Details for Patent: 8,450,372

Which drugs does patent 8,450,372 protect, and when does it expire?

Patent 8,450,372 protects ZOLINZA and is included in one NDA.

This patent has forty-one patent family members in twenty-three countries.

Summary for Patent: 8,450,372

Title:	Formulations of suberoylanilide hydroxamic acid and methods for producing same
Abstract:	The present invention provides a pharmaceutical composition or crystalline composition with a specific dissolution profile, which comprises suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient. The present invention provides a process of producing said crystalline composition or pharmaceutical composition. The present invention also provides compositions with a specific particle size distribution.
Inventor(s):	Jeannie Chow Wong, Aaron S. Cote, Erik A. Dienemann, Kimberly Gallagher, Craig Ikeda, Justin Moser, Pavol Rajniak, Robert A. Reed, Cindy Starbuck, Hsien-Hsin Tung, Qingxi Wang, Benjamin Max Cohen, Vincent R. Capodanno, Brian Sell, Thomas A. Miller
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US12/686,843
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

United States Patent 8,450,372 Scope and Claims: How Broad Is the Dissolution-Profile Method of Treating Cancer With Suberoylanilide Hydroxamic Acid (SAHA)?

Executive summary. US 8,450,372 is a US method-of-treatment patent anchored to oral administration of solid-form suberoylanilide hydroxamic acid (SAHA) (or salts/hydrates) with tightly defined in vitro dissolution targets measured under a specific USP Apparatus II helical sinker protocol (900 mL, 2.0% Tween, 37±0.5°C, 100 rpm), plus optional but claim-amplifying controls on particle size distributions, X-ray diffraction (XRD) identity, crystalline form unit-cell parameters, unit dose formats (50 mg/100 mg/200 mg), and a specific blending/encapsulation manufacturing route. The claim set is structured for layered infringement: a generic or biosimilar-style “noninfringement” posture would need to miss at least one essential constraint in the dissolution profile, measurement method, particle distribution, crystalline identity, or formulation manufacturing definition.

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What does US Patent 8,450,372 claim and what does infringement require?

Core answer (claims 1 and 2). To infringe independent claims 1 or 2, the accused product must be used in the claimed way: a method of treating cancer where a patient is given an oral pharmaceutical composition that contains SAHA (suberoylanilide hydroxamic acid) (or a salt/hydrate) in solid form, with SAHA having an in vitro dissolution profile that falls within the claim’s numerical window, measured using a precise USP dissolution protocol.

Key claim architecture

• Treatment hook. “Method of treating cancer in a patient”
• Administration mode. Oral administration
• Active ingredient identity. SAHA (or salt/hydrate)
• Physical form. Solid form
• Dissolution profile constraint. Measured on “about 100 mg of active ingredient” (claim 1) or with timepoint ranges (claim 2)
• Measurement system constraint. USP Apparatus II with helical sinker; 900 mL; 2.0% Tween; 37±0.5°C; 100 rpm
• Dissolution target.
  • Claim 1: similarity factor f2 ≥ 56 to 100 vs a reference dissolution profile with timepoint % dissolved values
  • Claim 2: timepoint % dissolved in defined ranges at 10/15/20/30/45/60 minutes

What the “dissolution profile” language likely does legally

Because the claims constrain both numerical dissolution behavior and the method of measurement, infringement is comparatively formulation-specific. Even if an accused composition contains SAHA, it still must reproduce the claimed dissolution behavior under the stated test conditions. This creates a practical barrier for challengers because dissolution testing is sensitive to particle size, grade, excipients, manufacturing, and hydrodynamic setup.

Inline claim translation into infringement elements (US 8,450,372 independent claims):

1. Cancer in patient (including non-Hodgkin’s lymphoma in dependent claims)
2. Oral administration of a solid SAHA composition
3. SAHA in an amount consistent with the dissolution test basis (about 100 mg in claim 1; ranges defined in claim 2)
4. In vitro dissolution profile under the claimed USP II helical sinker protocol
5. Dissolution window satisfied:
   • claim 1 via f2 similarity to a specified reference profile; and/or
   • claim 2 via specific % dissolved timepoint bands

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How do claims 1 and 2 differ: f2 similarity factor vs point-by-point dissolution ranges?

Executive distinction.

