Details for Patent: 7,456,219

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Which drugs does patent 7,456,219 protect, and when does it expire?

Patent 7,456,219 protects ZOLINZA and is included in one NDA.

This patent has ninety patent family members in twenty-eight countries.

Summary for Patent: 7,456,219

Title:	Polymorphs of suberoylanilide hydroxamic acid
Abstract:	The present invention provides methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or inhibiting histone deacetylase (HDAC) by administration of pharmaceutical compositions comprising potent HDAC inhibitors. The oral bioavailability of the active compounds in the pharmaceutical compositions of the present invention is surprisingly high. Moreover, the pharmaceutical compositions unexpectedly give rise to high, therapeutically effective blood levels of the active compounds over an extended period of time. The present invention further provides a safe, daily dosing regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo. The present invention also provides a novel Form I polymorph of SAHA, characterized by a unique X-ray diffraction pattern and Differential Scanning Calorimetry profile, as well a unique crystalline structure.
Inventor(s):	Thomas A. Miller, Victoria M. Richon, Judy H. Chiao
Assignee:	Merck HDAC Research LLC
Application Number:	US10/600,132
Patent Claim Types: see list of patent claims	Use; Process;

United States Patent 7,456,219: Vorinostat Form I Claims, Scope, Expiry and Patent Landscape

US Patent 7,456,219 protects a crystalline polymorph of suberoylanilide hydroxamic acid, known as SAHA or vorinostat, rather than the active molecule broadly. Its core limitations are the Form I crystal structure, specified powder X-ray diffraction peaks, a DSC melting maximum near 164.4°C, and, in many claims, recrystallization from methanol, ethanol, isopropanol, or aqueous mixtures of those solvents. The patent does not claim a therapeutic indication, dosage regimen, capsule formulation, or method of treating cancer.

The patent is important because a commercial vorinostat product normally contains crystalline active pharmaceutical ingredient. A generic manufacturer can therefore face infringement risk even after the broader chemical and composition-of-matter protection for SAHA has expired.

What does US Patent 7,456,219 protect?

US 7,456,219 is directed to polymorphic Form I of SAHA. The claims define the material through analytical fingerprints and, in several claim groups, through the process used to obtain it.

Protection category	Principal claim coverage
Form I by XRPD and DSC	Claims 1, 2, 6, 7, 9
Form I made by recrystallization	Claims 3-5, 12-16
DSC test conditions	Claims 10, 11, 15, 16
Plate-shaped crystals	Claim 8
SAHA synthesis and crude isolation	Claims 17, 18
Methanol, ethanol and isopropanol variants	Claims 19-33
Methanol-water recrystallization	Claims 34-43
Specific 2:1 methanol-water mixture	Claims 35, 37, 40 and 42

The claims use the phrase "active ingredient consisting of" Form I. That language narrows the claimed subject matter to the specified SAHA crystalline material. It does not generally claim a pharmaceutical composition containing any amount of vorinostat, nor does it cover all polymorphs or amorphous forms of SAHA.

How do the XRPD and DSC limitations define SAHA Form I?

The principal analytical definition combines copper-source powder X-ray diffraction with differential scanning calorimetry.

The broadest XRPD profile recited in the claims includes peaks at approximately:

9.0, 9.4, 17.5, 19.4, 20.0, 24.0, 24.4, 24.8, 25.0, 28.0 and 43.3 degrees 2θ.

A narrower profile appears in claims 6, 7 and 12-14, among others. It requires peaks at approximately:

9.4, 17.5, 19.4, 20.0, 24.0 and 28.0 degrees 2θ.

Certain claims also require the absence of peaks in specified ranges, including approximately 13.4-14.0 and 22.7-23.0 degrees 2θ. These negative limitations distinguish Form I from other crystalline forms or mixtures.

The DSC limitation requires a single maximum at approximately 164.4°C, with a permitted range of plus or minus 2.0°C. Claims 10, 11, 15 and 16 prescribe testing parameters, including:

• Heating from 50°C;
• A heating rate of 10°C per minute;
• Heating to at least 30°C above the observed melting temperature;
• PerkinElmer standard aluminum pans and covers; and
• Nitrogen purge at approximately 20 milliliters per minute.

