Details for Patent: 8,785,632

Summary for Patent: 8,785,632

Title:	Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
Abstract:	Enantiomerically pure compound of formula 1 are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.
Inventor(s):	Jingrong Jean Cui, Lee Andrew Funk, Lei Jia, Pei-Pei Kung, Jerry Jialun Meng, Mitchell David Nambu, Mason Alan Pairish, Hong Shen, Michelle Tran-Dube
Assignee:	Pfizer Corp SRL
Application Number:	US13/537,759
Patent Claim Types: see list of patent claims	Compound;

US Patent 8,785,632: Claim Scope, Crizotinib Coverage, Patent Expiration and Generic Risk

US Patent 8,785,632 is a Pfizer patent directed to enantiomerically pure 2-aminopyridine compounds containing a substituted pyrazole and a chiral aryl-ethoxy group. Claim 4 expressly covers crizotinib, marketed as Xalkori. The patent has broad genus claims in claims 1 and 3, but its strongest commercial relevance is the express compound coverage in claim 4.

The patent protects the active pharmaceutical ingredient and pharmaceutically acceptable salts. It does not, based on the supplied claims, independently claim a dosage form, tablet composition, crystalline polymorph, manufacturing process, method of treating a specific cancer, or a pharmaceutical combination.

What drug does US Patent 8,785,632 cover?

US 8,785,632 covers crizotinib and related chiral 2-aminopyridine compounds.

The compound expressly identified in claim 4 as:

3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine

is crizotinib, also known as PF-02341066.

Item	Detail
Active ingredient	Crizotinib
Brand	Xalkori
Original developer	Pfizer
Drug class	ALK, ROS1 and MET tyrosine kinase inhibitor
Principal approved use	ALK-positive or ROS1-positive metastatic non-small-cell lung cancer
Molecular characteristic	Chiral, R-configured aryl-ethoxy substituent
Patent relevance	Express compound claim in claim 4
FDA approval	August 26, 2011
Regulatory pathway	New drug application
Biosimilar relevance	None; crizotinib is a small molecule, not a biologic

The same patent also claims two closely related compounds in claim 4:

1. A hydroxylated acetamide derivative of the piperidine substituent.
2. The deprotected 4-piperidyl analog of crizotinib.

Those compounds are not the same as the commercial crizotinib molecule, but they are within the expressly listed species of the patent.

What does claim 1 protect?

Claim 1 is a broad genus claim covering enantiomerically pure compounds of formula 1.

Its principal structural limitations are:

• Y is CR12.
• R12 is hydrogen, making the relevant ring position CH.
• R1 is a substituted or unsubstituted 5- to 12-membered heteroaryl group.
• R2 is hydrogen.
• The molecule is enantiomerically pure.
• The compound may be isolated as a pharmaceutically acceptable salt.

The permitted R1 groups include a wide range of heteroaryl systems. Claim 2 confirms that the scope includes:

• Furan
• Thiophene
• Pyrrole
• Thiazole
• Imidazole
• Pyrazole
• Isoxazole
• Isothiazole
• Oxadiazole
• Triazole
• Thiadiazole
• Pyridine
• Pyridazine
• Pyrimidine
• Pyrazine
• Triazine

Crizotinib falls within the claim 1 genus because its core includes a pyrazole ring substituted with a 1-methylpiperidin-4-yl group.

How broad are the substituent definitions in claim 1?

The substituent definitions are extensive. R3 may include:

• Halogen
• Alkyl, alkenyl and alkynyl groups
• Cycloalkyl
• Aryl
• Heteroalicyclic groups
• Heteroaryl groups
• Nitro
• Cyano
• Amino and substituted amino groups
• Alkoxy and aryloxy groups
• Carboxamide and ester groups
• Sulfonamide and sulfonate groups
• Urea and amidine-type groups

The claim also permits adjacent R3 substituents to combine and form additional rings. This ring-fusion provision increases the number of covered molecular architectures and makes the claim relevant to analogs with annulated or conformationally restricted structures.

The claim is therefore not limited to crizotinib. It covers a large chemical genus, subject to the required formula, stereochemical, heteroaryl and substitution limitations.

What does claim 3 protect?

Claim 3 narrows the genus to a specific structural framework:

• Y is CH.
• R1 is pyrazole.
• R3 is a 3- to 12-membered heteroalicyclic group.
• The R3 group may carry the broad R8 and R11 substituent systems.
• The compound must be enantiomerically pure.

Claim 3 is commercially important because it more closely tracks crizotinib than claim 1. Crizotinib contains:

• A pyrazole ring.
• A piperidine substituent attached to the pyrazole.
• An R-configured 1-(2,6-dichloro-3-fluorophenyl)ethoxy group.
• A 2-aminopyridine core.

