Details for Patent: 10,385,078

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Which drugs does patent 10,385,078 protect, and when does it expire?

Patent 10,385,078 protects ALUNBRIG and is included in one NDA.

This patent has forty-three patent family members in thirty-two countries.

Summary for Patent: 10,385,078

Title:	Crystalline forms of 5-chloro-N4-[-2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-YL) piperidin-1-YL]phenyl}pyrimidine-2,4-diamine
Abstract:	Crystalline forms of brigatinib, pharmaceutical compositions comprising the same, and methods of their preparation and use of the same are disclosed herein.
Inventor(s):	Leonard W. Rozamus, Pradeep Sharma
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US15/520,694
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 10,385,078: Brigatinib Crystal Form A Claims, Patent Scope, Exclusivity, and Generic Risk

US Patent 10,385,078 protects crystalline Form A of brigatinib, including defined X-ray powder diffraction, or XRPD, peak sets, pharmaceutical compositions containing the form, and treatment of ALK-positive metastatic non-small cell lung cancer, including patients previously treated with crizotinib. The patent is a solid-form patent rather than a broad composition-of-matter patent.

The commercial importance of the patent depends on whether marketed Alunbrig tablets contain the claimed Form A, whether an ANDA applicant uses the same polymorph, and whether the patent is listed in the FDA Orange Book against the relevant product. A generic applicant may avoid literal infringement by using a different brigatinib solid form, but that strategy raises pharmaceutical development, bioequivalence, stability, and regulatory risks.

What does US Patent 10,385,078 protect?

US 10,385,078 protects a specific crystalline form of brigatinib identified primarily by XRPD characteristics. The patent does not claim every form of brigatinib, every brigatinib formulation, or every method of treating lung cancer with any brigatinib material.

Item	Patent position
Patent	US 10,385,078 B2
Subject matter	Crystalline Form A of brigatinib
Issued	August 20, 2019
Primary protection	Defined XRPD peak pattern
Composition protection	Pharmaceutical compositions containing Form A
Therapeutic protection	Treatment of NSCLC, including ALK-positive metastatic NSCLC
Patient subgroup	Patients previously treated with crizotinib
Product relevance	Alunbrig tablets, if the marketed drug contains the claimed form
Patent type	Solid-state, formulation-adjacent, and method-of-use claims
Expected nominal term	Approximately March 2036, subject to the patent’s recorded term adjustment and any applicable regulatory adjustment

The patent’s claims are narrow in chemical identity but potentially broad in commercial effect. A generic manufacturer can make the same active ingredient while still infringing if the final product contains the claimed crystalline form.

How broad is claim 1 of US 10,385,078?

Claim 1 covers crystalline Form A of brigatinib having XRPD peaks at:

• 9.6° 2θ
• 17.2° 2θ
• 19.4° 2θ
• 20.1° 2θ
• 23.1° 2θ
• 27.7° 2θ

Each peak is subject to a variance of ±0.2° 2θ.

The claim is a product-by-physical-property claim. It does not require a particular manufacturing process, solvent system, particle size, tablet composition, dosage strength, or therapeutic use. A product may infringe claim 1 regardless of how the crystal was manufactured.

The key legal issue is whether the accused material exhibits the claimed diffraction pattern. The presence of the six listed peaks is central. The claim does not expressly require that the accused sample have only those six peaks. Other peaks may be present if the claimed peaks remain within the stated tolerance and the material otherwise corresponds to Form A.

How does the XRPD limitation affect infringement?

XRPD is a structural fingerprint for a crystalline solid. In an infringement investigation, the relevant evidence would normally include:

1. Powder sampling from the finished drug or active pharmaceutical ingredient.
2. XRPD testing under controlled instrument conditions.
3. Peak-position comparison against the claimed ±0.2° 2θ ranges.
4. Assessment of polymorph mixtures, hydrates, solvates, amorphous content, and preferred orientation.
5. Correlation with reference Form A material.

A single peak outside the stated tolerance does not automatically eliminate infringement if the remaining evidence establishes the claimed form. Conversely, matching several peaks may not be sufficient if the pattern is attributable to a different polymorph or a mixture.

The claim also raises ordinary solid-state claim-construction issues. Instrument calibration, sample preparation, radiation source, crystallinity, peak intensity, and detection thresholds can affect measured peak positions. These variables are relevant to both infringement and validity.

What do claims 2 and 3 add to the patent?

Claim 2 covers Form A having the XRPD pattern shown in Figure 2. It provides a figure-based limitation rather than a separate chemical structure.

