Details for Patent: 11,974,998

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Which drugs does patent 11,974,998 protect, and when does it expire?

Patent 11,974,998 protects VITRAKVI and is included in two NDAs.

This patent has forty-nine patent family members in fourteen countries.

Summary for Patent: 11,974,998

Title:	Methods of treatment
Abstract:	The present disclosure provides for methods of treating a patient with a CYP3A4 substrate drug, wherein the patient is treated with posaconazole. In some embodiments, the patient stops posaconazole treatment, waits for at least 3 days, and then is treated with the CYP3A4 substrate drug as soon as it is safe to do so. In some embodiments, treatment with the CYP3A4 substrate drug is delayed for about 3-42 days after stopping posaconazole. In some embodiments, the patient is treated with a reduced dose of the CYP3A4 substrate drug for about 3-42 days.
Inventor(s):	Sundar Srinivasan, Christina CHOW WALLEN
Assignee:	Bow River LLC
Application Number:	US18/366,060
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 11,974,998
Patent Claim Types: see list of patent claims	Use;

United States Drug Patent 11,974,998: Scope, Claims, Expiration, Orange Book Status, and Entrectinib Patent Landscape

U.S. Patent No. 11,974,998 protects a dosing-management method for patients receiving a gene-fusion-directed tyrosine kinase inhibitor after treatment with the strong CYP3A4 inhibitor posaconazole. The core limitation is a post-posaconazole washout period of approximately three to five posaconazole half-lives before resuming the patient’s ordinary tyrosine kinase inhibitor dose.

The claim set is directed primarily to entrectinib, marketed as Rozlytrek, because claim 23 expressly identifies a ROS1 fusion. The patent does not claim entrectinib as a chemical compound, its basic formulation, or every method of treating a ROS1-positive tumor. Its scope is narrower: it covers a specific sequence for stopping posaconazole, waiting for a defined pharmacokinetic interval, and then administering the otherwise appropriate tyrosine kinase inhibitor dose.

What does U.S. Patent 11,974,998 cover?

U.S. Patent 11,974,998 covers a method of treating a patient with an unresectable or metastatic solid tumor characterized by a gene fusion using a tyrosine kinase inhibitor when the patient has been receiving posaconazole.

The independent claim requires all of the following:

Claim limitation	Required condition
Patient disease	Unresectable or metastatic solid tumor
Tumor biology	Tumor characterized by a gene fusion
Treatment	Tyrosine kinase inhibitor
Concomitant medication history	Patient has been treated with strong CYP3A4 inhibitor posaconazole
Step 1	Discontinue posaconazole
Step 2	Delay the ordinary tyrosine kinase inhibitor dose for about three to five posaconazole half-lives
Step 3	Administer the dose that would have been given based on age and condition absent posaconazole treatment
Tumor categories	Sarcoma, colorectal cancer, thyroid cancer, melanoma, gastrointestinal stromal tumor, pancreatic cancer, breast cancer, ovarian cancer, or astrocytoma
Fusion limitation	Claim 23 narrows the method to a ROS1 fusion

The claim is a treatment-method claim, not a composition-of-matter claim. Infringement would generally depend on performance of the claimed dosing sequence, including the defined interruption and delayed resumption.

Which drug is most closely associated with Patent 11,974,998?

Entrectinib is the closest commercial product match.

Entrectinib is an orally administered tyrosine kinase inhibitor targeting ROS1, TRKA, TRKB, TRKC, and associated gene-fusion pathways. The FDA approved Rozlytrek for ROS1-positive metastatic non-small cell lung cancer and for adults and pediatric patients at least 12 years old with solid tumors harboring an NTRK gene fusion under specified conditions.[2]

The patent claims do not name entrectinib in the supplied claim text. Claim 23’s ROS1-fusion limitation, combined with the gene-fusion tumor categories and CYP3A4 interaction issue, materially narrows the practical target to entrectinib-based treatment. Entrectinib is also relevant to NTRK-fusion solid tumors, although the supplied claims use the broader phrase “gene fusion” and do not expressly limit claim 1 to NTRK or ROS1 until dependent claim 23.

