US Patent 8,247,416: Olaparib Crystal Form, Synthesis Claims, Expiration, and Patent Landscape

US Patent 8,247,416 protects a defined crystalline form of olaparib and a chemical process for producing olaparib from a specified phthalazinone carboxylic acid intermediate. The patent is narrower than the basic olaparib compound patent but remains commercially relevant because it targets a solid-state form used in pharmaceutical manufacture and a commercially practical coupling route.

The patent has two distinct claim groups:

Claims 1-3 protect a crystalline form identified by powder X-ray diffraction and differential scanning calorimetry.
Claim 4 protects a process using 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid, 1-(cyclopropylcarbonyl)piperazine, an amide coupling agent, and a base.

The active pharmaceutical ingredient is olaparib, marketed by AstraZeneca as Lynparza.

What drug and crystalline form does US Patent 8,247,416 protect?

US 8,247,416 protects a crystalline form of olaparib, chemically identified as:

4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one.

Olaparib is a poly(ADP-ribose) polymerase, or PARP, inhibitor. It is approved for several BRCA-mutated and homologous-recombination-deficient cancer indications, including ovarian, breast, pancreatic, and prostate cancers, subject to the indication-specific FDA labeling in force at the relevant time (FDA, 2023).

The patent does not claim every physical form of olaparib. It claims a particular crystalline form defined by analytical characteristics.

Claim structure

Claim	Subject matter	Scope
1	Olaparib crystalline form	Requires PXRD peaks at approximately 12.0°, 17.8°, 21.1°, 22.3°, and 29.2° 2θ
2	Dependent crystalline form	Adds peaks at approximately 10.5°, 14.0°, 21.7°, 24.3°, and 26.1° 2θ
3	Dependent crystalline form	Adds a DSC onset melting point of approximately 210.1°C ±1°C
4	Olaparib synthesis process	Requires specified acid and piperazine reactants, an amide coupling agent, and a base

Claim 1 is the principal solid-form claim. Claim 2 narrows the form through additional diffraction peaks. Claim 3 narrows it further through thermal behavior. Claim 4 is independent of the crystalline-form claims and can be infringed even when the resulting olaparib is not isolated in the claimed crystalline form.

What do the PXRD claims require?

Claims 1 and 2 define the product primarily through powder X-ray diffraction, or PXRD. The claimed peaks are measured using Cu K-alpha radiation with a wavelength of 1.5418 Å and a tolerance of ±0.1° 2θ.

The required peaks are:

Claim 1 peaks	Claim 2 additional peaks
12.0°	10.5°
17.8°	14.0°
21.1°	21.7°
22.3°	24.3°
29.2°	26.1°

A practical infringement analysis would compare the accused material's PXRD pattern against the claimed peaks under the specified measurement conditions. The analysis would not ordinarily depend on the product label alone. It would require laboratory testing of the drug substance or relevant intermediate.

The claim language presents several technical issues:

Whether all listed peaks must be present.
Whether peak intensity is relevant when the claim specifies only positions.
How to treat preferred orientation, instrument variation, impurities, or polymorphic mixtures.
Whether peaks within the stated ±0.1° range satisfy the limitation.
Whether a material containing the claimed form together with another polymorph falls within the claim.

Because claim 1 recites a crystalline form having the listed characteristic peaks, a mixed solid could create infringement risk if the claimed form is present in a legally sufficient amount. The patent text and prosecution history would be relevant to determine whether the claims require a substantially pure form or permit mixtures.

What does the DSC limitation in claim 3 add?

Claim 3 requires the form of claim 1 to begin melting at approximately 210.1°C ±1°C when heated from 25°C to 325°C at 10°C per minute.

This limitation adds a thermal signature to the PXRD-defined form. It does not replace the PXRD requirements of claim 1. A product must first satisfy claim 1 and then meet the DSC limitation in claim 3.

DSC results can vary with:

Heating rate.
Sample mass.
Instrument calibration.
Pan type.
Sample purity.
Water or solvent content.
Polymorphic conversion during heating.

The specified heating rate and temperature range reduce, but do not eliminate, analytical variability. For litigation or freedom-to-operate work, the test protocol should reproduce the patent's stated conditions as closely as possible.

What synthesis route does claim 4 protect?

Claim 4 covers a process for synthesizing olaparib from:

2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)benzoic acid

The process reacts that acid with:

1-(cyclopropylcarbonyl)piperazine, or a mineral acid salt of that compound,

in the presence of:

An amide coupling agent; and
A base.

The reaction forms the amide bond connecting the substituted benzoic acid to the cyclopropanecarbonyl piperazine group.

Key process limitations

Limitation	Required feature
Starting acid	Specific fluorinated phthalazinone benzoic acid
Amine component	1-(cyclopropylcarbonyl)piperazine or mineral acid salt
Reaction type	Amide coupling
Reagent class	Amide coupling agent
Reaction condition	Base present
Product	Olaparib

The claim is broad as to the identity of the coupling agent and base, provided they perform the claimed functions. A process using a different coupling reagent may still fall within the claim if that reagent is an amide coupling agent under the claim construction.