• Claim 1 protects a dissolution profile that is “similar” to a reference profile, using f2.
• Claim 2 protects compositions that meet explicit % dissolved bands at each timepoint.

Claim 1: f2 similarity factor mechanics (f2 ≥ 56)

• Reference profile:
  • 52.7% at 10 min
  • 61.7% at 15 min
  • 67.7% at 20 min
  • 75.5% at 30 min
  • 82.6% at 45 min
  • 87.0% at 60 min
• Constraint:
  • f2 ≥ 56 (with dependent claim tiers: f2 60–100; 65–100; 70–100)

Practical scope effect. f2 introduces flexibility compared with strict point-by-point limits, so long as the overall similarity is maintained across timepoints.

Claim 2: point-by-point bands

At each timepoint, the accused dissolution result must be within:

• 10 min: 46–60%
• 15 min: 55–69%
• 20 min: 61–75%
• 30 min: 69–83%
• 45 min: 76–90%
• 60 min: 80–94%

Practical scope effect. This is narrower than f2 if the accused curve deviates at one timepoint, even if overall shape remains similar. It also reduces interpretive ambiguity: an accused dissolution curve either lands in the bands or it does not.

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What USP dissolution testing conditions does the patent lock in, and why does that matter?

Measurement specification is claim-bounding. Independent claims require:

• USP Dissolution Apparatus II
• Helical sinker
• 900 mL dissolution medium
• 2.0% Tween
• 37 ± 0.5°C
• 100 rpm
• Timepoints at 10, 15, 20, 30, 45, 60 minutes

Infringement leverage for plaintiff, risk for generic formulators

• If an accused formulation uses SAHA with different excipients, particle size control, or manufacturing history, the dissolution curve can drift out of either:
  • f2 window (claim 1), or
  • the banded timepoint windows (claim 2).
• If a generic company attempts to test under alternative conditions, the claim still pins the conditions. The litigation fight becomes test replication and curve compliance.

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What formulations are covered: solid oral SAHA, unit doses, and powder blends?

Solid-form oral compositions

The independent claims cover SAHA (salt/hydrate acceptable) “as an active ingredient in solid form” administered orally.

Unit dose formats

Dependent claims specify:

• Single capsule/tablet: about 100 mg SAHA (claim 5)
• Two capsules/tabs: about 50 mg each (claim 5)
• Single capsule/tablet: about 200 mg (claim 6)

Powder blend language

Dependent claims cover “powder blend” formulations “of the active ingredient with or without the excipient in capsule form” (claims 10–16). This is important because it ties the protected embodiments to a manufacturing or compositional presentation, not just any oral dosage form.

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Does the patent cover specific particle size distributions for SAHA?

Yes. Dependent claims add particle-size fraction requirements, creating additional “design-around” hurdles.

Particle size fraction claims (claims 3 and 4)

• For particle sizes 120 to 250 microns: 4.0% to 12% (volume %)
• For particle sizes 35 to 40 microns: 3.0% to 7% (volume %)

Broader cumulative particle-size split (claims 38–45)

• Particle size < about 105 microns: 45–85% (volume %)
• Particle size > about 105 microns: 55–15% (volume %)

These claims appear to be intended to capture multiple ways of measuring the distribution: both selected fractions and a cumulative cut-point at 105 µm.

Scope impact. A generic SAHA formulation can contain the same API but still avoid infringement by shifting the distribution so that it no longer meets the specified fractions or cumulative percentages, assuming other elements are also avoided.

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Is the protected SAHA identity limited to a crystalline form with specific XRD peaks and unit-cell parameters?

Yes. A large block of dependent claims tightly define crystalline SAHA identity.

XRD peak-dependent claims (claims 17–30)

• “Crystalline suberoylanilide hydroxamic acid”
• XRD characteristic peaks at 9.4, 17.5, 19.4, 20.0, 24.0, 28.0 degrees 2θ using Copper X-ray source

These dependent claims are layered: they do not necessarily replace dissolution criteria, they further constrain the active ingredient specification.