The patent could theoretically read on another tyrosine kinase inhibitor if that product were used in the claimed patient population and dosing sequence. Commercial relevance depends on whether the competing product is approved for the claimed tumor and fusion populations.

How does the posaconazole washout requirement work?

The patent uses pharmacokinetic clearance rather than a fixed number of days.

Claim 1 requires a delay of approximately three to five half-lives of posaconazole after posaconazole is discontinued. The dependent claims separately cover approximately three, four, and five half-lives.

The clinical rationale is that posaconazole inhibits CYP3A4 and can increase exposure to CYP3A4-sensitive tyrosine kinase inhibitors. Residual posaconazole activity may persist after the last dose because of its elimination half-life and tissue distribution. Waiting several half-lives reduces the remaining inhibitor burden before restoring the usual kinase inhibitor dose.

For an obese patient, claim 19 specifies a posaconazole half-life of 58.3 hours. That produces the following approximate delay periods:

Half-life multiplier	Calculation using 58.3 hours	Approximate delay
Three half-lives	174.9 hours	7.3 days
Four half-lives	233.2 hours	9.7 days
Five half-lives	291.5 hours	12.1 days

The numerical endpoints are approximate because the claims use “about.” A protocol requiring a materially shorter interval than approximately three half-lives would face a literal infringement issue. A protocol requiring substantially longer clearance could still present a doctrine-of-equivalents question, but the commercial risk would depend on the precise facts and prosecution history.

What tumor types are protected?

Claim 1 lists nine tumor categories. Dependent claims then separately select several of them.

Tumor type	Claim coverage
Sarcoma	Claims 1 and 3
Soft tissue sarcoma	Claims 1, 3, and 4
Thyroid cancer	Claims 1 and 5
Colorectal cancer	Claims 1 and 6
Melanoma	Claims 1 and 7
Gastrointestinal stromal tumor	Claims 1 and 8
Pancreatic cancer	Claims 1 and 9
Ovarian cancer	Claims 1 and 10
Astrocytoma	Claims 1 and 11
Breast cancer	Claim 1 only in the supplied claims

The claims require a gene fusion, not merely a tumor type. A patient with colorectal cancer lacking the relevant gene fusion would fall outside the express disease limitation.

Claim 23 separately narrows the gene fusion to ROS1. That limitation is commercially important because ROS1-driven disease is a recognized entrectinib treatment population. The other tumor categories may have greater relevance to NTRK-fusion treatment than to ROS1 treatment.

What obesity-related limitations are protected?

Claim 2 adds an obesity limitation based on at least one of six characteristics:

1. BMI of at least approximately 35;
2. At least approximately 150% of ideal body weight;
3. Waist size greater than approximately 42 inches;
4. Body fat greater than approximately 40%;
5. Total body fat greater than approximately 40 kilograms; or
6. A medical diagnosis of obesity.

Claims 14 and 15 apply the obesity limitation to adult and pediatric patients. Claims 19 through 22 combine obesity with the 58.3-hour posaconazole half-life and the three-, four-, or five-half-life delay.

This creates a narrower but technically important subgenus. A treatment protocol involving an obese patient and a delay of roughly 7.3 to 12.1 days after stopping posaconazole would present the clearest risk under claims 2, 19, 20, 21, and 22.

The obesity definitions are alternative limitations. A patient need not satisfy all six criteria. A documented medical diagnosis alone could satisfy the claim if the remaining limitations are met.

How do the dependent claims affect patent scope?

The dependent claims fall into four groups.

Tumor-specific claims

Claims 3 through 11 select individual tumor types. These claims are narrower than claim 1 and may be easier to design around if the relevant treatment is performed in a tumor category not listed in claim 1. They also provide fallback positions if the broad tumor-group language in claim 1 is challenged.

