

This creates a clear species claim within the broader acid-deprotection limitation of claim 1. A process using hydrochloric acid would fall within claim 2 if all other limitations are met.

Claim 3

Claim 3 recites the precursor using the more explicit formula (2), with:

• Et representing ethyl;
• TfO representing trifluoromethanesulfonate;
• Boc representing tert-butoxycarbonyl.

It requires acetonitrile radiofluorination, hydrochloric-acid deprotection, substantial avoidance of methanol, and PET administration.

Claim 3 is technically narrower than a claim allowing any acid because it expressly requires hydrochloric acid.

Claim 4

Claim 4 is similar to claim 3 but does not specify hydrochloric acid. It requires acid-mediated deprotection generally.

Its potential scope is broader than claim 3 with respect to the acid, although the claim remains limited by the specific precursor, acetonitrile reaction, no-substantial-methanol condition, and tumor PET administration.

Claim 5

Claim 5 repeats the process and diagnostic limitations using formula (1), while describing R3 as a tert-butoxycarbonyl protective group rather than simply a substituent.

It is directed to substantially the same commercial process as claim 1. Its wording may create a separate infringement route if a court treats the protective-group language as materially distinct.

How should the claims be construed?

The important claim-construction issues are the precursor identity, solvent requirement, acid deprotection, and the phrase "substantially does not give methanol."

Specific precursor limitation

The precursor is not any fluorination precursor for fluciclovine F 18. It must contain the specified ethyl ester, trifluoromethanesulfonate leaving group, and Boc-protected amino functionality in the claimed arrangement.

A process using a different leaving group, a different ester, or a different amino-protecting group would present a stronger non-infringement position. The doctrine of equivalents could still be relevant, but the claim’s detailed structural limitations reduce the practical range of equivalents.

Acetonitrile limitation

The radiofluorination reaction must be carried out in acetonitrile. This is a meaningful limitation because radiopharmaceutical manufacturers may use different solvent systems, solvent mixtures, or automated synthesis protocols.

A process using dimethyl sulfoxide, tert-butanol, another polar aprotic solvent, or a solvent mixture without acetonitrile could avoid literal infringement if acetonitrile is not present as the claimed reaction medium.

The commercial significance depends on whether the accused process uses acetonitrile at the fluorination stage, not merely whether acetonitrile appears elsewhere in the synthesis or equipment-cleaning process.

Acid deprotection limitation

Claims 1, 3, 4 and 5 require acid-mediated deprotection. Claim 2 and claim 3 specifically require hydrochloric acid.

A process that uses a different deprotection mechanism, such as base-mediated cleavage, hydrogenolysis, thermal decomposition, or a protected intermediate that is removed by another reagent, may fall outside the literal claims.

"Substantially does not give methanol"

This phrase is a result-oriented limitation. It distinguishes the claimed process from production routes that generate methanol as a meaningful byproduct.

The likely dispute would concern:

• the quantitative threshold for "substantially does not give";
• whether trace methanol is permitted;
• whether methanol must be measured in the final product, reaction mixture, or process stream;
• whether methanol formation is inherent in a competing process;
• whether the limitation is treated as a process condition or merely a product-quality result.

The patent specification and prosecution history would be central to determining whether the phrase has a defined numerical meaning. The supplied claims do not state an express methanol concentration threshold.

What product and diagnostic use are covered?

The covered radiotracer is fluciclovine F 18, an artificial amino acid labeled with fluorine-18. FDA approved Axumin for PET imaging in men with suspected recurrent prostate cancer based on elevated prostate-specific antigen levels after prior treatment. The FDA label identifies fluciclovine F 18 as a radioactive diagnostic agent administered intravenously for PET imaging.[2]

The patent claims use for "diagnosing tumors" rather than only recurrent prostate cancer. That language is potentially broader than the original FDA indication, but patent infringement and FDA-approved use are separate questions.

The claims do not appear to cover:

• unlabeled fluciclovine;
• fluorine-18 agents with a different molecular structure;
• PET imaging using FDG;
• PSMA-targeted PET agents;
• MRI, CT, SPECT or non-PET diagnosis;
• administration without the claimed production process.

What is the patent expiration date and exclusivity timeline?

Event	Date or period
U.S. patent	U.S. 9,387,266
Grant date	July 12, 2016
Patent term basis	Generally 20 years from the earliest effective nonprovisional or PCT filing date
Expected expiration	Late 2032, subject to USPTO patent-term adjustment
FDA approval of Axumin	May 2016
FDA exclusivity	Product-specific regulatory exclusivity, if any, is distinct from the patent term
Orange Book relevance	Patent listing depends on FDA-approved product and current FDA listing records

The practical exclusivity period is controlled by the latest enforceable barrier among patent term, FDA exclusivity, regulatory approval requirements, and commercial manufacturing capability.