These testing conditions matter in litigation. XRPD peak positions can shift with instrument calibration, sample preparation, preferred orientation and radiation source. DSC results can vary with heating rate, pan configuration, sample mass and atmosphere. The patent attempts to reduce those variables by incorporating instrument and test-protocol details into dependent claims.

What is the claim structure of US 7,456,219?

Claims 1 and 2: broad product definitions

Claims 1 and 2 define Form I primarily by XRPD and DSC. Claim 2 adds the absence of at least one peak in specified ranges. These are the principal composition claims for the polymorph.

A manufacturer may infringe if its isolated vorinostat matches the claimed analytical profile, even if its crystallization process differs. The process used to produce the material is not an express limitation of claims 1 and 2.

Claims 3 through 5: product-by-process protection

Claims 3, 4 and 5 require Form I obtained by recrystallizing crude SAHA from methanol, ethanol, isopropanol, or a mixture of one of those solvents with water.

These are product-by-process claims. Their practical scope depends on whether the claim is interpreted as requiring both:

1. The claimed Form I product; and
2. The recited production process or process characteristics.

US courts generally treat product-by-process language as limiting for infringement analysis, even though the patentability of the product may be assessed under the identity of the product rather than the process alone. The precise treatment depends on the claim language, prosecution history and Federal Circuit precedent.

Claims 6 through 9: narrower analytical and physical forms

Claims 6 and 7 use a reduced set of XRPD peaks. Claim 7 adds the absence of peaks near 13.4-14.0 and 22.7-23.0 degrees 2θ. Claim 8 adds a plate-shaped form. Claim 9 adds DSC to claim 7.

The narrower claims may be easier to practice around analytically, but they can be useful if a commercial batch does not satisfy every limitation of the broader peak list while still meeting the reduced profile.

Claims 17 and 18: upstream synthesis steps

Claims 17 and 18 describe preparation of crude SAHA through:

1. Reaction of suberic acid with aniline to produce suberanilic acid or a salt;
2. Reaction with methanol to produce methyl suberanilate;
3. Reaction with hydroxylamine hydrochloride to produce crude SAHA;
4. Addition of sodium methoxide to obtain a clear solution; and
5. Addition of glacial acetic acid to precipitate crude SAHA.

These claims do not independently claim the chemical synthesis in the abstract. They are dependent on Form I product claims and therefore remain tied to the claimed active ingredient.

Claims 34 through 43: methanol-water routes

Claims 34-43 focus on Form I produced by recrystallization from methanol and water. Several claims specify a 2:1 methanol-to-water mixture. Claims 36, 38 and 41-43 add the upstream synthesis sequence and, in some cases, the sodium methoxide and acetic acid precipitation steps.

These claims create a more specific process pathway. They are relevant to manufacturers using a legacy or substantially similar crystallization process, but they do not necessarily reach a manufacturer that produces the same Form I through a materially different process if the applicable claim contains process limitations.

What patents protect vorinostat besides US 7,456,219?

The patent estate for vorinostat has historically included separate layers of protection.

Patent layer	Subject matter	Commercial relevance
Original SAHA composition patents	SAHA molecule and anticancer uses	Broad molecule protection; generally expired before the Form I patent
Polymorph patent	Crystalline SAHA Form I	US 7,456,219
Manufacturing patents	Preparation, purification or crystallization	May create process-specific barriers
FDA exclusivity	New chemical entity and clinical data exclusivity	Regulatory barrier independent of patent infringement
Product labeling	Approved indications and prescribing information	Relevant to induced or contributory infringement theories

The supplied claims show no method-of-use patent claims. They do not claim treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, multiple myeloma, or other disease states. They also do not claim a specific oral capsule, excipient system, dosage strength or packaging configuration.

The original SAHA research was associated with Columbia University and the National Cancer Institute, while commercialization of Zolinza involved Merck and affiliated entities. The 7,456,219 patent is associated with the later polymorph and manufacturing estate rather than the original broad discovery claims.

When does US Patent 7,456,219 lose exclusivity?

The patent was issued on November 25, 2008. Its earliest priority date is understood to be in 2004, and the public patent record identifies an expected expiration in July 2025, subject to the official patent-term calculation and any applicable patent-term adjustment or pediatric extension. The commonly reported expiration date is July 23, 2025.

