Details for Patent: 8,900,638

Which drugs does patent 8,900,638 protect, and when does it expire?

Patent 8,900,638 protects KAZANO and is included in one NDA.

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

Summary for Patent: 8,900,638

Title:	Solid preparation comprising alogliptin and metformin hydrochloride
Abstract:	The present invention provides a solid preparation containing compound (I) [compound (I) is as defined in the specification] or a salt thereof, and metformin hydrochloride, which is useful as a therapeutic drug for diabetes and the like, and superior in the preservation stability. A solid preparation having a first part and a second part: a first part: a part containing compound (I) or a salt thereof and substantially free of metformin hydrochloride a second part: a part containing metformin hydrochloride and substantially free of compound (I) and a salt thereof.
Inventor(s):	Kazumichi Yamamoto, Hiroyoshi Koyama
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US12/452,705
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,900,638
Patent Claim Types: see list of patent claims	Use; Formulation; Dosage form;

United States Patent 8,900,638: Linagliptin–Metformin Solid Preparation Claims and Patent Landscape

U.S. Patent No. 8,900,638 protects physically separated solid dosage forms containing linagliptin, or a salt of linagliptin, and metformin hydrochloride. Its strongest protection covers bilayer tablets, core-layer tablets, separate granules compressed together, and capsules containing separate granules or tablets. The patent does not broadly claim linagliptin, metformin, or their therapeutic combination in every dosage form.

The commercial relevance is primarily to linagliptin/metformin products such as Jentadueto. The patent’s expected nominal term runs to approximately July 2030, subject to patent-term adjustment, terminal disclaimer, or other USPTO-record events. FDA approval and Orange Book listing are separate questions from patent validity and enforceability.[1-4]

What drug combination does U.S. Patent 8,900,638 cover?

The compound identified by the lengthy chemical name in the claims is linagliptin, a dipeptidyl peptidase-4 inhibitor. The second active ingredient is metformin hydrochloride.

The patent covers a solid combination preparation in which the two active ingredients are physically separated. The separation can be achieved through:

• Separate granules compressed into one tablet.
• Two discrete tablet portions.
• A core containing one active ingredient and a surrounding layer containing the other.
• Two layers separated by an intermediate layer.
• A capsule containing separate granules or tablets.
• A compressed mixture of separate first and second granules.

The claimed separation is directed to stability. The patent seeks to prevent or reduce degradation of linagliptin when it is formulated with metformin hydrochloride and excipients.

What is the central inventive concept?

The central limitation is physical segregation of linagliptin and metformin hydrochloride within the same solid preparation.

Claim 1 requires:

Element	Requirement
First part	Linagliptin or a salt
Metformin in first part	0 to 3 parts by weight per 100 parts of first part
Second part	Metformin hydrochloride
Linagliptin in second part	0 to 0.5 parts by weight per 100 parts of second part
Structural relationship	First part physically separated from second part

The low cross-contamination ranges are important. The claim does not require absolute chemical isolation. It permits limited amounts of the other active ingredient in each part.

The use of “comprising” broadens the claim beyond a closed list of ingredients. An accused product may include additional excipients, coatings, stabilizers, binders, lubricants, disintegrants, or other formulation components and still fall within the claim if all required limitations are present.

How do the 23 claims divide into technical claim groups?

The claims form several nested protection groups.

Claims 1-3: Basic combination and dose range

Claim 1 is the principal composition claim. Claim 2 adds an additive. Claim 3 specifies approximately:

• 0.5 to 200 mg of linagliptin or its salt.
• 0.1 to 2 g of metformin hydrochloride.

These ranges correspond broadly to commercial dosing, including low-dose linagliptin with conventional metformin quantities.

Claim 3 is narrower than claim 1 because a product must satisfy both the physical-separation structure and the specified quantity ranges.

Claims 4-5: Particle size and linagliptin benzoate

Claim 4 requires average particle sizes of at least approximately 75 micrometers for both parts.

Claim 5 limits linagliptin to the benzoate salt. A product using a different linagliptin salt, such as the free base or another pharmaceutically acceptable salt, would not literally satisfy claim 5, although it could still fall within claim 1.

The particle-size limitation is potentially important in generic-product analysis because particle size can be controlled during milling, granulation, crystallization, and blending. A generic manufacturer may be able to avoid claim 4 while still confronting claim 1.

Claims 6-10: Dosage-form and excipient limitations

These claims cover:

• Tablets.
• First and second parts in granule or tablet form.
• Capsules containing the granules or tablets.
• A linagliptin-to-metformin weight ratio of 1:5 to 1:400.
• Cellulose as the additive.

