Details for Patent: 9,211,291

Which drugs does patent 9,211,291 protect, and when does it expire?

Patent 9,211,291 protects NERLYNX and is included in one NDA.

This patent has sixty-four patent family members in thirty-two countries.

Summary for Patent: 9,211,291

Title:	Treatment regimen utilizing neratinib for breast cancer
Abstract:	An extended regimen for treatment of HER-2/neu overexpressed/amplified cancer is described, with involves delivering a course of neratinib therapy to HER-2/neu overexpressed/amplified cancer patients following the completion of surgical and adjuvant therapy. The neratinib regimen may be continued for upwards of twelve months to five years. Also provided are pharmaceutical kits designed to facilitate compliance with the regimen.
Inventor(s):	Anna Berkenblit, Florence Marie Helene Binlich, Paul Goss
Assignee:	Wyeth LLC
Application Number:	US13/256,910
Patent Claim Types: see list of patent claims	Use; Delivery; Dosage form;

US Patent 9,211,291: Neratinib Extended-Adjuvant Breast Cancer Patent Scope and Landscape

US Patent No. 9,211,291 protects a specific extended-adjuvant treatment sequence for early-stage HER2-positive breast cancer: at least 12 cycles of trastuzumab-based adjuvant therapy, followed by neratinib within roughly two weeks to one year after completion of surgery and standard adjuvant treatment. The core commercial embodiment is oral neratinib, typically 240 mg daily for 12 months.

The patent is an indication and regimen patent, not a basic compound patent. Its principal value is the treatment sequence that underlies the FDA-approved extended-adjuvant use of Nerlynx. The strongest claim elements are the prior completion of trastuzumab, the timing window, and the early-stage HER2-positive patient population. A generic applicant seeking approval for the same labeled use would face a method-of-use patent issue, although the practical risk would depend on Orange Book listing, Paragraph IV strategy, labeling carve-outs, and the patent's enforceability.

What does US Patent 9,211,291 cover?

The patent covers methods and regimens for administering neratinib after completion of a defined trastuzumab-containing adjuvant course in early-stage HER2-positive breast cancer.

Claim element	Scope under the supplied claims	Commercial relevance
Disease setting	Early-stage HER2-positive breast cancer	Tracks the intended post-surgery adjuvant market
Prior therapy	At least 12 cycles of trastuzumab adjuvant therapy	Defines the sequencing requirement
Timing	Neratinib begins about two weeks to one year after completion of surgical and standard adjuvant therapy	Captures delayed, extended-adjuvant treatment
Duration	Eight months to five years; dependent claims emphasize at least 12 months	Covers the FDA-approved one-year course
Route	Oral administration	Aligns with Nerlynx tablets
Dose	120 mg to 300 mg daily, including 240 mg daily	Captures the commercial dose
Outcomes	Improved IDFS, DFS-HER2-positive DCIS, overall survival, time to distant recurrence, and distant disease-free survival	Adds outcome-oriented method claims
Prior chemotherapy	May include doxorubicin, cyclophosphamide, paclitaxel, docetaxel, carboplatin, lapatinib, pertuzumab, bevacizumab, trastuzumab-DM1, or anthracycline-based therapy	Broadens coverage across common HER2-positive regimens
Patient biology	Hormone receptor-positive, estrogen receptor-positive, or progesterone receptor-positive patients	Covers important post-trastuzumab subgroups
Concomitant therapy	Endocrine therapy and bisphosphonates	Reduces design-around opportunities for those combinations

Claim 1 is the principal regimen claim. Claims 2 through 8 narrow the regimen by duration, route, dosage form, dosing frequency, and dose. Claim 9 is a separate method claim directed to improving specified clinical outcomes. Claims 10 and 11 add prior trastuzumab plus chemotherapy details. Claim 12 restates the extended-adjuvant concept with a minimum 12-month neratinib course. Claims 13 through 18 address timing, concomitant treatment, and hormone receptor status.

What are the key limitations of claim 1?

Claim 1 requires all of the following:

1. The patient has early-stage HER2-positive breast cancer.
2. The patient has completed at least 12 cycles of trastuzumab adjuvant therapy.
3. Neratinib is delivered after that trastuzumab course.
4. Neratinib begins about two weeks to one year from completion of surgical and standard adjuvant therapy.