Claim 3 lists a more extensive set of 17 peaks:

6.1, 8.6, 9.6, 10.8, 11.3, 13.5, 14.3, 15.9, 17.2, 18.9, 19.4, 20.1, 21.8, 22.6, 23.1, 23.9, and 27.7° 2θ, each with a variance of ±0.2° 2θ.

Claim 3 is narrower than claim 1 because it requires a larger defined peak set. It may be more difficult to invalidate through an argument that the six-peak definition in claim 1 reads on an ordinary or previously known brigatinib crystal. It may also be easier to design around if a manufacturer can produce a different polymorph with a materially different XRPD profile.

Claims 2 and 3 are useful fallback positions. If claim 1 is challenged for lack of clarity, anticipation, or insufficient structural definition, the patent holder can rely on the figure and the expanded peak list as narrower limitations.

What pharmaceutical compositions are protected by claim 4?

Claim 4 covers a pharmaceutical composition containing Form A and at least one pharmaceutically acceptable carrier, vehicle, or excipient.

The claim is broad at the excipient level. It is not limited to a particular:

• Tablet strength
• Release profile
• Binder
• Disintegrant
• Filler
• Lubricant
• Film coating
• Manufacturing process
• Brigatinib loading
• Route of administration

A conventional tablet containing the claimed Form A and ordinary pharmaceutical excipients could fall within claim 4. The claim does not, however, automatically cover a formulation containing amorphous brigatinib, another polymorph, a solvate, or a salt that does not meet claim 1.

Because claim 4 depends on claim 1, proof of the claimed crystalline form remains necessary. The presence of brigatinib in a tablet is not enough by itself.

What methods of treatment are protected by claims 5 through 8?

Claims 5 through 8 protect treatment methods using the claimed Form A.

Claim	Added limitation
5	Treating NSCLC by administering Form A
6	ALK-positive NSCLC
7	ALK-positive metastatic NSCLC
8	Patient previously treated with crizotinib

Claim 5 is the broadest therapeutic claim. Claim 8 is the narrowest and most closely aligned with the original clinical positioning of brigatinib following crizotinib treatment.

The treatment claims require administration of Form A, not merely administration of brigatinib in an unspecified form. A generic product that uses a different polymorph may avoid literal infringement of the method claims, although inducement and contributory infringement theories may remain relevant depending on product labeling, formulation evidence, and the facts of a specific case.

The claims do not expressly require a particular dose or dosing schedule. They also do not require that the patient have a specific ALK mutation, although the ALK-positive limitation appears in claims 6 through 8.

When does US Patent 10,385,078 lose exclusivity?

The patent has an expected nominal expiration around March 2036 based on a 20-year term calculated from its earliest claimed priority date. The enforceable expiration date must be taken from the USPTO patent record after accounting for patent term adjustment.

Exclusivity category	Approximate position
Patent term	Approximately through March 2036
FDA new-chemical-entity exclusivity	Expired before the patent term
Orphan-drug exclusivity	Not the principal exclusivity mechanism for this patent analysis
Pediatric exclusivity	Must be assessed separately from the patent term
Patent-term extension	Any extension would require a specific regulatory record
Generic approval	May be delayed by listed patents, statutory exclusivity, litigation, or settlement

Brigatinib received FDA approval for Alunbrig in April 2017 under the accelerated approval pathway for certain patients with metastatic ALK-positive NSCLC previously treated with crizotinib. FDA later granted traditional approval for a broader first-line indication in May 2021.[2]

The five-year new chemical entity exclusivity period associated with the original approval does not extend to 2036. The remaining commercial barrier is primarily patent-based.

Is US 10,385,078 listed in the Orange Book?

The relevant Orange Book question is whether US 10,385,078 is listed for Alunbrig and which approved strength, dosage form, and use code are associated with the listing.

Orange Book listing determines whether an ANDA applicant must make a certification under 21 U.S.C. § 355(j)(2)(A)(vii). A Paragraph IV certification alleges that the listed patent is invalid, unenforceable, or will not be infringed by the proposed generic product.

For a solid-form patent, the listing analysis is fact-sensitive. The patent must claim the approved drug product, an approved method of using the drug, or subject matter that meets FDA listing requirements. A patent that only claims an unapproved manufacturing process may not qualify for Orange Book listing, while a patent claiming the drug product or an approved method of use may qualify.

The FDA’s electronic Orange Book should be used to confirm:

• Whether US 10,385,078 is currently listed.
• The listed patent expiration date.
• The associated Alunbrig strengths.
• Any use code.
• Whether the listing has been delisted, corrected, or superseded.[3]

What Paragraph IV challenges are likely against the patent?

A Paragraph IV challenge to US 10,385,078 would likely focus on four technical and legal theories.