The patent is not a composition-of-matter patent covering fluciclovine F 18 itself. Its expiry should therefore be analyzed together with any other listed Axumin patents, formulation rights, manufacturing know-how and regulatory exclusivity.

Patent-term adjustment must be confirmed from the USPTO patent data. The expected 2032 endpoint should not be treated as a substitute for the official patent-term calculation.

What is the Orange Book status of U.S. Patent 9,387,266?

U.S. Patent 9,387,266 is associated with the Axumin fluciclovine F 18 product and has been identified in connection with the product’s U.S. patent protection. The relevant FDA-listed product is Axumin, approved under NDA 208054.

Orange Book listing does not automatically establish that every claim covers the approved product. FDA listing reflects the sponsor’s certification that the patent claims the drug, an approved method of using the drug, or a relevant product attribute under the Hatch-Waxman framework.

The patent’s claims are method claims. That makes the listed use and the product’s approved administration instructions important. A generic or 505(b)(2) applicant would need to assess whether its proposed labeling and manufacturing process practice the claimed steps.

Are there Paragraph IV challenges or generic launch risks?

A Paragraph IV applicant seeking approval for a fluciclovine F 18 product could challenge the patent by asserting that it is invalid, not infringed, or not properly listable.

The principal challenge routes would be:

1. Non-infringement: Use a different precursor, solvent, deprotection chemistry or manufacturing sequence.
2. Invalidity: Challenge written description, enablement, definiteness, anticipation or obviousness.
3. Claim construction: Argue that "substantially does not give methanol" is indefinite or not met by the proposed process.
4. Regulatory distinction: Use a different labeling strategy or approval pathway that does not include the claimed diagnostic method.
5. Process confidentiality: Design around the manufacturing limitations while producing the same radiotracer.

Generic entry is more complex than for a conventional oral drug. Fluciclovine F 18 is a short-lived radiopharmaceutical with a 109.7-minute physical half-life. Commercial supply depends on cyclotron access, radiochemistry equipment, validated synthesis, quality control and time-sensitive distribution.

A successful Paragraph IV challenge would not by itself eliminate the need to solve those manufacturing and distribution constraints.

Which companies compete with Axumin and fluciclovine F 18?

Axumin competes in the PET imaging market with other prostate-cancer and oncology tracers, including:

Product class	Representative product	Competitive issue
Fluciclovine PET	Axumin	Established amino-acid PET agent; recurrent prostate cancer imaging
PSMA PET	PYLARIFY, Pluvicto-related PSMA platform, Illuccix and related agents	Higher prostate-specific targeting and expanding clinical adoption
Glucose PET	FDG	Broad oncology use, lower specificity for some prostate-cancer settings
Choline PET	C-11 or F-18 choline agents	Regional availability and shorter or different production requirements
MRI and CT	Conventional imaging	Lower radiopharmaceutical manufacturing complexity but different sensitivity and specificity

PSMA PET has become the main commercial competitive threat in recurrent prostate cancer imaging. That competitive pressure limits the commercial value of process exclusivity even if U.S. 9,387,266 remains enforceable.

How strong is the patent estate for Axumin?

The strength of U.S. 9,387,266 is best characterized as targeted rather than broad.

Strengths

• It covers a commercially relevant fluciclovine F 18 production route.
• It includes specific process conditions likely to be used in automated radiopharmaceutical synthesis.
• It links production to the diagnostic use of the resulting tracer.
• The no-substantial-methanol limitation may distinguish the claimed route from older processes.

Weaknesses

• It does not broadly claim fluciclovine F 18 as a composition.
• It does not cover every precursor or fluorination solvent.
• It requires both process and administration limitations.
• The methanol limitation may create proof and definiteness disputes.
• Radiopharmaceutical manufacturers may have practical design-around options.
• The commercial market faces substitution from PSMA PET agents.

The patent is strongest against a manufacturer that uses the exact precursor, acetonitrile radiofluorination, acid deprotection and methanol-avoiding process described in the claims. It is weaker against a manufacturer using a materially different precursor or synthesis route.

What manufacturing and intellectual-property barriers remain after patent expiry?

Patent expiry would remove the patent-based exclusion for the claimed process, but competitors would still face:

• FDA drug approval or applicable radiopharmaceutical regulatory requirements;
• chemistry, manufacturing and controls validation;
• sterile manufacturing controls;
• radionuclide quality specifications;
• cyclotron and target-system access;
• automated synthesis equipment;
• short distribution windows;
• hospital and imaging-center contracts;
• reimbursement and clinical adoption;
• trade-secret process knowledge;
• third-party patent rights in alternative precursors or manufacturing equipment.