The claim does not require a particular chemotherapy backbone in its independent form. It also does not expressly require 240 mg daily, tablets, or a 12-month course. Those limitations appear in dependent claims and in the separate claim 12 regimen.

The phrase "at the completion of at least twelve cycles of trastuzumab adjuvant therapy" is central. A treatment involving fewer than 12 trastuzumab cycles may fall outside the literal scope of claim 1, subject to the interpretation of "cycles" and potential doctrine-of-equivalents arguments. A patient who receives 12 cycles but starts neratinib more than one year after the relevant surgical and standard-adjuvant endpoint presents a stronger non-infringement position.

The claim also raises a timing-construction issue. The one-year period is measured from completion of "surgical and standard adjuvant therapy," while the sequence separately refers to completion of trastuzumab. In the FDA-approved clinical setting, the relevant commercial pattern is initiation of neratinib shortly after trastuzumab completion, generally within one year of completing the primary treatment course.

How do claims 2 through 8 affect infringement risk?

Claims 2 through 8 create narrower fallback positions around the commercial regimen.

Duration and route

Claim 2 covers an eight-month to five-year course. Claim 3 narrows this to at least approximately 12 months. A one-year course is therefore directly within the claimed range.

Claim 4 requires oral administration, and claim 5 narrows oral delivery to tablets. These claims map closely onto Nerlynx's approved dosage form.

Daily dose

Claim 7 covers 120 mg to 300 mg daily. Claim 8 specifically covers 240 mg. The approved Nerlynx regimen is 240 mg once daily for one year, subject to dose reductions for toxicity and diarrhea management.

A product label that recommends the full 240 mg dose would create a direct overlap with claims 7 and 8 if the label also instructs treatment after the required trastuzumab course. Dose-reduction instructions do not necessarily eliminate risk because the claimed range includes lower doses, and inducement analysis may focus on the recommended use rather than every dose actually administered.

What is the scope of the outcome claims?

Claim 9 targets methods for improving:

• Invasive disease-free survival;
• Disease-free survival in HER2-positive DCIS;
• Overall survival;
• Time to distant recurrence; and
• Distant disease-free survival.

Claim 12 contains a broader combination of these outcome concepts and requires at least 12 months of neratinib following at least 12 cycles of trastuzumab-based adjuvant treatment.

Outcome language can create claim-construction and enablement issues. A method-of-treatment claim generally does not require that every treated patient achieve the claimed clinical benefit. The relevant issue is whether the treatment is administered with the claimed therapeutic purpose and whether the specification adequately supports the asserted result.

The clinical foundation for the commercial indication is the ExteNET study, which evaluated one year of neratinib after trastuzumab-based therapy. The trial reported an invasive disease-free survival benefit, with the effect more pronounced in hormone receptor-positive patients and in patients who started neratinib relatively soon after trastuzumab completion (Chan et al., 2016; FDA, 2017).

How does the patent cover hormone receptor-positive patients?

Claims 15 through 18 expressly cover hormone receptor-positive patients, including estrogen receptor-positive and progesterone receptor-positive patients.

This subgroup language is commercially important because the ExteNET benefit was particularly relevant in hormone receptor-positive disease. The claims do not appear limited to patients who receive endocrine therapy, although claim 14 separately covers concomitant endocrine treatment.

A treatment involving a hormone receptor-positive, HER2-positive patient who completed trastuzumab and then receives oral neratinib is therefore within the most commercially important portion of the patent's claim set.

When does US Patent 9,211,291 lose exclusivity?

The public patent record identifies US 9,211,291 as a method-of-use patent with an August 2006 priority date and a US patent term that extends into 2027. The projected base expiration is approximately August 2027, subject to patent-term adjustment, terminal-disclaimer effects, patent-term extension, and any legally operative correction.

Event	Date or period
Earliest disclosed priority	August 21, 2006
US patent issuance	December 15, 2015
FDA approval of Nerlynx	July 17, 2017
Commercial indication	Extended adjuvant treatment of early-stage HER2-positive breast cancer after trastuzumab-based therapy
Projected base patent expiry	Approximately August 2027

The patent's effective commercial life began before FDA approval because the patent issued in 2015. FDA approval did not create the patent right, but it made the claimed regimen commercially actionable through the approved label.

Patent expiration is distinct from FDA regulatory exclusivity. Nerlynx received standard new chemical entity exclusivity associated with its 2017 approval. That regulatory exclusivity period expired before the projected end of the method patent term. The remaining barrier is therefore primarily patent-based rather than NCE-exclusivity-based.