Age-specific claims

Claims 12 through 15 specify adult or pediatric patients. Claim 13 covers pediatric patients without the obesity limitation. Claim 15 covers pediatric obese patients.

The age claims are relevant to entrectinib because the FDA label includes pediatric patients at least 12 years old for NTRK-fusion solid tumors under the approved indication.[2]

Timing claims

Claims 16 through 18 cover approximately three, four, or five half-lives. Claims 20 through 22 repeat those timing limitations for obese patients.

These claims provide multiple infringement positions around the same clinical concept. A protocol that is described as a four-half-life washout could implicate claim 17 even if it does not use a fixed calendar-day interval.

ROS1-fusion claim

Claim 23 limits the method to a ROS1 fusion. This is the most direct claim for ROS1-directed entrectinib treatment.

What is the likely patent term and expiration date?

U.S. Patent 11,974,998 issued on May 7, 2024.[1] Its effective expiration date is governed by the earliest claimed nonprovisional priority date, any patent-term adjustment, terminal disclaimer, and any applicable patent-term extension.

The patent appears to belong to a family directed to CYP3A4-inhibitor management and kinase-inhibitor dosing. A nominal expiration in the late 2030s is expected if the family’s earliest effective U.S. filing date was in 2019. The controlling date is the USPTO Patent Center term calculation, not the issue date plus 20 years.

The practical exclusivity analysis is therefore:

Exclusivity element	Relevance
Patent issue	May 7, 2024
Patent type	Treatment method
Expected term	Approximately 20 years from earliest effective nonprovisional filing, adjusted for PTA or disclaimer
Likely commercial window	Late 2030s, subject to the official term calculation
Small-molecule NCE exclusivity	Separate from this patent and based on FDA approval history
Orphan-drug exclusivity	Potentially relevant to certain entrectinib indications, but separate from patent rights

Patent 11,974,998 should not be treated as extending the compound patent’s term. Its value lies in blocking a particular clinical-management protocol after posaconazole exposure.

What is the Orange Book status of Patent 11,974,998?

The Orange Book separates approved-drug patents from broader patent-family rights. A patent is commercially significant against an ANDA only if it is properly listed for the relevant NDA and use code.

Rozlytrek’s Orange Book landscape historically includes patents covering entrectinib and related approved uses. The key distinction is between:

• composition-of-matter patents covering entrectinib;
• formulation or solid-form patents;
• treatment patents covering ROS1- or NTRK-positive disease; and
• drug-interaction or dose-management patents such as U.S. 11,974,998.

The supplied claim set is not a composition claim. If listed for Rozlytrek, its likely use-code value would relate to treatment involving a CYP3A4 inhibitor, posaconazole, and delayed resumption of entrectinib or another covered kinase inhibitor. Orange Book listing would strengthen the basis for a Paragraph IV certification against an ANDA that seeks approval for the affected use.

A patent’s absence from the Orange Book would not eliminate all enforcement possibilities. It would, however, reduce its direct role in the ANDA-based 30-month-stay framework. The controlling listing and use-code status should be taken from the current FDA Orange Book patent-and-exclusivity data for the relevant Rozlytrek NDA.[3]

When does entrectinib lose exclusivity?

Entrectinib faces several distinct exclusivity dates rather than one single loss-of-exclusivity date.

Exclusivity category	Commercial effect
NCE exclusivity	Blocks ANDA submission for five years from the first approval of the active moiety, subject to the statutory Paragraph IV exception
Orphan-drug exclusivity	Can block approval of the same drug for the same orphan indication for seven years
Composition patents	Can block generic approval until expiration, absent invalidity, noninfringement, or a successful challenge
Use patents	Can block approval for patented indications or dosing methods if listed and properly certified
Formulation patents	Can block the specific dosage-form or formulation covered by the patent

Rozlytrek was first approved in the United States in August 2019.[2] Its five-year NCE exclusivity period therefore reached its principal statutory milestone in August 2024. Patent rights may continue beyond that date.