Unit-cell/space group-dependent claims (claims 36–37)

• Unit cell parameters:
  • a = 10.9 Å
  • b = 7.9 Å
  • c = 16.4 Å
  • α = 90°, β = 97.8°, γ = 90°
• Space group: P21/n

Scope impact. If an accused composition uses a different crystalline form, polymorph, or a non-matching crystalline material, the dependent crystalline identity claims may be easier to avoid, though independent claims 1–2 do not explicitly require polymorph identity. Practically, plaintiffs typically assert both dissolution and identity-dependent claims to reduce “curve-only” defenses.

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Does the patent specify SAHA manufacturing: blending fractions and encapsulation steps?

Yes. Dependent claims define a specific route that can be important in method-of-use/follow-on manufacturing evidence and for inducement or contributory liability theories.

Blending + encapsulating (claims 31–35)

Claim 31:

• Blend about 60–5% of first batch:
  • mean particle size < 60 µm
• plus 40–95% of second batch:
  • mean particle size 100–250 µm
• then encapsulate to produce the pharmaceutical composition

Claim 32:

• Blend 40–20% of first batch:
  • mean particle size 25–45 µm
• plus 60–80% second batch:
  • mean particle size 130–180 µm
• encapsulate

Claim 33 and claim 35 provide a sub-range:

• Claim 33: 30% first batch (25–45 µm) + 70% second batch (130–180 µm)
• Claim 35 mirrors the same blending in context of the dependent claim chain.

Scope impact

Manufacturing-process claims can be used to support infringement narratives tied to specific supplier or process evidence. If a generic uses an alternative blending scheme that yields the correct dissolution curve, it can still potentially infringe dissolution-based independent claims; but it may avoid the process-dependent dependent claims.

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Which cancers does the patent cover: is it limited to non-Hodgkin’s lymphoma?

Dependent claims specify non-Hodgkin’s lymphoma. Claims 46–61 state “the cancer is non-Hodgkins Lymphoma” tied to various claim dependencies.

Scope effect.

• Independent claims cover “cancer” broadly.
• Dependent claims narrow to non-Hodgkin’s lymphoma for stronger specificity.

From a litigation standpoint, the non-Hodgkin’s lymphoma dependent claims can matter for aligning the claimed use with labeling, physician practice, and the accused product’s prescribed indications.

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How strong is the patent estate likely to be around US 8,450,372’s dissolution-and-crystal claims?

Based only on the claim language supplied, US 8,450,372 has a “multi-layered” structure that can support a robust infringement case for plaintiffs:

• Dissolution conditions are exact and testable.
• Dissolution performance is numerically bounded.
• Multiple dependent layers can restrict accused products:
  • unit dose,
  • specific powder blend formats,
  • particle size distribution fractions,
  • XRD peak identity,
  • unit cell parameters,
  • and blending/encapsulation process.

Design-around avenues implied by the claim set:

• Move dissolution profile outside f2 and/or timepoint bands.
• Maintain dissolution similarity but shift particle size distribution outside specified fractions.
• Use a crystalline form not matching the claimed XRD peaks or unit-cell/space group.
• Use alternative manufacturing/blending without the claimed percentages and mean particle sizes.

The real-world strength of the patent estate depends on other related US patents covering the same SAHA product, including API polymorphs, manufacturing methods, compositions, and clinical use. That additional landscape is not provided here.

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Patent landscape map: what adjacent IP would typically intersect with these claim elements?

Even without asserting other specific patent numbers (not provided), US 8,450,372’s claim elements point to the following intersection zones where competing patents commonly exist:

1) SAHA polymorph and crystalline form IP

• XRD peak sets
• unit cell parameters / space group
• polymorph interconversion
• solid-state stability data

2) SAHA particle engineering and dissolution-control formulations

• particle size milling and classification
• particle size fraction blending targets
• excipient selection for Tween-like surfactant behavior
• manufacturing that produces “helical sinker compatible” dissolution profiles

3) Method-of-use and oral dosing instructions

• cancer indications, including non-Hodgkin’s lymphoma
• oral administration claims
• unit dose mg strengths and regimen-dependent constraints

4) Manufacturing process claims for composition preparation

• blending ratios and mean size windows
• encapsulation or tableting constraints
• process reproducibility tied to dissolution behavior

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When does US 8,450,372 lose exclusivity? (expiration and regulatory exclusivity timelines)

No filing date, publication date, patent term adjustments, or FDA exclusivity/patent listing details are included in the input. Without those data, expiration and Orange Book-driven exclusivity timing cannot be computed from the claim text.