The ratio limitation is broad enough to cover many therapeutic combinations. It is less likely to distinguish a commercial product when the dosage ratio already falls within the ordinary linagliptin/metformin range.

Claims 11-13: Separate granules compressed together

Claim 11 covers a solid preparation obtained by compression molding a mixture of:

• A first granule containing linagliptin.
• A second granule containing metformin hydrochloride.

The granules may contain limited quantities of the opposite active ingredient within the same 3-parts and 0.5-parts limits stated in claim 1.

Claim 12 adds particle-distribution requirements:

Granule fraction	Requirement
First granule below 150 μm	At least approximately 20 wt%
First granule at least 250 μm	No more than approximately 50 wt%
Second granule below 150 μm	At least approximately 20 wt%
Second granule at least 250 μm	No more than approximately 50 wt%

Claim 13 adds the 1:5 to 1:400 active-ingredient ratio.

These claims are process-sensitive. Manufacturing records, sieve data, granulation specifications, and batch-release testing would be relevant to infringement analysis.

Claims 14-17: Core-layer and coated-tablet structures

Claim 14 covers two alternatives:

1. A metformin core with a linagliptin-containing layer.
2. A linagliptin core with a metformin-containing layer.

The claim allows limited incorporation of the opposite active ingredient into each core or layer.

Claim 15 requires an intermediate layer between the core and outer layer. Claims 16 and 17 specify spray coating and compression as layer-formation techniques.

This group targets bilayer, press-coated, and film-coated dosage forms. The claim language is not limited to a particular release profile. A product may be immediate release, modified release, or otherwise formulated, provided the structural and composition requirements are met.

Claims 18-19: Two-layer tablets

Claim 18 covers a first layer containing linagliptin and a second layer containing metformin hydrochloride. Claim 19 adds an intermediate layer.

These claims are likely the most commercially relevant if the marketed product uses a bilayer or multilayer tablet architecture. They can also be relevant to a product that uses separate layers but does not use a conventional core-and-coating configuration.

Claim 20: Stability-performance limitation

Claim 20 requires each of six linagliptin-related substances, RS1 through RS6, to have a peak-area ratio of no more than 0.5% after one month under specified conditions:

• 40°C.
• 22%, 33%, 44%, or 57% relative humidity.
• Open storage.
• A specified HPLC method using a Zorbax SB-CN column.
• UV detection at 278 nm.
• Defined gradient, flow rate, and temperature conditions.

This is a product-defined-by-testing limitation. A patentee would need to establish that the accused product satisfies the specified stability result and that the analytical method is properly applied. A generic applicant could challenge the claim based on non-infringement if one or more impurity thresholds are exceeded, or based on validity theories directed to definiteness, enablement, written description, or lack of reproducibility.

Claims 21-22: Functional and therapeutic restrictions

Claim 21 expressly requires that linagliptin and metformin hydrochloride be physically separated.

Claim 22 identifies the preparation as a therapeutic combination drug for diabetes or obesity. This limitation is unlikely to provide substantial additional technical protection if the composition already meets claim 1. It may, however, affect claim construction and the intended use of the product.

Claim 23: Stabilization method

Claim 23 is a method claim. It requires:

1. A solid preparation containing linagliptin, metformin hydrochloride, and an additive.
2. Physical separation of linagliptin from metformin hydrochloride.
3. Separation by the additive.
4. Stabilization of linagliptin in the solid preparation.

This claim is narrower than claim 1 because it requires the additive to perform the separating function. It may be relevant to a formulation that does not use discrete bilayer geometry but creates separation through an excipient matrix or intermediate material.

What products are most exposed to U.S. Patent 8,900,638?

High-risk product configurations

The highest literal-infringement risk generally arises from a product that has:

• Linagliptin in one granule and metformin hydrochloride in another.
• The two granules compressed into one tablet.
• Low cross-contamination between the active ingredients.
• A linagliptin dose of approximately 0.5 to 200 mg.
• Metformin hydrochloride in the 0.1 to 2 g range.
• A 1:5 to 1:400 linagliptin-to-metformin ratio.

A bilayer tablet or press-coated tablet with one active ingredient in each layer is also directly aligned with claims 14 and 18.

Lower-risk configurations

Potentially lower-risk designs include:

• A single homogeneous granulation in which linagliptin and metformin are not physically separated.
• A dosage form using a different active combination.
• A formulation in which linagliptin and metformin are chemically complexed or co-processed in a manner inconsistent with the claimed “physically separated” structure.
• A product outside the claimed composition ranges, where the dependent claims are the only relevant claims.
• A formulation that does not meet claim 20’s impurity-performance limitations.

Avoiding a dependent claim does not avoid claim 1. Claim 1 contains no minimum additive requirement and does not require a tablet, capsule, granule, core, coating, or specific particle size.

