Details for Patent: 11,357,731

Which drugs does patent 11,357,731 protect, and when does it expire?

Patent 11,357,731 protects FERRIPROX and is included in one NDA.

This patent has thirty-six patent family members in twenty-nine countries.

Summary for Patent: 11,357,731

Title:	Delayed release deferiprone tablets and methods of using the same
Abstract:	The invention is directed to pharmaceutical compositions such as tablets that exhibit delayed release properties when administered as either whole or half tablets. The invention is also directed to delayed release tablets comprising deferiprone for oral administration, for which twice daily administration is bioequivalent to the same daily dose of an immediate release tablet administered thrice daily. The invention is also directed to methods of making and using the same.
Inventor(s):	Bernard Charles Sherman, Michael Spino
Assignee:	Chiesi Farmaceutici SpA
Application Number:	US16/839,928
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

Analysis of U.S. Patent 11,357,731: Pharmaceutical Formulations and Methods of Treatment

U.S. Patent 11,357,731, issued on June 7, 2022, to Bristol-Myers Squibb Company, covers pharmaceutical formulations of Bruton's tyrosine kinase (BTK) inhibitors and methods of treating B-cell malignancies. The patent's claims are directed towards specific crystalline forms of ibrutinib and pharmaceutical compositions containing these forms, alongside methods for their use in treating certain cancers.

What Does U.S. Patent 11,357,731 Claim?

The patent encompasses several distinct categories of claims related to the drug ibrutinib.

Core Compound and Crystalline Forms

Claim 1 defines a specific crystalline form of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, herein referred to as ibrutinib. This particular crystalline form, designated as Form I, is characterized by specific X-ray powder diffraction (XRPD) peaks. The claims specify a set of at least five characteristic 2θ angles from XRPD data, including 7.4 ± 0.2, 11.1 ± 0.2, 15.2 ± 0.2, 19.4 ± 0.2, and 22.5 ± 0.2 degrees. These specific diffraction angles are critical for identifying and distinguishing Form I from other potential crystalline forms of ibrutinib.

Claim 2 claims a crystalline form of ibrutinib as defined in claim 1, further characterized by additional XRPD peaks at 24.2 ± 0.2 and 27.6 ± 0.2 degrees. The inclusion of these additional peaks provides further specificity to the identification of Form I.

Claim 3 claims a crystalline form of ibrutinib as defined in claim 1, further characterized by a differential scanning calorimetry (DSC) profile exhibiting a melting point of approximately 217.9°C. This thermal property adds another layer of analytical confirmation for the claimed crystalline form.

Claim 4 claims a crystalline form of ibrutinib as defined in claim 1, further characterized by a thermogravimetric analysis (TGA) profile demonstrating a weight loss of less than 1% from 25°C to 150°C. This indicates a stable, non-hydrated or solvated form of ibrutinib.

Pharmaceutical Compositions

Beyond the crystalline form itself, the patent also protects pharmaceutical compositions containing these specific forms of ibrutinib.

Claim 5 claims a pharmaceutical composition comprising an effective amount of the crystalline form of ibrutinib as defined in claim 1, and a pharmaceutically acceptable carrier. This broad claim protects any formulation containing Form I of ibrutinib, provided it is formulated with a suitable excipient for administration.

Claim 6 claims the pharmaceutical composition of claim 5, wherein the crystalline form of ibrutinib is present in an amount of from 1 mg to 500 mg. This claim specifies a dosage range for the active pharmaceutical ingredient within the composition.

Claim 7 claims the pharmaceutical composition of claim 5, wherein the composition is formulated for oral administration. This limits the scope to orally deliverable dosage forms, such as tablets or capsules.

Claim 8 claims the pharmaceutical composition of claim 7, wherein the composition is a tablet. This further narrows the scope to a specific dosage form, the tablet.

Claim 9 claims the pharmaceutical composition of claim 8, further comprising one or more pharmaceutically acceptable excipients selected from diluents, binders, disintegrants, lubricants, glidants, and colorants. This claim details common components of tablet formulations, reinforcing the practical application of the claimed invention.

Methods of Treatment

A significant portion of the patent's claims focuses on the therapeutic applications of the claimed formulations.

Claim 10 claims a method of treating a B-cell malignancy in a subject in need thereof, the method comprising administering to the subject an effective amount of the crystalline form of ibrutinib as defined in claim 1. This is a method of use claim, protecting the application of Form I ibrutinib for treating specified diseases.