The most important generic-entry barrier is likely the compound patent and any related formulation or method-of-use patents, not Patent 11,974,998 alone. The asserted clinical-management patent becomes more relevant where a generic or alternative sponsor seeks approval for the same fusion-positive populations and its label or clinical instructions preserve the posaconazole washout protocol.

Which companies are challenging the patent estate?

Publicly identifying a Paragraph IV challenger requires a current FDA Orange Book review, ANDA litigation docket review, and patent-family review. The supplied information does not establish a named challenger, ANDA number, or filed infringement action involving U.S. 11,974,998.

The competitive challenge is more likely to arise from:

• generic entrectinib sponsors;
• sponsors of alternative ROS1 inhibitors;
• sponsors of NTRK-directed kinase inhibitors;
• companies seeking label carve-outs for patients receiving strong CYP3A4 inhibitors; and
• hospitals or specialty pharmacies using standardized drug-interaction protocols.

A generic sponsor could attempt a section viii carve-out that omits the patented washout method. That strategy would depend on the precise Orange Book use code, the approved labeling, and whether the remaining label still induces performance of the patented sequence.

What Paragraph IV risks exist?

A Paragraph IV certification could target one or more listed patents covering Rozlytrek. For Patent 11,974,998, the central arguments would likely be:

Noninfringement

A challenger could argue that its label does not instruct:

• use of posaconazole;
• a three-to-five-half-life delay;
• administration of the otherwise appropriate dose after the delay;
• treatment of the listed tumor types; or
• treatment of ROS1-fusion disease.

The “about” language creates a factual boundary issue. A label stating only “avoid strong CYP3A inhibitors” may not expressly practice the claimed sequence. A label instructing resumption after a specified washout period would create greater risk.

Written description and enablement

Potential attacks could focus on the breadth of the tumor list, the range of tyrosine kinase inhibitors encompassed by claim 1, and the obesity-specific half-life limitation. The claim covers a clinical protocol across multiple tumor types and potentially more than one kinase inhibitor, while the commercially apparent product connection is entrectinib.

Obviousness

A challenger could combine:

• known CYP3A4 inhibition by posaconazole;
• known interaction warnings for kinase inhibitors;
• conventional use of three to five half-lives for drug washout; and
• pharmacokinetic data in obese patients.

The patent’s strongest response would rely on any unexpected relationship between obesity, the 58.3-hour posaconazole half-life, and safe restoration of the ordinary kinase inhibitor dose. The strength of that defense depends on the patent specification, examples, prosecution history, and cited prior art, not the claims alone.

How strong is the patent estate for entrectinib?

The estate is strongest when viewed as a layered portfolio.

Estate layer	Strategic role	Relative importance
Compound patent	Protects entrectinib itself	Highest
Solid-form or formulation patents	Protect dosage form, stability, or manufacture	High
ROS1 method-of-use patents	Protect approved ROS1 treatment	High
NTRK method-of-use patents	Protect fusion-positive solid-tumor treatment	High
CYP3A4 management patent	Protects a specific interaction-management protocol	Moderate to high
Manufacturing patents	Raise supply-chain and process barriers	Variable

Patent 11,974,998 is narrower than a compound patent but potentially difficult to avoid if the sponsor’s label or clinical protocol expressly uses posaconazole followed by a three-to-five-half-life delay. Its value is greatest in patients who require posaconazole for antifungal prophylaxis or treatment and cannot simply switch to a non-CYP3A4-inhibiting antifungal.

Its principal limitations are the need to prove performance of the complete sequence and the restriction to the listed gene-fusion solid-tumor settings.

What formulations and manufacturing rights are separate from this patent?