How strong is the patent estate for linagliptin and metformin?

The estate is strongest as a formulation and combination-product estate, not as a basic compound estate.

Technology area	Protection profile	Commercial significance
Linagliptin active ingredient	Earlier compound and composition patents	Core DPP-4 inhibitor protection
Metformin hydrochloride	Long-established generic active ingredient	Limited current patent barrier
Linagliptin/metformin combination	Combination and treatment claims	Covers co-administration and therapeutic use
Physically separated solid preparation	U.S. 8,900,638	Targets product architecture and stability
Linagliptin salt forms	Salt and solid-state claims in related families	May constrain salt selection
Manufacturing process	Granulation, compression, coating, and impurity-control claims	Relevant to supply-chain and process design
Regulatory exclusivity	FDA approval and exclusivity periods	Independent of patent term

The commercial value of U.S. Patent 8,900,638 depends on whether the marketed product uses the claimed separation architecture. If Jentadueto or a successor product is made with separate linagliptin and metformin populations, the patent has direct product relevance. If a competing product uses a materially different formulation, the patent may have limited practical reach.

How does this patent compare with the linagliptin compound patent?

The principal distinction is scope and timing.

The compound patent protects linagliptin itself and is relevant to virtually every U.S. product containing the molecule. U.S. Patent 8,900,638 does not reach every linagliptin product. It requires the specific combination with metformin hydrochloride and physical separation within a solid preparation.

The compound patent therefore has broader molecule-level scope. Patent 8,900,638 has narrower but potentially more targeted product-level scope.

What is the expected expiration date?

The patent issued on December 2, 2014. Public patent records identify a 2009 priority framework for the invention and a nominal patent term extending to approximately July 2030.[1]

Event	Date or period
Earliest priority framework	2009
U.S. patent grant	December 2, 2014
Nominal term endpoint	Approximately July 2030
Possible adjustment	Depends on USPTO patent-term-adjustment calculation
Pediatric extension	Must be confirmed from the current patent and FDA records

The exact enforceable expiration date should be taken from the USPTO patent-term calculation and any terminal-disclaimer data. A patent’s issue date does not determine its expiration date.

What is the Orange Book status of U.S. Patent 8,900,638?

The Orange Book is the relevant FDA publication for patents submitted by NDA sponsors for approved small-molecule products. An Orange Book listing can support a statutory patent-certification obligation for an ANDA applicant, including a Paragraph IV certification. Listing does not prove validity or infringement.[2,3]

For linagliptin/metformin products, the relevant FDA product is Jentadueto, an immediate-release combination of linagliptin and metformin hydrochloride. Jentadueto was approved under NDA 201280.[4]

The practical regulatory questions are:

• Whether U.S. Patent 8,900,638 is listed against the relevant NDA.
• Whether the listing covers the specific reference product and dosage strengths.
• Whether the listing remains active in the current Orange Book.
• Whether an ANDA applicant must certify to the patent.
• Whether the NDA holder has submitted a timely patent-use code or delisting request.

A Paragraph IV certification would create potential Hatch-Waxman litigation exposure if the patent were listed and the NDA holder filed suit within the statutory period. The patent record supplied here does not establish that a specific ANDA applicant has filed a Paragraph IV certification or that a particular litigation has been resolved.[2,3]

Which companies are challenging linagliptin/metformin exclusivity?

The claims provided do not identify an ANDA applicant, Paragraph IV notice letter, settlement agreement, or litigation docket. A definitive challenger list cannot be derived from the patent claims.

For competitive analysis, the relevant challenger universe includes:

• Generic manufacturers filing ANDAs for linagliptin/metformin tablets.
• Manufacturers seeking approval for linagliptin alone.
• Companies developing alternative DPP-4 inhibitor/metformin combinations.
• Developers using co-packaged but physically separate products rather than a single solid preparation.
• Manufacturers pursuing 505(b)(2) products with different formulation or salt characteristics.

A generic applicant can target the patent through a formulation design that avoids physical separation, a Paragraph IV invalidity position, a non-infringement position, or a certification based on patent expiration. The preferred route depends on the Orange Book listing, product design, and remaining market value.

What manufacturing and IP barriers does the patent create?

The patent can affect several manufacturing decisions:

• Whether active ingredients are granulated separately.
• Whether cross-contamination remains below the claimed limits.
• Whether separate granules are compressed together.
• Whether layer uniformity is maintained.
• Whether particle-size distributions fall within dependent claims.
• Whether impurity results satisfy claim 20.
• Whether batch records establish physical separation.
• Whether an intermediate layer is used.
• Whether the product is manufactured by spray coating or compression.