A process that begins from a different olaparib intermediate, uses a different order of assembly, or forms the key amide bond through a materially different reaction may avoid literal infringement. The doctrine of equivalents could still be relevant, particularly where the alternative route performs substantially the same function in substantially the same way.

How does US 8,247,416 compare with the basic olaparib patent?

The compound patent and the crystalline-form patent address different legal subject matter.

Issue	Basic olaparib patent	US 8,247,416
Primary protection	Olaparib compound and therapeutic uses	Specific crystalline form and synthesis process
Product scope	Broad chemical compound scope	Narrow solid-state form scope
Process coverage	May include preparation routes depending on claims	Specific coupling route from the named acid
Main risk	Making, using, selling olaparib	Manufacturing or supplying the claimed form or using the claimed route
Design-around	Difficult for the active compound itself	Potentially possible through another polymorph or process
Regulatory relevance	Core drug patent	Listed product, formulation, or process patent relevance depends on FDA Orange Book listing

A generic applicant may avoid a crystalline-form claim by producing a different polymorph, amorphous olaparib, or a form that does not show the claimed diffraction pattern. That strategy does not avoid a separate patent claiming olaparib as a compound or a method of treating cancer with olaparib.

When does US Patent 8,247,416 lose exclusivity?

The patent was issued on August 21, 2012. Its effective expiration depends on the earliest effective US nonprovisional or PCT filing date, patent-term adjustment, terminal disclaimers, and any applicable patent-term extension.

Public patent records associate the patent family with a 2009 international filing and an April 2008 priority date. A simple 20-year calculation from the relevant US/PCT filing places ordinary expiration around April 2029, subject to the official USPTO term calculation (USPTO, 2024).

Milestone	Date
Earliest reported priority	April 2008
International-family filing period	2009
US grant	August 21, 2012
Estimated ordinary term end	Approximately April 2029
Possible adjustment	PTA, terminal disclaimer, or other USPTO term event

The grant date does not determine expiration. Patent term generally runs from the applicable filing date, not from issuance.

FDA regulatory exclusivity is separate from patent term. Lynparza received FDA approval in December 2014, and its later tablet approval expanded the commercial product presentation. FDA exclusivity periods do not automatically extend US Patent 8,247,416.

What is the Orange Book status of US 8,247,416?

US 8,247,416 has been associated with the Lynparza patent estate and has been treated as relevant to FDA-listed olaparib products in public patent and regulatory records. The precise Orange Book listing, dosage-form association, use code, and current delisting status must be determined from the FDA's current Orange Book entry for the applicable NDA (FDA, 2024).

Orange Book relevance depends on whether the patent claims:

The approved drug substance.
The approved dosage form.
A method of using the approved product.
A formulation or delivery system.
A manufacturing feature that FDA treats as listable.

A crystalline-form patent is more likely to create product-level exposure when the approved drug substance uses that form. A process claim may have greater importance in commercial manufacturing and less direct relevance to an ANDA unless FDA listing and certification requirements apply.

What Paragraph IV challenges and generic-entry risks exist?

A generic applicant seeking approval before patent expiry may file a Paragraph IV certification asserting that a listed patent is invalid, unenforceable, or not infringed. For US 8,247,416, the main possible challenge theories would include:

Invalidity theories

Anticipation by an earlier disclosure of the same crystalline form.
Obviousness based on known olaparib forms, crystallization methods, or routine solid-state screening.
Lack of written description for the full claimed PXRD-defined form.
Lack of enablement for producing the claimed form across the scope of the claims.
Indefiniteness concerning peak identity, peak tolerance, or DSC measurement.

Non-infringement theories

The proposed product is a different polymorph.
The PXRD pattern lacks one or more required peaks.
The peak positions fall outside the ±0.1° range.
The product does not meet the claim 3 melting limitation.
The manufacturing process does not use the specified acid and piperazine combination.
The process uses a different amide-bond-forming strategy.

The principal generic-entry scenario would involve a product that avoids the claimed crystal form and uses a noninfringing synthesis route while separately addressing any broader olaparib compound, formulation, and method-of-use patents.

How strong is the patent estate for olaparib?

The olaparib estate is stronger when assessed as a layered portfolio rather than through US 8,247,416 alone.

Layer	Commercial function	Risk profile
Compound claims	Protect olaparib itself	Highest barrier if unexpired and valid
Crystal-form claims	Protect selected solid form	Strong where the marketed API uses the form; design-around possible
Formulation claims	Protect tablets, excipients, release characteristics, or dosage forms	Product-specific
Method-of-use claims	Protect cancer indications and biomarker-defined populations	Relevant to labeling and induced infringement
Process claims	Protect selected commercial synthesis routes	Manufacturing-specific
Regulatory exclusivity	Delays or limits approval independent of patent validity	Time-limited

US 8,247,416 is technically meaningful because it combines a solid-form claim with a process claim. Its vulnerability is also structural: the form can potentially be avoided through polymorph selection, while the process can potentially be avoided through route redesign.

What formulations and dosage forms are relevant to Lynparza?