Milestone	Date or period
Earliest priority	2004
US patent application period	2005 onward
Patent issued	November 25, 2008
Reported patent expiration	July 23, 2025
FDA NDA approval for Zolinza	October 6, 2006
NCE exclusivity period	Approximately five years from approval
Post-expiration generic risk	Dependent on ANDA approval and remaining enforceable claims

Patent expiration does not automatically permit immediate generic marketing. FDA approval, regulatory exclusivity, litigation stays, settlement terms, manufacturing readiness and other listed patents can affect launch timing.

What is the Orange Book status of vorinostat and Zolinza?

Zolinza is the brand product for vorinostat, marketed by Merck for oral treatment indications including cutaneous T-cell lymphoma. The FDA approved Zolinza under NDA 021991 in 2006. The FDA Orange Book is the controlling public source for listed patents, expiration dates and use codes.

US 7,456,219 has been publicly associated with the Zolinza patent estate as a polymorph or product patent. The listed patent does not appear, from the supplied claims, to be a method-of-use patent. Its relevance is the active ingredient supplied in the approved drug product.

A generic applicant submitting an ANDA must address listed patents through certification. A Paragraph IV certification alleges that a listed patent is invalid, unenforceable or not infringed. If the NDA holder files suit within 45 days, FDA approval may be stayed for up to 30 months, subject to statutory exceptions.

Which companies are challenging the vorinostat patent?

The claim text alone does not establish the identity of every ANDA filer, Paragraph IV challenger, lawsuit or settlement. Public records for a complete challenger analysis include FDA Paragraph IV notices, district court complaints, ANDA litigation dockets and Orange Book updates.

The principal commercial challenger category is generic manufacturers seeking approval for vorinostat capsules. A challenger would typically attack the patent through one or more of the following positions:

1. The proposed API is not Form I;
2. The XRPD profile does not satisfy the claimed peaks;
3. The DSC profile does not satisfy the claimed thermal limitation;
4. The product-by-process limitations are not met;
5. The claims are anticipated or obvious over prior SAHA polymorph and crystallization disclosures;
6. The claims are indefinite because of analytical tolerances or instrument-specific language; or
7. The patent is unenforceable because of inequitable conduct or other prosecution defects.

The most commercially effective design-around would be to use a non-Form I polymorph, an amorphous material, or a Form I manufacturing route that avoids applicable process limitations. That strategy carries regulatory risk because the generic product must remain pharmaceutically equivalent and meet drug-substance quality requirements.

How strong is the patent estate for US 7,456,219?

Strengths

The patent has several features that can make it commercially meaningful:

• It claims the specific crystal form likely used in the branded product.
• It uses multiple analytical identifiers rather than a single XRPD peak.
• It includes both broad and narrow peak sets.
• It adds process-specific claims covering common alcohol recrystallization solvents.
• It includes methanol-water embodiments and a defined 2:1 mixture.
• It contains dependent claims directed to synthesis, precipitation and DSC methodology.

Weaknesses

The estate also has material limitations:

• It does not claim SAHA generally.
• It does not claim a therapeutic use.
• It does not claim every crystalline or amorphous form.
• The claims are sensitive to analytical reproducibility.
• Product-by-process claims may be difficult to enforce where the accused manufacturer uses a different process.
• Many claims contain drafting errors and inconsistent wording, including duplicated solvent claims, typographical errors and apparent dependency defects.
• The patent’s reported July 2025 expiration substantially limits its remaining blocking value.

The strongest infringement theory would generally involve a generic API that matches the claimed Form I XRPD and DSC profile. The weaker theory would involve an accused product made through a different process that does not satisfy the applicable product-by-process limitation.

What formulation and manufacturing barriers remain after patent expiry?

US 7,456,219 does not protect a particular formulation. A generic applicant still must demonstrate pharmaceutical equivalence, including the correct dosage form, strength, quality attributes, dissolution performance and stability profile.