Anticipation

The challenger would seek an earlier publication or patent disclosing brigatinib Form A or an XRPD pattern that inherently corresponds to Form A. General disclosure of brigatinib would not ordinarily anticipate the specific crystalline form unless the claimed form was necessarily present or expressly disclosed.

Obviousness

The challenger could argue that a skilled person would have been motivated to screen brigatinib for polymorphs and would have had a reasonable expectation of obtaining Form A. The patent holder would likely rely on unexpected properties, improved stability, reproducibility, isolation advantages, or superior pharmaceutical processing characteristics.

Indefiniteness

The ±0.2° 2θ ranges could be challenged if the patent does not adequately explain the testing conditions or if the peak definition permits inconsistent results. XRPD claims are not inherently indefinite, but the specification must provide sufficient analytical context for a skilled person to determine whether a product falls within the claim.

Enablement and written description

The patent must support the claimed crystalline form and enable its production and identification. A specification that provides preparation examples, XRPD data, and characterization methods is generally stronger than one that provides only a list of peak positions.

How strong is the patent estate for Alunbrig?

US 10,385,078 is strategically important but should not be treated as the entire brigatinib patent estate.

Estate layer	Commercial function
Composition-of-matter patents	Protect brigatinib itself and can create the earliest broad barrier
Crystal-form patents	Prevent substitution with the claimed polymorph
Formulation patents	Protect tablet architecture, excipients, release, or stability features
Method-of-use patents	Protect approved or later-developed indications
Manufacturing patents	Protect synthetic routes, intermediates, purification, and crystallization
Regulatory exclusivity	Controls approval timing independently of patent validity

The ’078 patent is strongest when the approved Alunbrig product contains Form A and the generic applicant’s product uses the same form. Its value is weaker if a reliable alternative polymorph can be developed with acceptable bioequivalence, stability, manufacturability, and commercial scale-up.

A solid-form patent can still create significant generic risk even when the active ingredient’s broad composition patent has expired. Generic applicants must prove that their selected form does not infringe, or they must challenge the listed patent and accept litigation risk.

What generic launch scenarios exist?

Scenario 1: Same Form A

The generic applicant uses Form A and files a Paragraph IV certification. This creates the highest direct infringement risk. A patent-holder lawsuit filed within the statutory period can trigger a 30-month stay of final ANDA approval, subject to applicable exceptions and court developments.

Scenario 2: Different polymorph

The applicant uses a polymorph with a different XRPD pattern. This may avoid literal infringement of claims 1 through 4 and the treatment claims, but the applicant must establish that the alternative form is stable, manufacturable, bioequivalent, and acceptable under FDA chemistry, manufacturing, and controls review.

Scenario 3: Amorphous or noncrystalline material

An amorphous product may avoid a crystalline-form claim. It can create separate risks involving stability, dissolution, solid-state conversion during manufacturing or storage, and reproducibility.

Scenario 4: License or settlement

A generic company may resolve the dispute through a license, launch agreement, or other settlement. The commercial terms could establish an authorized entry date before patent expiration. Any agreement involving delayed entry or payment would face Federal Trade Commission and antitrust scrutiny.

Which companies are challenging Alunbrig patents?

A definitive competitor list requires current review of ANDA litigation records, FDA Paragraph IV notices, PACER or CourtListener dockets, and the Orange Book. The patent number alone does not establish that a specific generic manufacturer has filed a challenge.

Potential challengers in the brigatinib market would typically include large generic manufacturers and specialty oncology suppliers with the capability to develop a polymorph-controlled oral kinase inhibitor. Public identification of a challenger requires a filed district-court action, an FDA approval record, or a disclosed Paragraph IV notice.

No biosimilar pathway applies to brigatinib. Brigatinib is a chemically synthesized small molecule, so competition would occur through ANDAs or, in some circumstances, 505(b)(2) applications rather than biosimilar applications under the Public Health Service Act.

What manufacturing and intellectual-property barriers remain?

The main technical barriers are polymorph control and analytical reproducibility. A generic manufacturer must control:

• Crystallization solvent and temperature profile
• Seeding and supersaturation
• Drying conditions
• Residual solvent
• Particle size and morphology
• Conversion between polymorphs
• Moisture uptake
• Tablet compression behavior
• Long-term solid-state stability

The patent’s manufacturing coverage is narrower than a process patent because the issued claims provided by the requester do not expressly claim a method of preparing Form A. Nevertheless, the product claims can reach Form A regardless of the process used to make it.