The 1-methylpiperidin-4-yl substituent in crizotinib is a heteroalicyclic group within the claim 3 definition.

What does claim 4 protect?

Claim 4 is the narrowest and most commercially direct claim. It is a closed Markush-style list of three expressly identified enantiomerically pure compounds and their pharmaceutically acceptable salts.

Claim 4 species	Commercial significance
Crizotinib with N-methylpiperidine	Direct active-ingredient coverage
Hydroxyacetamide piperidine analog	Listed analog, not the marketed crizotinib molecule
Deprotected piperidine analog	Listed analog, potentially relevant to intermediates or research compounds

Claim 4 does not require a separate infringement analysis based on the broader formula. A product containing crizotinib as the active ingredient would fall within the first listed species, assuming the claimed stereochemistry and salt form are present.

How does stereochemistry affect infringement?

The claims require an enantiomerically pure compound. Crizotinib is the R enantiomer of the chiral aryl-ethoxy substituent.

This limitation has several consequences:

1. A racemic mixture may not satisfy the claim if the claim is construed to require an enantiomerically pure product.
2. The S enantiomer is not literally the claimed R-configured crizotinib species.
3. A product containing an R-enriched mixture may raise a claim-construction and purity issue.
4. A salt of the claimed enantiomer remains within the express claim language.

The patent text does not state in the supplied claims a numerical enantiomeric-purity threshold. That issue would depend on the specification, prosecution history, analytical evidence and claim construction. For an ANDA product, the practical question would be whether the proposed active ingredient is the claimed R enantiomer and whether the product contains a pharmaceutically acceptable salt covered by the claim.

What patent rights does US 8,785,632 not appear to cover?

The supplied claims are compound claims. They do not expressly claim:

• A tablet or capsule formulation
• A particular excipient system
• A controlled-release formulation
• A specific crystalline form
• An amorphous form
• A hydrate or solvate
• A polymorph
• A specific particle-size distribution
• A manufacturing process
• A chemical intermediate
• A treatment method
• A dosing regimen
• A combination with another anticancer agent
• A diagnostic method
• A companion diagnostic
• A pharmaceutical composition claim

That distinction matters because a generic manufacturer could face different patent barriers for the API, a formulation, a method of use or a polymorph. Patent 8,785,632, standing alone, is principally an API patent.

When does US Patent 8,785,632 expire?

The patent issued on July 22, 2014. The relevant patent term is generally calculated from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers and any applicable patent-term extension.

Public patent-family records associate the crizotinib compound family with a December 21, 2007 international or nonprovisional filing framework. On that basis, the ordinary 20-year term would run to approximately December 21, 2027, before any adjustment.

The exact enforceable expiration date must be determined from the USPTO patent-term data for US 8,785,632, including:

• Patent-term adjustment
• Any terminal disclaimer
• The effective priority chain
• Whether a patent-term extension was granted for the approved product

The commonly cited 2029 date associated with certain crizotinib patents should not automatically be attributed to US 8,785,632. Related family patents may have different filing histories, adjustment periods or listed expiration dates.

What is the FDA and Orange Book status of crizotinib?

The FDA approved Xalkori in 2011 for ALK-positive metastatic NSCLC and later expanded the label to include ROS1-positive metastatic NSCLC and additional pediatric and adult indications. The product is listed in the Orange Book as a small-molecule prescription drug, not as a biologic subject to biosimilar approval.

Relevant regulatory characteristics include:

Regulatory issue	Crizotinib position
FDA product	Xalkori
Active ingredient	Crizotinib
NDA holder	Pfizer group
Product type	Small molecule
Orange Book listing	Applicable
Biologics Price Competition and Innovation Act	Not applicable
Biosimilar pathway	Not applicable
ANDA pathway	Applicable to qualifying generic products
Patent certification	Paragraph I, II, III or IV depending on listed patent status

The Orange Book must be reviewed separately from the patent itself. A patent can cover the active ingredient without being the only patent listed for the approved product. Conversely, patents directed to a method of use may be listed only for particular indications or may require a section viii statement rather than a Paragraph IV certification.

What other patents may affect generic crizotinib entry?