Manufacturing barriers may include:

• Control of polymorphic conversion during drying and milling;
• Consistent particle-size distribution;
• Prevention of hydrate or solvate formation;
• Reproducible XRPD and DSC specifications;
• Residual-solvent control;
• Recrystallization yield and impurity clearance;
• Compliance with current good manufacturing practices; and
• Demonstration that the commercial API remains stable through formulation and storage.

These technical constraints can delay competition even when the patent no longer blocks launch.

What generic launch scenarios exist for vorinostat?

Scenario	Description	Commercial effect
Authorized or licensed entry	Generic launch under an agreement with the brand company	Earlier entry with controlled competition
Paragraph IV litigation	Generic challenges validity or infringement	Launch depends on litigation, settlement or court outcome
Non-Form I design-around	Generic uses another polymorph or solid form	Requires robust equivalence and stability evidence
Post-expiry entry	Launch after July 2025, subject to FDA approval	Patent-based blocking risk materially decreases
At-risk launch	Generic launches before final resolution	Exposure to damages, injunction and market disruption

Because the core patent is a solid-form patent, commercial entry may occur through a design-around rather than a direct attack on the molecule. The commercial value of the patent therefore depends on how closely the branded API specification tracks Form I and whether FDA will accept an alternative solid form without requiring extensive additional development.

Key Takeaways

• US 7,456,219 is a polymorph patent covering crystalline SAHA Form I, not vorinostat generally.
• The principal limitations are copper-source XRPD peaks and a single DSC maximum near 164.4°C.
• Several claims are product-by-process claims tied to recrystallization from methanol, ethanol, isopropanol or aqueous mixtures.
• Claims 17 and 18 add a specific SAHA synthesis and precipitation sequence.
• Claims 34-43 focus on methanol-water recrystallization, including a 2:1 methanol-water embodiment.
• The patent does not claim a therapeutic indication, dosage regimen or finished capsule formulation.
• The commonly reported expiration date is July 23, 2025, subject to the official term calculation and any applicable adjustment.
• Generic risk turns on API characterization, process evidence, Orange Book certifications and any litigation or settlement terms.
• The principal design-around options are a non-Form I solid form, an amorphous form or a different manufacturing process.
• After patent expiration, manufacturing controls and FDA pharmaceutical-equivalence requirements remain important entry barriers.

FAQs About US Patent 7,456,219 and Vorinostat

Is US Patent 7,456,219 a composition-of-matter patent?

No. It claims a specific crystalline polymorph of SAHA, defined primarily by XRPD and DSC characteristics. It does not claim all chemical forms of vorinostat.

Does the patent cover Zolinza capsules?

It can be relevant to Zolinza because the product contains vorinostat API, but the claims do not recite a capsule, excipient or dosage form. Infringement depends on whether the API in the accused product satisfies the applicable Form I and process limitations.

Can a generic use a different vorinostat polymorph?

Potentially. A different polymorph may avoid claims limited to Form I, but the generic must still satisfy FDA quality, stability, equivalence and manufacturing requirements.

Does recrystallization from ethanol alone infringe?

Not necessarily. The answer depends on the specific claim asserted, the resulting crystal form and whether the claim requires a particular product-by-process pathway. Ethanol is expressly identified in several process limitations, but process and product requirements must be analyzed together.

Are the XRPD peak ranges sufficient to identify Form I?

They are central claim limitations, but an infringement analysis would also examine the complete diffraction pattern, peak tolerances, instrument calibration, DSC result, sample preparation and any prosecution-history limitations.

References

1. United States Patent and Trademark Office. (2008). U.S. Patent No. 7,456,219, Polymorphs of suberoylanilide hydroxamic acid.
2. U.S. Food and Drug Administration. (2006). Zolinza (vorinostat) prescribing information, NDA 021991.
3. U.S. Food and Drug Administration. (2025). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. United States Code. (2024). 35 U.S.C. §§ 154, 156 and 271.
5. United States Code. (2024). 21 U.S.C. § 355(j).

Drugs Protected by US Patent 7,456,219

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Msd Sub Merck	ZOLINZA	vorinostat	CAPSULE;ORAL	021991-001	Oct 6, 2006		RX	Yes	Yes	7,456,219			Y

International Family Members for US Patent 7,456,219

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	462426
Australia	2003213684
Australia	2004266169
Australia	2004283717
Australia	2008246251
Australia	2009201668