Geographic coverage is territorial. US 10,385,078 applies in the United States only. Corresponding foreign applications or patents must be analyzed separately in Europe, Japan, Canada, China, and other commercial markets. Foreign counterparts may differ in claim scope, validity, expiration, prosecution history, and enforceability.

What is the commercial exposure associated with US 10,385,078?

The patent’s revenue exposure is linked to Alunbrig sales during the period in which the product depends on Form A and no acceptable noninfringing alternative is available. Public financial reporting generally provides product-level Alunbrig revenue, not revenue attributable to a particular patent.

The relevant commercial variables are:

1. Alunbrig annual sales.
2. The percentage of sales exposed to US generic substitution.
3. The date of first generic approval.
4. The scope of any settlement.
5. The ability of a generic to use a noninfringing polymorph.
6. The number of competing ANDA applicants.
7. Payer substitution and authorized-generic strategy.

A successful Paragraph IV challenge could materially accelerate erosion. A noninfringing-form strategy could delay entry even if the ’078 patent is invalidated, because development and FDA review of an alternative solid form require additional time.

Key Takeaways

• US 10,385,078 is a crystalline-form patent covering brigatinib Form A.
• Claim 1 is defined by six XRPD peaks with a ±0.2° 2θ tolerance.
• Claims 2 and 3 provide narrower XRPD fallback positions.
• Claim 4 covers pharmaceutical compositions containing Form A.
• Claims 5 through 8 cover treatment of NSCLC, including ALK-positive metastatic disease after crizotinib.
• The patent’s expected nominal term runs to approximately March 2036, subject to USPTO term adjustment.
• The central generic question is whether Alunbrig and proposed generic products contain the claimed Form A.
• A different polymorph or amorphous form may provide a design-around, but it must satisfy FDA quality and bioequivalence requirements.
• Brigatinib is a small molecule, so biosimilar risk does not apply.
• Orange Book listing, current patent status, and Paragraph IV litigation must be confirmed against current FDA and court records.

Frequently Asked Questions

Does US 10,385,078 cover all brigatinib products?

No. It covers Form A meeting the claimed XRPD characteristics, plus compositions and treatment methods involving that form.

Can a generic use brigatinib after the basic compound patent expires?

Yes, subject to applicable patents, FDA exclusivity, regulatory requirements, and infringement risk involving crystalline forms, formulations, methods of use, or manufacturing.

Does a different brigatinib polymorph automatically avoid infringement?

No. It may avoid literal infringement of the Form A claims, but the alternative must be analytically distinct and must not infringe other patents.

Is an XRPD peak match alone sufficient to prove infringement?

Usually not. Peak matching is central, but courts and experts may also evaluate sample preparation, instrument conditions, polymorph mixtures, crystallinity, and reference standards.

Are biosimilars a competitive threat to Alunbrig?

No. Brigatinib is a small-molecule drug. The relevant competitors are ANDA-based generic products and potentially 505(b)(2) products.

References

1. U.S. Patent and Trademark Office. (2019). U.S. Patent No. 10,385,078, crystalline form of brigatinib. https://patents.google.com/patent/US10385078B2/en
2. U.S. Food and Drug Administration. (2021). FDA approves brigatinib for metastatic ALK-positive non-small cell lung cancer. https://www.fda.gov
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
4. U.S. Food and Drug Administration. (2017). Alunbrig prescribing information. https://www.accessdata.fda.gov
5. U.S. Code, 21 U.S.C. § 355. New drugs. https://uscode.house.gov/crew/
6. U.S. Patent and Trademark Office. (2024). Manual of Patent Examining Procedure, Chapter 2700: Patent term. https://www.uspto.gov/web/offices/pac/mpep/mpep-2700.html

Drugs Protected by US Patent 10,385,078

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Takeda Pharms Usa	ALUNBRIG	brigatinib	TABLET;ORAL	208772-001	Apr 28, 2017		RX	Yes	No	10,385,078		Y	Y		TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
Takeda Pharms Usa	ALUNBRIG	brigatinib	TABLET;ORAL	208772-002	Apr 28, 2017		RX	Yes	Yes	10,385,078		Y	Y		TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
Takeda Pharms Usa	ALUNBRIG	brigatinib	TABLET;ORAL	208772-003	Oct 2, 2017		RX	Yes	No	10,385,078		Y	Y		TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)

Foreign Priority and PCT Information for Patent: 10,385,078

PCT Information
PCT Filed	October 21, 2015	PCT Application Number:	PCT/US2015/056701
PCT Publication Date:	April 28, 2016	PCT Publication Number:	WO2016/065028

International Family Members for US Patent 10,385,078

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2015335950
Canada	2965169
Chile	2017000979
China	107108559
China	111825717
China	111888368
China	119735613