What is the Orange Book status of US 9,211,291?

US 9,211,291 has been associated with the Nerlynx patent estate and is the type of method-of-use patent that can be listed in the FDA Orange Book for the approved extended-adjuvant indication. Orange Book treatment matters because an ANDA applicant must address listed patents through certification.

The relevant certification options are:

• Paragraph I: no patent information is listed;
• Paragraph II: the patent has expired;
• Paragraph III: the applicant will wait until patent expiration;
• Paragraph IV: the patent is invalid, unenforceable, or will not be infringed; and
• A section viii statement: the applicant will omit the patented use from its label.

For US 9,211,291, the likely generic pathway is a Paragraph IV challenge or a section viii carve-out, depending on the scope of the approved generic label and the FDA's listing treatment. A section viii strategy is difficult if the only commercially meaningful use of neratinib is the patented post-trastuzumab regimen. It becomes more viable if the applicant can market the drug for non-infringing uses, if such uses are approved, or if the patented indication can be cleanly removed from the label.

The Orange Book should be checked for the current listed patent number, use code, expiration date, and any patent-term adjustment. Those fields control the practical ANDA timeline.

Which companies are challenging the neratinib patent estate?

The supplied information does not identify an ANDA filer, Paragraph IV notice, district-court complaint, settlement, or licensed generic launch involving US 9,211,291. The patent number alone does not establish that a Paragraph IV challenge has occurred.

The principal commercial parties are:

Party	Role
Puma Biotechnology	Commercial sponsor and holder of US neratinib rights
Pfizer/Wyeth lineage	Originator development and earlier neratinib rights holder
FDA	Approval, labeling, Orange Book and ANDA authority
Potential ANDA applicants	Future generic manufacturers able to challenge listed patents

A patent challenge would normally become visible through a Paragraph IV notice, a Hatch-Waxman complaint filed within 45 days, an FDA patent-listing update, or a public company disclosure. No such event should be inferred solely from the existence of the patent.

What patent litigation affects US 9,211,291?

US 9,211,291 is a method-of-use patent. Litigation risk would most likely arise through Hatch-Waxman litigation after a generic applicant files an ANDA with a Paragraph IV certification.

The principal litigation questions would be:

1. Whether the patent is properly listed for the proposed Nerlynx use;
2. Whether the generic label induces the patented post-trastuzumab use;
3. Whether the claims are anticipated or obvious in view of prior trastuzumab and neratinib studies;
4. Whether the claims adequately describe and enable the claimed patient population and outcomes;
5. Whether the patent's priority chain and written-description support are intact; and
6. Whether any terminal disclaimer or patent-term issue limits enforceability.

The patent's vulnerability is higher than that of a compound patent because the claims concern treatment sequencing and timing. The patent holder's defense is that the specific post-trastuzumab extended-adjuvant strategy, timing window, duration, and clinical benefit were not established by a single prior-art reference and produced a clinically meaningful result.

How strong is the patent estate for neratinib?

The estate has differentiated layers:

Patent layer	Protection	Relative business value
Compound patents	Neratinib molecule and related chemical matter	Historically fundamental, but early compound protection is no longer the main US barrier
Formulation patents	Solid forms, dosage forms, stability, or administration technologies	Can extend protection if listed and enforceable
Method-of-use patents	Post-trastuzumab extended-adjuvant treatment	Directly aligned with Nerlynx's approved indication
Later continuation patents	Potentially narrower patient, dose, timing, or combination claims	May affect generic launch timing
Regulatory exclusivity	FDA NCE and other exclusivities	Time-limited and separate from patent rights

US 9,211,291 is strong commercially because it tracks the approved use rather than an obscure research application. It is narrower legally than a composition-of-matter patent because infringement requires the claimed treatment sequence. Its value is highest while Nerlynx's principal label remains the patented post-trastuzumab indication.

The patent is less effective against:

• Off-label use that does not meet the 12-cycle trastuzumab requirement;
• Treatment outside the claimed timing window;
• A label that omits the patented use and does not encourage it;
• Non-infringing indications supported by separate FDA approval; and
• A generic launched after patent expiration.

What formulation patents protect Nerlynx?

US 9,211,291 does not primarily protect a formulation. Its claims cover a treatment regimen and clinical use. The tablet and oral-delivery limitations narrow the method but do not independently create a broad composition or formulation monopoly.