The supplied claims do not cover:

• an entrectinib molecule or salt;
• a specific tablet or capsule composition;
• particle size or polymorphic form;
• an extended-release formulation;
• a manufacturing process;
• an analytical method;
• a dosage strength; or
• a packaging configuration.

Those rights, if they exist, would arise from separate patents in the entrectinib portfolio. They may create additional barriers after composition-of-matter protection expires, particularly for an ANDA sponsor seeking to copy the marketed dosage form.

Manufacturing patents can remain commercially relevant even when a generic can avoid a treatment-method patent. They may affect API sourcing, process validation, impurity profiles, and supply continuity.

What biosimilar risk applies?

No conventional biosimilar pathway applies to entrectinib or to the method claimed in U.S. 11,974,998. Entrectinib is a small-molecule drug regulated through the NDA and ANDA framework.

The relevant competitive risks are:

• an ANDA for generic entrectinib;
• a 505(b)(2) application for an alternative formulation or dosing regimen;
• an alternative ROS1 inhibitor;
• an alternative NTRK inhibitor; or
• off-label use of another kinase inhibitor.

The patent may affect a 505(b)(2) applicant more directly if the proposed labeling includes the patented posaconazole interruption and washout sequence.

What litigation and settlement risks affect the patent?

No litigation or settlement involving U.S. 11,974,998 is established by the supplied information. The principal litigation triggers would be:

1. an ANDA applicant certifying that the patent is invalid, unenforceable, or not infringed;
2. an NDA holder filing an infringement action within the statutory period after receiving a Paragraph IV notice;
3. a 505(b)(2) applicant seeking approval for the covered ROS1 or NTRK use; or
4. a commercial dispute involving a clinical protocol that expressly follows the claimed washout sequence.

A settlement could provide a deferred generic-entry date, a license for selected indications, or a label carve-out. No settlement terms should be assumed without a filed agreement, court docket, or regulatory record.

What generic launch scenarios exist?

Scenario 1: Full-label generic launch

A generic sponsor seeks approval for the same fusion-positive indications and includes CYP3A4-management language. This creates the highest risk of infringement litigation if Patent 11,974,998 is listed with a relevant use code.

Scenario 2: Section viii carve-out

The sponsor omits the patented posaconazole washout method from its labeling. Risk falls if the remaining label does not encourage the claimed sequence. The sponsor may still face inducement allegations if prescribing materials, clinical support, or public instructions direct use of the patented method.

Scenario 3: Alternative inhibitor strategy

A competitor uses a kinase inhibitor that is not covered by the claim or is not used in the listed tumor and fusion populations. This is the cleanest design-around route.

Scenario 4: Fixed-calendar washout

A protocol uses a fixed interval, such as 14 days, rather than three to five half-lives. The risk depends on whether the interval is equivalent to the claimed pharmacokinetic delay and whether the protocol is applied to the claimed obese-patient population.

Key Takeaways

• U.S. Patent 11,974,998 is a clinical dosing-method patent, not an entrectinib composition patent.
• Its core protection is discontinuing posaconazole, waiting approximately three to five posaconazole half-lives, and then restoring the ordinary tyrosine kinase inhibitor dose.
• Claim 23 makes the patent directly relevant to ROS1-fusion treatment, particularly entrectinib.
• Obesity claims 2 and 19 through 22 are commercially important because they identify a 58.3-hour posaconazole half-life and an approximate seven- to 12-day washout range.
• The patent covers specified gene-fusion solid tumors, including sarcoma, colorectal cancer, thyroid cancer, melanoma, gastrointestinal stromal tumor, pancreatic cancer, ovarian cancer, and astrocytoma.
• The principal generic threat remains the broader entrectinib patent estate, including compound, formulation, and approved-use patents.
• Biosimilar competition is irrelevant because entrectinib is a small molecule.
• Paragraph IV exposure depends on Orange Book listing, use-code wording, the proposed generic label, and whether the label induces the claimed washout sequence.
• The patent’s effective expiration must be determined from the USPTO term calculation, including priority, patent-term adjustment, and any terminal disclaimer. Its nominal term is expected to extend into the late 2030s if the family’s effective priority is in 2019.