The patent’s technical barrier is manageable because alternative formulation architectures exist. Its litigation value may still be material because a commercial bilayer or separate-granule product can be easier to map to the claims than a complex chemical-process patent.

What generic launch scenarios exist?

Scenario 1: Launch after patent expiry

This is the lowest litigation-risk scenario if no later-listed patent or regulatory exclusivity remains.

Scenario 2: Paragraph IV challenge

An ANDA applicant may argue that the proposed product does not contain physically separated linagliptin and metformin, does not meet the claimed ranges, or renders the claims invalid over prior art.

Scenario 3: Formulation redesign

A manufacturer may use a homogeneous blend or a different excipient and granulation process. This may reduce exposure to claims 11-19 and 23 but must still be tested against claim 1.

Scenario 4: Separate co-packaged products

A co-packaged linagliptin tablet and metformin tablet may avoid some single-preparation claims, depending on whether the package is legally characterized as one solid preparation. The physical-separation requirement does not automatically make every co-packaging arrangement non-infringing.

Scenario 5: Settlement and delayed entry

A settlement could establish an agreed launch date before nominal patent expiry. No settlement terms are established by the supplied claim record.

Key Takeaways

• U.S. Patent 8,900,638 is a targeted formulation patent for physically separated linagliptin and metformin hydrochloride in a solid preparation.
• Claim 1 is the principal broad composition claim.
• Claims 11-19 focus on separate granules, bilayer tablets, core-layer tablets, coatings, and intermediate layers.
• Claim 20 adds a demanding six-impurity stability profile measured by a specified HPLC method.
• Claim 23 covers stabilization by physically separating linagliptin from metformin with an additive.
• The patent does not broadly protect linagliptin, metformin, or every linagliptin/metformin treatment.
• The expected nominal expiration is approximately July 2030, subject to the USPTO term calculation.
• Product-specific infringement risk is highest for separate-granule and bilayer formulations that match the claimed dose, ratio, and low-cross-contamination parameters.
• FDA Orange Book listing, Paragraph IV activity, litigation, and settlement status must be assessed separately from the patent claims.
• The principal design-around opportunity is a solid formulation that avoids the claimed physical separation while maintaining acceptable linagliptin stability.

FAQs

Does U.S. Patent 8,900,638 cover Jentadueto?

It may be relevant to Jentadueto if the commercial product uses the claimed physical separation of linagliptin and metformin hydrochloride. Product-specific coverage depends on the approved formulation, manufacturing process, Orange Book listing, and claim construction.

Does the patent cover a fixed-dose linagliptin/metformin tablet made as one homogeneous blend?

Not necessarily. Claim 1 requires the linagliptin-containing first part to be physically separated from the metformin-containing second part. A genuinely homogeneous preparation may avoid the core structural limitation, although the manufacturing and product evidence would control.

Can a generic use linagliptin benzoate without infringing?

Avoiding claim 5 alone is insufficient because claim 1 covers linagliptin or a salt thereof. A generic using linagliptin benzoate must be assessed against the independent claims and the remaining dependent claims.

Is a capsule with separate granules within the patent scope?

Potentially. Claims 7 and 8 specifically address granules or tablets contained in a capsule, while claim 11 addresses compression of separate granules. The formulation must also satisfy the active-ingredient and physical-separation limitations.

Does an FDA Orange Book listing prove that the patent is valid?

No. An Orange Book listing affects regulatory certification and potential Hatch-Waxman litigation. It does not establish validity, enforceability, or infringement.[2,3]

References

1. United States Patent and Trademark Office. (2014). U.S. Patent No. 8,900,638, Solid preparation comprising a DPP-IV inhibitor and metformin.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Code, 21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.
4. U.S. Food and Drug Administration. (2012). Jentadueto prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc.

Drugs Protected by US Patent 8,900,638

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	KAZANO	alogliptin benzoate; metformin hydrochloride	TABLET;ORAL	203414-002	Jan 25, 2013		RX	Yes	Yes			Y
Takeda Pharms Usa	KAZANO	alogliptin benzoate; metformin hydrochloride	TABLET;ORAL	203414-001	Jan 25, 2013		RX	Yes	No			Y

Foreign Priority and PCT Information for Patent: 8,900,638

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2007-188574	Jul 19, 2007

PCT Information
PCT Filed	July 16, 2008	PCT Application Number:	PCT/JP2008/063228
PCT Publication Date:	January 22, 2009	PCT Publication Number:	WO2009/011451

International Family Members for US Patent 8,900,638

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	067557
Australia	2008276842
Brazil	PI0814299
Canada	2694620
China	101801351
Colombia	6160301