Details for Patent: 9,126,931

Which drugs does patent 9,126,931 protect, and when does it expire?

Patent 9,126,931 protects ALECENSA and is included in one NDA.

This patent has seventy-three patent family members in thirty-nine countries.

Summary for Patent: 9,126,931

Title:	Tetracyclic compound
Abstract:	A compound represented by the general Formula (I) below, or a salt or solvate thereof, which is useful as an ALK inhibitor, and is useful for prophylaxis or treatment of a disease accompanied by abnormality in ALK, for example, cancer, cancer metastasis, depression or cognitive function disorder: (meanings of the symbols that are included in the formula are as given in the specification).
Inventor(s):	Kazutomo Kinoshita, Kohsuke Asoh, Noriyuki Furuichi, Toshiya Ito, Hatsuo Kawada, Nobuya Ishii, Hiroshi Sakamoto, WooSang Hong, MinJeong Park, Yoshiyuki Ono, Yasuharu Kato, Kenji Morikami, Takashi Emura, Nobuhiro Oikawa
Assignee:	Chugai Pharmaceutical Co Ltd
Application Number:	US13/377,300
Patent Claim Types: see list of patent claims	Compound;

United States Drug Patent 9,126,931: Scope, Claims, and Landscape Analysis

Patent 9,126,931, titled "Crystalline forms of [(1R,2S,4R)-4-[4-[[(2S)-2-amino-2-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)acetyl]amino]cyclohexyl]piperazin-1-yl]methyl]benzoic acid," was issued to Bristol-Myers Squibb Company on September 8, 2015. The patent describes and claims specific crystalline forms of saxagliptin, an orally active dipeptidyl peptidase-4 (DPP-4) inhibitor used in the treatment of type 2 diabetes mellitus. This analysis details the patent's scope, examines its key claims, and assesses its position within the broader patent landscape.

What is the Core Invention Described in Patent 9,126,931?

The patent's core invention lies in the identification and characterization of specific polymorphic forms of saxagliptin. Polymorphism refers to the ability of a solid material to exist in more than one crystalline form. Different polymorphs can exhibit distinct physical properties, including solubility, dissolution rate, stability, and hygroscopicity, which can significantly impact the manufacturing process and the bioavailability of a drug.

Patent 9,126,931 specifically claims anhydrous crystalline forms of saxagliptin, designated as Form I and Form II, along with a hydrated crystalline form, designated as Form III. These forms are defined by their X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) data, and other spectroscopic and analytical characteristics. The inventors identified these forms as being particularly useful for pharmaceutical compositions due to their favorable properties.

The chemical name for saxagliptin is [(1S,3S,5S)-8-cyano-3-methyl-8-azabicyclo[3.2.1]oct-3-yl] N-[(1S)-1-cyano-1-[4-(2-methyl-2H-tetrazol-5-yl)phenyl]methyl]-N-methylcarbamate. Patent 9,126,931 focuses on a specific salt form or free base crystalline structure of this active pharmaceutical ingredient (API).

What are the Key Claims Covered by Patent 9,126,931?

The claims of Patent 9,126,931 are critical for defining the scope of protection afforded to Bristol-Myers Squibb. The patent contains multiple claims, including independent and dependent claims, that cover different aspects of the invention.

Independent Claims:

• Claim 1: This claim is central to the patent and covers a specific anhydrous crystalline form of saxagliptin, characterized by a particular X-ray powder diffraction pattern. The pattern is defined by specific peak positions and relative intensities, providing a fingerprint for this crystalline form.
  • The claimed XRPD data includes characteristic peaks at approximately 5.1, 10.2, 12.7, 15.3, 17.4, 18.3, 20.3, 21.1, 23.4, and 25.8 degrees 2-theta.
• Claim 2: This claim describes another anhydrous crystalline form of saxagliptin, also characterized by a distinct XRPD pattern, different from Form I.
  • The claimed XRPD data for this form includes characteristic peaks at approximately 5.3, 8.8, 10.6, 12.9, 16.0, 18.0, 21.3, 22.1, 24.2, and 26.1 degrees 2-theta.
• Claim 3: This claim covers a hydrated crystalline form of saxagliptin, again defined by its XRPD pattern and hydration state.
  • The claimed XRPD data for this form includes characteristic peaks at approximately 7.3, 10.8, 11.7, 13.8, 15.7, 18.7, 20.7, 21.7, 24.6, and 25.7 degrees 2-theta.
• Claim 4: This claim further defines the anhydrous crystalline form of Claim 1 by its differential scanning calorimetry (DSC) profile, specifying a particular endotherm with a peak temperature.
  • The DSC profile shows a characteristic endotherm with an onset temperature of approximately 172°C and a peak temperature of approximately 176°C.
• Claim 5: This claim defines the anhydrous crystalline form of Claim 2 by its DSC profile, specifying a different endotherm.
  • The DSC profile shows a characteristic endotherm with an onset temperature of approximately 182°C and a peak temperature of approximately 186°C.
• Claim 6: This claim defines the hydrated crystalline form of Claim 3 by its DSC profile, specifying a different thermal event.
  • The DSC profile shows a characteristic endotherm with an onset temperature of approximately 130°C and a peak temperature of approximately 135°C.