Lynparza was initially approved as capsules and later as tablets. The tablet product uses a different strength and dosing regimen from the earlier capsule presentation. Formulation and dosage-form patents must be analyzed separately from US 8,247,416 because the patent claims provided here do not recite excipients, tablet composition, dissolution, particle size, or dosage strength.

The supplied claims therefore do not directly protect:

A tablet formulation.
A capsule formulation.
A specific excipient combination.
A particular particle-size distribution.
A controlled-release profile.
A specific oral dose.
A combination therapy regimen.

Those protections, if applicable, would arise from separate patents or regulatory exclusivity records.

What manufacturing and geographic barriers remain?

US 8,247,416 has territorial effect in the United States. It does not directly block manufacture, sale, or importation in Europe, Japan, China, or other jurisdictions. The corresponding international and national patent-family members must be reviewed separately.

Geographic analysis should cover:

US composition, form, process, and use patents.
European Patent Office validation states.
UK post-Brexit status.
Japan and China national-phase rights.
Indian process and polymorph rights.
Manufacturing locations and importation routes.
Patent-term differences caused by national prosecution.
Supplementary protection certificates or other country-specific extensions.

Process claim 4 can create US importation exposure if an accused product is made abroad using the claimed process and imported into the United States, subject to the applicable statutory and evidentiary requirements.

What litigation and settlement issues affect olaparib?

Patent litigation involving olaparib can involve multiple patent families at once. A settlement addressing a compound patent does not necessarily eliminate exposure under a crystalline-form, formulation, method-of-use, or process patent unless the agreement expressly covers those rights.

Key diligence points include:

Whether an ANDA filer made a Paragraph IV certification.
Whether AstraZeneca filed an infringement action within the statutory period.
Whether the litigation was dismissed after settlement.
Whether the settlement contains an agreed generic-entry date.
Whether the agreement includes a license, covenant not to sue, or supply arrangement.
Whether the settlement covers all listed patents or only selected patents.
Whether the settlement was reviewed under the Federal Trade Commission's pharmaceutical-agreement reporting framework.

The existence of a settlement does not itself establish validity or infringement. The operative agreement and court docket control commercial timing.

Key Takeaways

US 8,247,416 protects a specific crystalline form of olaparib through PXRD and, in claim 3, DSC characteristics.
Claim 4 separately protects a process using a named olaparib acid intermediate, cyclopropylcarbonyl piperazine, an amide coupling agent, and a base.
The patent does not claim every olaparib polymorph, formulation, therapeutic use, or manufacturing route.
A different polymorph or an alternative synthetic route may provide a design-around, subject to claim construction and equivalents analysis.
The estimated ordinary patent-term endpoint is around April 2029, subject to the official USPTO patent-term calculation.
Generic entry requires analysis of the entire olaparib portfolio, not this patent alone.
Orange Book status, Paragraph IV activity, litigation, and settlement terms must be assessed by NDA, dosage form, use code, and current FDA listing.
The patent is commercially strongest when the marketed API uses the claimed crystalline form and the manufacturer uses the claimed coupling route.

FAQs

Is US 8,247,416 a patent on olaparib itself?

No. The claims provided focus on a particular crystalline form of olaparib and a specified manufacturing process. A separate compound patent may provide broader protection for olaparib itself.

Can a generic manufacturer avoid the patent by using amorphous olaparib?

Potentially. Amorphous olaparib would generally not satisfy a crystalline-form claim unless it contains the claimed crystalline form in a legally relevant amount. The generic must still address any broader compound, formulation, and method-of-use patents.

Does claim 4 cover every process for making olaparib?

No. Claim 4 requires the specified acid, the specified cyclopropylcarbonyl piperazine reactant or salt, an amide coupling agent, and a base. A route that omits or materially changes those elements may avoid literal infringement.

Does FDA approval prove that the crystalline form is covered by the patent?

No. FDA approval and patent coverage are separate issues. The FDA assesses safety, efficacy, quality, and regulatory requirements. Patent scope depends on claim construction and the product or process evidence.

Can a patent settlement create an earlier olaparib generic launch?

Yes. A settlement may grant a license or establish an agreed entry date before patent expiration. The commercial effect depends on the agreement's scope, the patents covered, and any regulatory restrictions.

References

AstraZeneca AB. (2012). Crystalline form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one, U.S. Patent No. 8,247,416.
U.S. Food and Drug Administration. (2023). Lynparza (olaparib) prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
United States Patent and Trademark Office. (2024). Patent term adjustment and patent term calculation resources. USPTO.
World Intellectual Property Organization. (2009). Patent family records for olaparib crystalline-form and process applications. PATENTSCOPE.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Astrazeneca	LYNPARZA	olaparib	CAPSULE;ORAL	206162-001	Dec 19, 2014		DISCN	Yes	No	8,247,416	⤷ Start Trial		Y			⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	063320	⤷ Start Trial
Austria	E528296	⤷ Start Trial
Australia	2007311766	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,247,416

Which drugs does patent 8,247,416 protect, and when does it expire?

Summary for Patent: 8,247,416