Radiopharmaceutical production is local or regional because the short half-life limits transport. That makes manufacturing capacity and logistics important commercial barriers even after patent expiration.

What patent litigation and settlement issues affect the product?

The supplied claim record does not identify a court judgment, Paragraph IV settlement or license settlement concerning U.S. 9,387,266. The relevant legal exposure would center on whether a competing manufacturer practices the claimed synthesis sequence.

Potential litigation evidence would include:

• ANDA or 505(b)(2) Paragraph IV notices;
• Hatch-Waxman district-court complaints;
• declaratory-judgment actions;
• inter partes review petitions;
• FDA Orange Book patent-listing disputes;
• licenses between the patent owner, Axumin sponsor and radiopharmaceutical manufacturers.

A settlement could permit entry before the expected 2032 patent endpoint, but the supplied information does not establish such an agreement.

How does U.S. 9,387,266 compare with composition and use patents?

Patent type	Scope	Relevance to U.S. 9,387,266
Composition patent	Covers the molecule or labeled compound	U.S. 9,387,266 is not principally a composition claim
Method-of-use patent	Covers administration for a disease or diagnostic purpose	The patent includes tumor PET administration
Manufacturing patent	Covers precursor, solvent, reaction and purification steps	This is the patent’s principal protection
Formulation patent	Covers injectable composition, excipients or stability	The supplied claims do not focus on formulation
Device or kit patent	Covers synthesis modules, cassettes or diagnostic kits	No such limitation appears in the supplied claims
Trade secret	Protects confidential process parameters	May supplement the patent after or outside patent expiry

Key Takeaways

• U.S. Patent 9,387,266 protects a specific method for producing fluciclovine F 18 and using it for tumor PET.
• The required process uses a defined Boc-protected precursor, radioactive fluoride, acetonitrile, acid deprotection and conditions that substantially avoid methanol.
• Claim 2 and claim 3 specifically require hydrochloric acid.
• The patent does not broadly cover every method of making fluciclovine F 18.
• The patent was granted July 12, 2016, with an expected term extending into late 2032, subject to official patent-term adjustment.
• The principal design-around opportunities involve changing the precursor, solvent, deprotection chemistry or process sequence.
• Axumin faces competitive pressure from PSMA PET agents, particularly in recurrent prostate cancer imaging.
• Radiopharmaceutical manufacturing capacity, cyclotron access and short half-life logistics remain important barriers independent of patent protection.

FAQs About U.S. Patent 9,387,266

Does U.S. Patent 9,387,266 cover Axumin itself?

It covers a claimed method for producing and administering the fluciclovine F 18 used in Axumin. It is not a broad composition-of-matter claim to every molecule or formulation containing fluciclovine F 18.

Can a company avoid the patent by using a solvent other than acetonitrile?

Potentially. The supplied claims expressly require acetonitrile for the radioactive-fluoride reaction. A different solvent system may provide a literal non-infringement position, subject to claim construction and equivalents analysis.

Does claim 3 require hydrochloric acid?

Yes. Claim 3 expressly requires hydrochloric acid for deprotection. Claim 4 allows acid generally, while claim 2 narrows claim 1 to hydrochloric acid.

Is a fluciclovine F 18 product infringing if it is made outside the United States?

U.S. patent exposure can arise from importing, selling, offering for sale or using an infringing product in the United States. The territorial analysis depends on the acts performed and the applicable statutory provisions, including process-patent provisions where relevant.

Does patent expiration eliminate FDA approval requirements for competing fluciclovine products?

No. Patent expiry removes the relevant patent barrier but does not eliminate FDA approval, chemistry-manufacturing-controls obligations, sterile manufacturing requirements or radiopharmaceutical quality standards.

References

1. United States Patent and Trademark Office. (2016). U.S. Patent No. 9,387,266, Method for producing 1-amino-3-[18F]fluorocyclobutanecarboxylic acid. U.S. Department of Commerce.

2. U.S. Food and Drug Administration. (2016). Axumin (fluciclovine F 18) injection prescribing information. FDA.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

4. U.S. Food and Drug Administration. (2016). FDA approves new diagnostic imaging drug for prostate cancer. FDA.

Drugs Protected by US Patent 9,387,266

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Blue Earth	AXUMIN	fluciclovine f-18	SOLUTION;INTRAVENOUS	208054-001	May 27, 2016		RX	Yes	Yes	9,387,266					METHOD OF DIAGNOSING TUMORS USING POSITRON EMISSION TOMOGRAPHY

Foreign Priority and PCT Information for Patent: 9,387,266

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2005-343653	Nov 29, 2005

International Family Members for US Patent 9,387,266

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2006319987
Brazil	PI0619213
Canada	2629227
China	101316812
European Patent Office	1978015
European Patent Office	3354639
Spain	2663496