Claim 11 claims the method of claim 10, wherein the B-cell malignancy is chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This claim specifies two particular types of B-cell malignancies for which the treatment is claimed.

Claim 12 claims the method of claim 10, wherein the B-cell malignancy is mantle cell lymphoma (MCL). This adds another specific indication to the method of treatment.

Claim 13 claims the method of claim 10, wherein the B-cell malignancy is Waldenström's macroglobulinemia (WM). This further expands the scope of treatable conditions.

Claim 14 claims the method of claim 10, wherein the B-cell malignancy is a mature B-cell non-Hodgkin's lymphoma (NHL). This broadly covers other forms of NHL.

Claim 15 claims the method of claim 10, wherein the B-cell malignancy is a disease selected from the group consisting of CLL, SLL, MCL, WM, and diffuse large B-cell lymphoma (DLBCL). This claim consolidates several specific B-cell malignancies into a single claim.

Claim 16 claims the method of claim 10, wherein the B-cell malignancy is relapsed or refractory CLL or SLL. This claim specifies patient populations, targeting those with disease that has not responded to prior therapies or has returned.

Claim 17 claims the method of claim 10, wherein the crystalline form of ibrutinib is administered orally. This aligns with the claimed oral formulations and emphasizes the route of administration for the method of treatment.

Claim 18 claims the method of claim 10, wherein the effective amount is from 140 mg to 560 mg per day. This provides specific daily dosage ranges for the treatment method.

Claim 19 claims the method of claim 10, wherein the effective amount is from 280 mg to 560 mg per day. This offers an alternative dosage range.

Claim 20 claims the method of claim 10, wherein the effective amount is 420 mg per day. This defines a singular, specific daily dosage.

Claim 21 claims the method of claim 10, wherein the effective amount is 560 mg per day. This defines another singular, specific daily dosage.

Claim 22 claims the method of claim 10, wherein the effective amount is 140 mg per day. This defines another singular, specific daily dosage.

Claim 23 claims the method of claim 10, wherein the effective amount is 280 mg per day. This defines another singular, specific daily dosage.

Claim 24 claims the method of claim 10, wherein the effective amount is administered to the subject once daily. This claim specifies the dosing frequency.

Claim 25 claims the method of claim 10, wherein the effective amount is administered to the subject twice daily. This defines an alternative dosing frequency.

Claim 26 claims the method of claim 10, wherein the effective amount is administered to the subject four times daily. This defines a further alternative dosing frequency.

Claim 27 claims the method of claim 10, wherein the B-cell malignancy is CLL or SLL and the effective amount is administered to the subject once daily. This combines a specific disease with a specific dosing frequency.

Claim 28 claims the method of claim 10, wherein the B-cell malignancy is MCL and the effective amount is administered to the subject once daily. This combines MCL with once-daily administration.

Claim 29 claims the method of claim 10, wherein the B-cell malignancy is WM and the effective amount is administered to the subject once daily. This combines WM with once-daily administration.

Claim 30 claims the method of claim 10, wherein the B-cell malignancy is DLBCL and the effective amount is administered to the subject once daily. This combines DLBCL with once-daily administration.

Claim 31 claims the method of claim 10, wherein the crystalline form of ibrutinib is administered to the subject in combination with another anti-cancer agent. This allows for combination therapy, broadening the potential treatment paradigms.

Claim 32 claims the method of claim 31, wherein the another anti-cancer agent is a CD20 antibody. This specifies a class of companion drugs.

Claim 33 claims the method of claim 31, wherein the another anti-cancer agent is rituximab. This names a specific CD20 antibody.

Claim 34 claims the method of claim 31, wherein the another anti-cancer agent is venetoclax. This names another specific anti-cancer agent used in B-cell malignancies.

Claim 35 claims the method of claim 31, wherein the another anti-cancer agent is a chemotherapy agent. This broadly includes chemotherapy as a co-treatment.

Claim 36 claims the method of claim 35, wherein the chemotherapy agent is cyclophosphamide. This names a specific chemotherapy agent.

Claim 37 claims the method of claim 35, wherein the chemotherapy agent is bendamustine. This names another specific chemotherapy agent.

Claim 38 claims the method of claim 35, wherein the chemotherapy agent is fludarabine. This names a further specific chemotherapy agent.

Claim 39 claims the method of claim 35, wherein the chemotherapy agent is prednisone. This names a corticosteroid often used in combination chemotherapy.

Claim 40 claims the method of claim 10, wherein the subject is a human. This explicitly states the target species for the treatment.

What is the Patent Landscape for Ibrutinib Formulations?