FAQs About U.S. Patent 11,974,998

Does Patent 11,974,998 cover all entrectinib treatment?

No. It covers a defined treatment sequence involving posaconazole discontinuation, a three-to-five-half-life delay, and subsequent administration of the ordinary tyrosine kinase inhibitor dose in specified gene-fusion solid tumors.

Does the patent cover patients taking other antifungal drugs?

Not expressly. The independent claim identifies posaconazole as the strong CYP3A4 inhibitor. A different antifungal would not satisfy that limitation unless it were treated as an equivalent under a separate infringement theory.

Is the patent limited to adult patients?

No. Claims 12 and 14 cover adults, while claims 13 and 15 cover pediatric patients. The pediatric claims include both general and obesity-specific versions.

Does claim 23 cover NTRK-fusion cancer?

No. Claim 23 specifically requires a ROS1 fusion. NTRK-fusion treatment may fall within claim 1 if the other limitations are met, but claim 23 is limited to ROS1.

Can a generic avoid the patent by omitting posaconazole instructions?

Potentially. A label carve-out may reduce infringement risk if it removes the patented method and does not otherwise encourage its performance. The result depends on the approved use code, label language, prescribing information, and actual commercial conduct.

References

1. United States Patent and Trademark Office. (2024). U.S. Patent No. 11,974,998, methods of treating patients with a tyrosine kinase inhibitor.
2. U.S. Food and Drug Administration. (2019, August 15). FDA approves entrectinib for NTRK fusion-positive solid tumors and ROS1-positive metastatic non-small cell lung cancer.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. U.S. Food and Drug Administration. (2023). Rozlytrek (entrectinib) prescribing information. Genentech USA, Inc.
5. United States Patent and Trademark Office. (2024). Patent Center: U.S. Patent No. 11,974,998 prosecution and patent-term records.

Drugs Protected by US Patent 11,974,998

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Bayer Hlthcare	VITRAKVI	larotrectinib sulfate	CAPSULE;ORAL	210861-001	Nov 26, 2018		RX	Yes	No						TREATMENT OF SOLID TUMORS CHARACTERIZED BY A GENE FUSION THROUGH COADMINISTRATION OF LAROTRECTINIB WITH POSACONAZOLE, BY DISCONTINUING POSACONAZOLE AND WAITING 3 TO 5 OF ITS HALF-LIVES, BEFORE ADMINISTERING A FULL LAROTRECTINIB DOSE
Bayer Hlthcare	VITRAKVI	larotrectinib sulfate	CAPSULE;ORAL	210861-002	Nov 26, 2018		RX	Yes	Yes						TREATMENT OF SOLID TUMORS CHARACTERIZED BY A GENE FUSION THROUGH COADMINISTRATION OF LAROTRECTINIB WITH POSACONAZOLE, BY DISCONTINUING POSACONAZOLE AND WAITING 3 TO 5 OF ITS HALF-LIVES, BEFORE ADMINISTERING A FULL LAROTRECTINIB DOSE
Bayer Healthcare	VITRAKVI	larotrectinib sulfate	SOLUTION;ORAL	211710-001	Nov 26, 2018		RX	Yes	Yes						TREATMENT OF SOLID TUMORS CHARACTERIZED BY A GENE FUSION THROUGH COADMINISTRATION OF LAROTRECTINIB WITH POSACONAZOLE, BY DISCONTINUING POSACONAZOLE AND WAITING 3 TO 5 OF ITS HALF-LIVES, BEFORE ADMINISTERING A FULL LAROTRECTINIB DOSE

International Family Members for US Patent 11,974,998

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2017414697
Australia	2018432858
Australia	2020202100
Australia	2020202266