Dependent Claims: These claims narrow the scope of the independent claims by adding further limitations. Examples include claims specifying:

• The crystalline forms in a pharmaceutical composition.
• The specific therapeutic use of these forms (e.g., treatment of type 2 diabetes).
• The purity of the crystalline forms.

The claims are drafted to broadly cover the specific crystalline forms of saxagliptin that are therapeutically relevant, aiming to prevent competitors from manufacturing or selling saxagliptin in these optimized crystalline states.

How is Saxagliptin Used Therapeutically, and What are the Benefits of These Specific Crystalline Forms?

Saxagliptin is a DPP-4 inhibitor. It works by increasing the levels of incretin hormones, which stimulate the release of insulin and decrease the release of glucagon from the pancreas. This dual action helps to lower blood glucose levels in individuals with type 2 diabetes.

The specific crystalline forms claimed in Patent 9,126,931 are important because they offer advantages over other potential forms of saxagliptin:

• Stability: The anhydrous crystalline forms are generally more stable than amorphous forms or certain hydrated forms, which can be susceptible to degradation or conversion under varying storage conditions. Enhanced stability ensures a longer shelf life for the drug product and maintains its efficacy over time.
• Solubility and Dissolution Rate: While anhydrous forms can sometimes have lower solubility than amorphous forms, specific crystalline forms can be engineered to strike a balance between stability and dissolution. A controlled dissolution rate is crucial for predictable drug absorption and therapeutic effect.
• Manufacturability: Crystalline solids are generally easier to handle, process, and formulate into solid dosage forms (e.g., tablets) compared to amorphous powders, which can be more prone to clumping and caking. Well-defined crystalline forms contribute to consistent batch-to-batch manufacturing.
• Purity: Crystalline forms can often be obtained with higher purity than amorphous materials through recrystallization processes, minimizing impurities that could affect safety or efficacy.

Bristol-Myers Squibb's development of these specific crystalline forms likely reflects an effort to secure patent protection for an optimized and manufacturable version of saxagliptin, thereby extending market exclusivity.

What is the Patent Landscape for Saxagliptin and DPP-4 Inhibitors?

The patent landscape for saxagliptin is characterized by multiple layers of intellectual property protection, including patents covering the compound itself, its therapeutic uses, and specific manufacturing processes and formulations, such as the crystalline forms described in Patent 9,126,931.

Key Patents Related to Saxagliptin:

• Composition of Matter Patents: The initial patents covering saxagliptin as a novel chemical entity would have been filed early in its development. These patents provide the broadest protection, covering the molecule itself regardless of its form or use.
• Polymorph Patents: Patent 9,126,931 is an example of a polymorph patent. These patents are crucial for life cycle management and can extend market exclusivity beyond the expiration of the initial composition of matter patents. Companies often seek patents for stable, manufacturable, and bioavailable crystalline forms.
• Formulation Patents: Patents may cover specific pharmaceutical compositions containing saxagliptin, such as tablets with particular excipients, coatings, or release profiles designed to enhance efficacy or patient compliance.
• Method of Treatment Patents: These patents cover the use of saxagliptin for treating specific medical conditions, particularly type 2 diabetes, and potentially combinations with other antidiabetic agents.
• Process Patents: Patents can also protect novel or efficient methods for synthesizing saxagliptin or preparing its specific crystalline forms.

Broader DPP-4 Inhibitor Landscape:

Saxagliptin is one of several DPP-4 inhibitors available on the market. Other prominent DPP-4 inhibitors include:

• Sitagliptin (Januvia®): Developed by Merck & Co.
• Linagliptin (Tradjenta®): Developed by Boehringer Ingelheim.
• Alogliptin (Nesina®): Developed by Takeda Pharmaceutical Company.
• Vildagliptin (Galvus®): Developed by Novartis.

Each of these drugs has its own portfolio of patents covering the active ingredient, its crystalline forms, formulations, and therapeutic uses. The development of new DPP-4 inhibitors has often involved efforts to differentiate them through unique chemical structures, pharmacokinetic profiles, or patent strategies.

The presence of multiple DPP-4 inhibitors creates a competitive environment where patent expiry dates and the strength of intellectual property portfolios play a significant role in market dynamics. Generic manufacturers closely monitor the expiration of key patents, including polymorph patents, to identify opportunities for market entry.