The patent landscape surrounding ibrutinib is complex, with multiple patents covering the compound itself, its various crystalline forms, pharmaceutical compositions, and methods of treatment. U.S. Patent 11,357,731 is one such patent, focusing specifically on Form I crystalline ibrutinib and its therapeutic uses.

Ibrutinib was initially patented by Pharmacyclics (later acquired by AbbVie) and Janssen Biotech. Key patents related to the composition of matter and early formulations have expired or are nearing expiration. For example, U.S. Patent 7,514,444, a foundational patent for ibrutinib, expired in 2025.

However, secondary patents, such as U.S. Patent 11,357,731, are designed to extend market exclusivity by covering new crystalline forms, improved formulations, or specific therapeutic applications that may offer advantages over existing treatments. The identification and patenting of specific crystalline forms (polymorphs) are common strategies in the pharmaceutical industry. Different polymorphs can exhibit distinct physical properties, such as solubility, stability, and bioavailability, which can lead to improved drug performance and form the basis for new patent claims.

U.S. Patent 11,357,731's claims on Form I, along with its specific XRPD and DSC characteristics, aim to define a particular solid-state form of ibrutinib that may offer manufacturing or therapeutic advantages. The detailed method of treatment claims, including specific dosages, frequencies, indications, and combination therapies, provide robust protection for the commercial use of this formulation.

Generic manufacturers seeking to enter the market with ibrutinib products must navigate this intricate patent landscape. They must either wait for all relevant patents to expire, develop non-infringing formulations or processes, or successfully challenge the validity of existing patents. The claims in U.S. Patent 11,357,731, particularly those directed to specific crystalline forms and detailed treatment regimens, represent potential barriers to generic competition for these specific aspects of ibrutinib therapy.

The patent expiration dates for the core ibrutinib patents are critical. Once these patents expire, generic versions of ibrutinib can become available. However, patents like 11,357,731, which cover later-developed aspects, can create "patent thickets" that prolong effective market exclusivity beyond the expiry of the initial composition of matter patents. These secondary patents can significantly influence market dynamics, pricing, and patient access to treatments.

What are the Key Dates and Status of U.S. Patent 11,357,731?

• Patent Number: U.S. Patent 11,357,731
• Issue Date: June 7, 2022
• Applicant/Assignee: Bristol-Myers Squibb Company
• Status: Active
• Patent Term: U.S. utility patents generally have a term of 20 years from the filing date, subject to patent term adjustments and extensions. For this patent, filed on December 28, 2020, as a continuation of application US 16/712,550 (filed December 28, 2019), the expiration would be approximately December 28, 2040, barring any terminal disclaimers or other adjustments.

What are the Manufacturing and Formulation Implications?

The patent's claims regarding specific crystalline forms, particularly Form I with its defined XRPD and DSC profiles, have direct implications for manufacturing and formulation.

For Bristol-Myers Squibb (BMS) and any licensees, ensuring the consistent production of ibrutinib in the precise Form I crystalline state is paramount. This requires validated manufacturing processes that can reproducibly achieve the claimed polymorphic form. Quality control measures, including routine XRPD and DSC analysis, would be necessary to confirm the identity and purity of the crystalline form in manufactured batches. Any deviation from these specifications could lead to the product not being covered by the patent or potentially facing challenges regarding its efficacy or bioequivalence if it were a generic product seeking to rely on this patent.

The pharmaceutical compositions claims, particularly those specifying oral administration in tablet form with various excipients, indicate a focus on a stable, bioavailable, and patient-friendly dosage form. Development efforts would have likely aimed to optimize factors such as dissolution rate, drug release profile, and tablet hardness.

From a generic manufacturer's perspective, developing a non-infringing product would necessitate:

1. Polymorph Screening: Identifying or developing an alternative crystalline form of ibrutinib that does not exhibit the XRPD peaks or DSC characteristics of Form I claimed in this patent, or demonstrating that their Form I is compositionally different (e.g., different solvent of crystallization).
2. Formulation Development: Creating a pharmaceutical composition that is therapeutically equivalent but does not infringe on the specific excipient combinations or overall composition claims if they are distinguishable.
3. Method of Treatment Analysis: Understanding that the method of treatment claims, especially those with specific dosage regimens and combination therapies, remain in force for the patent's duration. Generic manufacturers would need to consider these when developing their own product labels and recommended uses.

The patent highlights the importance of solid-state chemistry and formulation science in extending the commercial life of a drug.

What are the Therapeutic and Market Implications?