Separate neratinib formulation patents may address solid-state properties, pharmaceutical compositions, dosage forms, or manufacturing processes. Those patents must be evaluated independently by patent number, listed status, claim scope, and expiration date. A generic could avoid an unexpired formulation patent by using a different formulation while still infringing the method patent through its label.

Are biosimilar risks relevant to Nerlynx?

No. Neratinib is a chemically synthesized small-molecule kinase inhibitor, not a biologic. Biosimilar approval under the Public Health Service Act is therefore not the relevant competitive pathway.

The relevant threat is an ANDA generic. A generic applicant would seek approval under section 505(j) of the Federal Food, Drug, and Cosmetic Act and would address listed patents through Paragraph II, III, IV, or section viii certification.

This distinction matters because generic entry can occur through therapeutic equivalence without demonstrating biosimilarity, and the principal commercial dispute will concern patent validity, infringement, labeling, and launch timing.

How does neratinib compare with competing HER2 therapies?

Neratinib occupies a post-trastuzumab extended-adjuvant position rather than the initial adjuvant or metastatic treatment position.

Therapy	Primary setting	Administration	Competitive relationship
Trastuzumab	Adjuvant and metastatic HER2-positive disease	Intravenous or subcutaneous, depending on product	Precedes neratinib in the patented sequence
Pertuzumab	Combination adjuvant and metastatic therapy	Intravenous	Can be part of prior standard therapy or a competing strategy
T-DM1	Adjuvant treatment for residual disease after neoadjuvant therapy	Intravenous	May reduce the eligible population for post-trastuzumab neratinib
Tucatinib	HER2-positive advanced or metastatic disease	Oral	Primarily a later-line competitor, not a direct substitute in the approved extended-adjuvant setting
Neratinib	Extended adjuvant after trastuzumab-based treatment	Oral tablet	The patented treatment sequence

The main market risk is not biosimilar substitution. It is treatment-selection pressure from pertuzumab, T-DM1, newer HER2-directed regimens, toxicity concerns, and narrower use of extended adjuvant therapy in patients with lower recurrence risk.

What generic launch scenarios exist?

Launch after patent expiration

This is the lowest-litigation path. A generic waits until the relevant listed patent expires and launches subject to FDA approval and any remaining listed patent rights.

Paragraph IV challenge

A challenger may argue that US 9,211,291 is invalid, unenforceable, or not infringed. The most likely arguments would involve obviousness of administering neratinib after trastuzumab, lack of written description for the broad timing and outcome language, and non-infringement based on a carved-out label.

Section viii carve-out

A generic may seek to omit the patented extended-adjuvant use. The success of this approach would depend on whether the remaining label has a meaningful non-infringing use and whether the proposed labeling still encourages the patented sequence.

Settlement or license

Puma and an ANDA applicant could settle through a delayed-entry license, an authorized-generic arrangement, or another commercial agreement. No settlement involving this patent should be assumed without a public court filing, FDA record, or company disclosure.

What geographic coverage does the patent provide?

US 9,211,291 provides US protection only. Foreign counterparts require separate review in each jurisdiction. The relevant commercial markets include Europe, Japan, Canada, Australia, and other jurisdictions where neratinib is approved or marketed.

A US expiration date does not determine foreign entry. Foreign patent terms, supplementary protection certificates, national prosecution outcomes, Orange Book equivalents, and local use-claim standards can produce materially different launch dates.

What manufacturing and intellectual-property barriers remain?

Manufacturing barriers are secondary to the method patent for the specific claims supplied. A generic manufacturer still must address:

• Neratinib active pharmaceutical ingredient sourcing;
• Tablet formulation and bioequivalence;
• Impurity and stability specifications;
• Process patents and proprietary know-how;
• FDA chemistry, manufacturing, and controls requirements;
• Patent-listed formulation or use claims; and
• Labeling that avoids inducing the patented indication.

A manufacturer can potentially design around a formulation patent while remaining exposed to the method patent. Conversely, a section viii label may reduce method-of-use exposure but leave formulation or process patents unresolved.