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What generic entry risks exist for SAHA products around this patent?

Primary risk driver is dissolution compliance. A generic manufacturer must ensure that its SAHA oral solid does not meet the dissolution profile constraints under the pinned USP II helical sinker method in claim 1 or claim 2.

Secondary risk drivers

Even if dissolution is modified:

• Particle size distribution claims (120–250 µm and 35–40 µm fractions; <105 µm vs >105 µm split) can still create exposure if the accused product is tested and shown to match.
• If crystalline identity is pursued or inherited from supplier material, XRD and unit cell-dependent claims can still be asserted.

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What would a claim chart look like for US 8,450,372 (infringement checklist)?

Claim 1 checklist (conceptual)

1. Cancer treatment in a patient
2. Oral administration
3. Solid-form SAHA (or salt/hydrate)
4. Composition provides dissolution profile meeting:
   • f2 ≥ 56 vs reference profile at 10–60 min timepoints
5. Dissolution measured with:
   • USP II helical sinker, 900 mL, 2.0% Tween, 37±0.5°C, 100 rpm
6. About 100 mg active ingredient basis

Claim 2 checklist (conceptual)

Same items 1–3 and 5–6, plus:

• Dissolution must fall in the point-by-point bands:
  • 46–60% (10 min), 55–69% (15 min), 61–75% (20 min), 69–83% (30 min), 76–90% (45 min), 80–94% (60 min)

Dependent-claim overlays

• Claim 3/4: particle fraction targets
• Claims 5–6: dose strength and unit structure
• Claims 10–16: powder blend in capsules
• Claims 17–30: crystalline SAHA with specified XRD peaks
• Claims 31–35: blending + encapsulating process routes
• Claims 36–37: unit cell parameters and space group
• Claims 46–61: non-Hodgkin’s lymphoma specific use

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Key Takeaways

• US 8,450,372 is a dissolution-performance-driven method-of-treatment patent for oral solid SAHA with strict USP Apparatus II helical sinker conditions and numerical dissolution constraints (f2 similarity in claim 1; point-by-point bands in claim 2).
• The claim set adds multiple dependent layers that can tighten infringement to specific particle size distributions, crystalline SAHA identity (XRD peaks; unit cell parameters; space group), dose formats, and blending/encapsulation manufacturing.
• The principal design-around path is to shift dissolution behavior so results fall outside the protected f2 and/or timepoint % dissolved windows under the pinned test protocol.
• Secondary design-around paths include shifting particle size fractions and/or using non-matching crystalline forms and different manufacturing/blending routes.

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FAQs

1) Can a product that contains SAHA avoid US 8,450,372 by changing only the excipient?
Yes, if excipient changes shift the USP II helical sinker dissolution curve so it no longer meets the claim 1 f2 or claim 2 timepoint bands under the specified test conditions.

2) Does the patent require a specific dissolution medium composition beyond “2.0% Tween”?
The claim specifies 900 mL of 2.0% Tween and the full USP II helical sinker protocol parameters; those conditions are part of what must be met for the dissolution-profile limitation.

3) Are the particle size claims separate from the dissolution claims?
They appear as dependent add-ons. Avoiding the dissolution window may avoid independent claim infringement, but if an accused product meets dissolution, particle size-dependent limitations can still support additional infringement theories.

4) If an accused product matches the dissolution profile but uses a different SAHA polymorph, does it still infringe?
Independent claims 1–2 do not explicitly require the crystalline identity definitions found in dependent claims; however, plaintiffs can still assert dependent crystalline identity claims if the active material is within the specified XRD/unit-cell definitions.

5) Does “non-Hodgkin’s lymphoma” narrow the independent claims?
No. It is provided in dependent claims (46–61), narrowing those dependent embodiments while independent claims cover “cancer” more broadly.

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References (APA)

1. Claim text provided in the prompt for US Patent 8,450,372 (United States).

Drugs Protected by US Patent 8,450,372

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						TREATMENT OF CUTANEOUS MANIFESTATIONS IN PATIENTS WITH CUTANEOUS T-CELL LYMPHOMA (CTCL)

International Family Members for US Patent 8,450,372

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	055953
Argentina	095159
Australia	2006249440
Australia	2009201650
Australia	2009201652