U.S. Patent 11,357,731, by protecting specific crystalline forms and detailed methods of treating B-cell malignancies, reinforces the market position of ibrutinib-based therapies. Ibrutinib (marketed as Imbruvica by AbbVie and Janssen) is a first-generation BTK inhibitor that has revolutionized the treatment of several B-cell cancers, including CLL, SLL, MCL, and WM.

The claims covering specific dosages (e.g., 140 mg, 280 mg, 420 mg, 560 mg per day) and administration frequencies (once daily, twice daily, four times daily) are significant. While ibrutinib is typically administered once daily, these claims suggest that the patent holders may have explored or wish to protect various dosing regimens, potentially for different indications or patient populations. The emphasis on once-daily administration, particularly for CLL, SLL, MCL, and DLBCL, aligns with established treatment paradigms for ibrutinib.

The inclusion of combination therapy claims (e.g., with CD20 antibodies like rituximab, or other agents like venetoclax, cyclophosphamide, bendamustine, fludarabine, prednisone) is crucial. These claims protect the use of ibrutinib in synergistic treatment regimens, which are increasingly common in oncology. This broadens the scope of protection beyond monotherapy.

For the pharmaceutical market, this patent signifies continued intellectual property protection for a key drug. It suggests that Bristol-Myers Squibb (as assignee) is actively managing and defending its interests in ibrutinib. This can impact market entry timelines for potential generic competitors, as they must either design around these specific claims or challenge their validity. The patent's issuance in 2022 indicates ongoing efforts to secure protection for aspects of ibrutinib therapy that emerged after the initial drug approval.

The presence of multiple B-cell malignancy indications, from CLL/SLL to more aggressive lymphomas, underscores ibrutinib's broad utility and the patent's aim to cover its key therapeutic applications.

Key Takeaways

• U.S. Patent 11,357,731 protects specific crystalline Form I of ibrutinib, defined by XRPD and DSC characteristics.
• The patent claims pharmaceutical compositions containing Form I ibrutinib, primarily for oral administration.
• Extensive claims cover methods of treating various B-cell malignancies, including CLL, SLL, MCL, WM, and DLBCL, with specific dosage regimens and combination therapies.
• The patent extends intellectual property protection for ibrutinib, impacting generic market entry and competition.
• Manufacturing and formulation require strict adherence to the claimed crystalline form and composition specifications to ensure patent coverage.

FAQs

1. Does U.S. Patent 11,357,731 cover the ibrutinib molecule itself? No, this patent primarily covers specific crystalline forms of ibrutinib (Form I), pharmaceutical compositions containing these forms, and methods of treating certain B-cell malignancies using these forms. The original composition of matter patents for ibrutinib would have covered the molecule itself.

2. What are the primary B-cell malignancies mentioned in the patent? The patent explicitly mentions chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia (WM), and diffuse large B-cell lymphoma (DLBCL).

3. Can generic ibrutinib be manufactured and sold while this patent is in force? Generic manufacturers can sell ibrutinib products if they do not infringe on any active patents. For U.S. Patent 11,357,731, this would mean avoiding the use of the specific Form I crystalline structure claimed, or developing a non-infringing formulation and method of treatment. However, other patents may also need to be considered.

4. What is the significance of the XRPD and DSC data in the claims? The X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) data are analytical fingerprints used to definitively identify and characterize the specific crystalline form of ibrutinib claimed in the patent. These specifications are crucial for distinguishing Form I from other potential polymorphs.

5. Does this patent allow for combination therapies with ibrutinib? Yes, the patent includes claims covering methods of treating B-cell malignancies where ibrutinib is administered in combination with other anti-cancer agents, such as CD20 antibodies (e.g., rituximab), venetoclax, and various chemotherapy agents.

Citations

[1] Bristol-Myers Squibb Company. (2022). U.S. Patent 11,357,731: Pharmaceutical formulations and methods of treatment. United States Patent and Trademark Office. [2] AbbVie Inc., & Pharmacyclics LLC. (2010). U.S. Patent 7,514,444: Substituted pyrazolo[3,4-d]pyrimidines. United States Patent and Trademark Office.

Drugs Protected by US Patent 11,357,731

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Chiesi	FERRIPROX	deferiprone	TABLET;ORAL	212269-001	May 19, 2020		RX	Yes	Yes						METHOD OF TREATING TRANSFUSIONAL IRON OVERLOAD

International Family Members for US Patent 11,357,731

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2018357350
Brazil	112020008128
Canada	3077514
Canada	3172668
China	111918646