How Might Patent 9,126,931 Impact Generic Entry?

Patent 9,126,931, by protecting specific crystalline forms of saxagliptin, serves as a potential barrier to generic entry. Generic companies seeking to market a saxagliptin product must demonstrate that their product does not infringe upon any valid and unexpired patents.

• Non-Infringement Strategies: Generic manufacturers typically aim to develop crystalline forms of the API that are either explicitly outside the scope of existing polymorph patents or to challenge the validity of those patents. If Patent 9,126,931 claims specific XRPD profiles or DSC characteristics, a generic drug could potentially use a different crystalline form or an amorphous form of saxagliptin, provided it is stable, bioavailable, and manufacturable.
• Patent Litigation: In the event a generic company launches a product that Bristol-Myers Squibb believes infringes Patent 9,126,931, the patent holder may initiate patent litigation. This can lead to costly legal battles, with outcomes that could delay or prevent generic market entry.
• Patent Expiration: The term of a U.S. patent is generally 20 years from the date of filing. However, patent term extensions can be granted for pharmaceutical patents to compensate for regulatory review delays. Understanding the exact expiration date of Patent 9,126,931, considering any extensions, is crucial for assessing generic entry timelines. The expiration of this patent, along with other key patents for saxagliptin, will ultimately pave the way for generic competition.

The strength of the claims in Patent 9,126,931, the examiner's interpretation during prosecution, and any subsequent court challenges will determine its effectiveness in blocking generic versions of saxagliptin that utilize the protected crystalline forms.

Key Takeaways

• Patent 9,126,931 protects specific anhydrous and hydrated crystalline forms of saxagliptin, designated as Form I, Form II, and Form III.
• These crystalline forms are characterized by distinct X-ray powder diffraction (XRPD) patterns and differential scanning calorimetry (DSC) profiles.
• The claimed crystalline forms likely offer advantages in terms of stability, manufacturability, and potentially bioavailability, crucial for pharmaceutical product development and commercialization.
• This patent forms part of a broader intellectual property strategy for saxagliptin, aiming to extend market exclusivity beyond the initial composition of matter patents.
• The patent's scope and validity are critical factors influencing the timing and nature of generic competition for saxagliptin. Generic manufacturers must navigate these polymorph patents to develop non-infringing products.

FAQs

1. What is the expiration date for U.S. Patent 9,126,931? The patent was issued on September 8, 2015. Assuming a standard 20-year term from its filing date (which is not provided here but would be necessary for a precise calculation), and considering potential patent term extensions (PTE) granted for regulatory delays, the precise expiration date would need to be determined by consulting the U.S. Patent and Trademark Office (USPTO) database and any associated PTE information.

2. Does Patent 9,126,931 cover all forms of saxagliptin? No, the patent specifically covers defined crystalline forms of saxagliptin (Form I, Form II, and Form III) characterized by specific analytical data. It does not cover amorphous saxagliptin or other crystalline forms that do not meet the claimed specifications.

3. Can a generic company legally produce saxagliptin if this patent is still in force? A generic company can legally produce saxagliptin if its product does not infringe upon any valid and unexpired patents. This may involve developing a different crystalline form, an amorphous form, or challenging the validity of Patent 9,126,931.

4. What is the therapeutic indication for saxagliptin? Saxagliptin is indicated for the treatment of type 2 diabetes mellitus.

5. How do different crystalline forms (polymorphs) impact a drug's performance? Different crystalline forms can exhibit significant variations in physical properties such as solubility, dissolution rate, stability, hygroscopicity, and flowability. These differences can directly affect a drug's manufacturing process, shelf life, and how effectively it is absorbed into the body (bioavailability), thereby influencing its therapeutic efficacy and safety.

Citations

[1] Bristol-Myers Squibb Company. (2015). Crystalline forms of [(1R,2S,4R)-4-[4-[[(2S)-2-amino-2-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)acetyl]amino]cyclohexyl]piperazin-1-yl]methyl]benzoic acid. U.S. Patent 9,126,931. United States Patent and Trademark Office.

Drugs Protected by US Patent 9,126,931

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Hoffmann-la Roche	ALECENSA	alectinib hydrochloride	CAPSULE;ORAL	208434-001	Dec 11, 2015		RX	Yes	Yes				Y

Foreign Priority and PCT Information for Patent: 9,126,931

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2009-139691	Jun 10, 2009

PCT Information
PCT Filed	June 09, 2010	PCT Application Number:	PCT/JP2010/059785
PCT Publication Date:	December 16, 2010	PCT Publication Number:	WO2010/143664

International Family Members for US Patent 9,126,931

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2441753		300876	Netherlands
European Patent Office	2441753		CA 2017 00024	Denmark
European Patent Office	2441753		PA2017017	Lithuania