Key Takeaways

• US 9,211,291 is a method-of-use patent for extended-adjuvant neratinib after at least 12 cycles of trastuzumab.
• The commercial embodiment is oral neratinib, 240 mg daily, for approximately 12 months.
• The core timing window is about two weeks to one year after completion of surgery and standard adjuvant therapy.
• Claims expressly cover early-stage HER2-positive disease, outcome improvement, hormone receptor-positive patients, endocrine therapy, and several chemotherapy backbones.
• The patent is projected to expire around August 2027, subject to term adjustments and other patent-specific extensions.
• Neratinib faces generic, not biosimilar, competition.
• A generic applicant would likely consider Paragraph IV certification or a section viii use carve-out.
• The patent's commercial strength comes from its alignment with the FDA-approved Nerlynx indication.
• Its legal strength is narrower than a compound patent because infringement depends on patient selection, treatment sequencing, timing, and label conduct.
• Separate neratinib formulation, process, continuation, and foreign patents must be analyzed independently.

FAQs About US Patent 9,211,291

Does US 9,211,291 cover neratinib as a chemical compound?

No. The supplied claims cover treatment regimens and methods of use. They do not claim the neratinib molecule as such.

Does a 240 mg neratinib dose infringe the patent?

It can, if administered to an early-stage HER2-positive patient after at least 12 trastuzumab cycles and within the claimed timing window. Claims 7 and 8 specifically address the 120 mg to 300 mg daily range and the 240 mg dose.

Does the patent require exactly 12 months of neratinib?

No. Claim 3 covers at least approximately 12 months, while claim 2 covers a broader eight-month to five-year range. Claim 12 expressly requires at least 12 months.

Can a generic launch before 2027 with a skinny label?

Potentially, if the FDA accepts a section viii carve-out that removes the patented extended-adjuvant use and the resulting label does not induce that use. The commercial feasibility depends on whether an approvable non-infringing indication remains.

Is trastuzumab biosimilar competition a direct patent risk to neratinib?

No. Trastuzumab biosimilars may affect the prior-treatment market and prescribing economics, but they do not directly invalidate or remove US 9,211,291. Neratinib itself is subject to small-molecule generic competition.

References

1. Chan, A., Delaloge, S., Holmes, F. A., Moy, B., Iwata, H., Harvey, V. J., et al. (2016). Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer: ExteNET, a multicentre, double-blind, randomised controlled trial. The Lancet Oncology, 17(3), 367-377. https://doi.org/10.1016/S1470-2045(15)00551-3

2. U.S. Food and Drug Administration. (2017). Nerlynx (neratinib) prescribing information. https://www.accessdata.fda.gov

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/

4. U.S. Patent and Trademark Office. (2015). U.S. Patent No. 9,211,291, methods for treating breast cancer. https://patents.google.com/patent/US9211291B2

5. Puma Biotechnology, Inc. (2024). Form 10-K annual report. U.S. Securities and Exchange Commission. https://www.sec.gov/edgar.shtml

6. U.S. Food and Drug Administration. (2024). Generic drug user fee amendments and ANDA patent certifications. https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/anda-submissions-content-and-format.

Drugs Protected by US Patent 9,211,291

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Puma Biotech	NERLYNX	neratinib maleate	TABLET;ORAL	208051-001	Jul 17, 2017		RX	Yes	Yes	9,211,291					EXTENDED ADJUVANT TREATMENT OF ADULT PATIENTS WITH EARLY STAGE HER2-OVEREXPRESSED/AMPLIFIED BREAST CANCER, TO FOLLOW ADJUVANT TRASTUZUMAB BASE THERAPY
Puma Biotech	NERLYNX	neratinib maleate	TABLET;ORAL	208051-001	Jul 17, 2017		RX	Yes	Yes	9,211,291					EXTENDED ADJUVANT TREATMENT OF ADULT PATIENTS WITH EARLY-STAGE HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2)-POSITIVE BREAST CANCER, TO FOLLOW ADJUVANT TRASTUZUMAB BASED THERAPY

Foreign Priority and PCT Information for Patent: 9,211,291

PCT Information
PCT Filed	March 24, 2010	PCT Application Number:	PCT/US2010/028448
PCT Publication Date:	October 14, 2010	PCT Publication Number:	WO2010/117633

International Family Members for US Patent 9,211,291

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3000467		301237	Netherlands
European Patent Office	3000467		PA2023520	Lithuania
European Patent Office	3000467		LUC00310	Luxembourg
European Patent Office	3000467		CA 2023 00021	Denmark
European Patent Office	3000467		2023C/527	Belgium
European Patent Office	3000467		122023000045	Germany
European Patent Office	3000467		26/2023	Austria