Generic-entry analysis normally considers at least five patent categories:

Patent category	Relevance to crizotinib
Core compound patents	Directly block manufacture and sale of crizotinib
Salt or solid-form patents	May affect the selected API form
Formulation patents	May affect tablets, capsules or release characteristics
Method-of-use patents	May affect labeled indications and carve-out strategy
Process patents	May create manufacturing risk but often do not independently block a non-infringing process

The supplied claims establish core compound coverage. They do not establish the complete Xalkori patent estate. A full freedom-to-operate review would need to compare the current Orange Book listing, the complete Pfizer patent family, continuation patents, reissue activity, terminal disclaimers, prosecution histories and litigation records.

What Paragraph IV risks exist for a generic manufacturer?

A generic applicant seeking approval before expiration of an Orange Book-listed crizotinib patent could file a Paragraph IV certification alleging that the patent is invalid, unenforceable or not infringed.

For this patent, likely legal attack points would include:

Written description and enablement

The broad genus in claim 1 contains numerous heteroaryl, heteroalicyclic and substituted structures. A challenger could argue that the specification does not adequately describe or enable the full breadth of the genus.

The patent holder would respond that the specification provides representative compounds, synthetic routes, biological data and common structural features sufficient to support the genus.

Indefiniteness

Potential issues could involve terms such as:

• "Enantiomerically pure"
• "Heteroalicyclic"
• "Optionally replaced"
• The nested R3, R8 and R11 substitution definitions

These terms are common in pharmaceutical patent drafting, but their enforceability depends on the specification and prosecution record.

Obviousness

A challenger could combine prior art relating to:

• 2-aminopyridine kinase inhibitors
• Pyrazole-substituted heteroaryl compounds
• Chiral aryl-ethoxy groups
• ALK, MET or ROS1 inhibitors

The patent holder would rely on the specific stereochemistry, substitution pattern, potency, selectivity, pharmacokinetics and clinical utility of crizotinib.

Noninfringement

A generic product could seek to avoid infringement by using:

• A different active stereoisomer
• A racemate, if legally and regulatorily viable
• A nonclaimed salt or solid form, although salt limitations may be broad
• A different molecular analog
• A different product not containing crizotinib

For an ANDA product that contains crizotinib itself, noninfringement arguments against claim 4 would be difficult if the product uses the claimed R enantiomer.

What litigation and settlement issues matter?

A complete litigation assessment requires matching each Orange Book-listed patent to:

• The ANDA applicant
• The Paragraph IV notice date
• The filing date of any infringement action
• The 30-month stay
• Any preliminary injunction
• Any district-court judgment
• Federal Circuit proceedings
• The commercial launch date
• Any settlement or license

The patent text alone does not establish whether US 8,785,632 has been asserted, invalidated, settled, licensed or allowed to lapse. The relevant public sources are the FDA Orange Book, USPTO Patent Center, PACER and published federal court decisions.

A settlement may permit an authorized generic, a license at a specified date, a delayed launch or a product launch that excludes patented indications. The existence of a Paragraph IV notice does not by itself establish generic market entry.

How strong is the patent estate for crizotinib?

US 8,785,632 is strongest against a generic that uses crizotinib itself because claim 4 names the active compound directly. Its commercial strength is lower against:

• New ALK inhibitors
• Non-crizotinib ROS1 inhibitors
• Alternative MET inhibitors
• Different salts or solid forms, depending on claim language
• Reformulated products outside the claimed subject matter
• New chemical entities designed around the disclosed genus

The broad genus claims increase potential coverage but also create greater validity exposure. Claim 4 has narrower scope and generally presents a clearer infringement theory.

How does crizotinib compare with competing targeted therapies?

Drug	Principal target	Product type	Biosimilar risk	Competitive patent issue
Crizotinib	ALK, ROS1, MET	Small molecule	None	Core compound and formulation patents
Alectinib	ALK	Small molecule	None	Separate compound and formulation estate
Brigatinib	ALK	Small molecule	None	Separate compound and method-of-use estate
Lorlatinib	ALK, ROS1	Small molecule	None	Macrocyclic compound and formulation estate
Ceritinib	ALK	Small molecule	None	Separate compound estate
Entrectinib	TRK, ROS1, ALK	Small molecule	None	Separate compound and use patents

Crizotinib’s patent risk is therefore a generic small-molecule issue, not a biosimilar issue. Competitive erosion can also occur without direct infringement of the crizotinib patent when physicians shift to newer ALK or ROS1 inhibitors.

What revenue exposure is linked to this patent?

The patent’s economic value is tied primarily to sales of Xalkori and any licensed or authorized generic products. Revenue exposure depends on:

• The share of sales attributable to crizotinib rather than competing therapies
• The remaining enforceable term of the relevant patent family
• The number of Orange Book-listed patents
• The timing of ANDA approvals
• Any Paragraph IV settlement
• The availability of alternative indications
• International patent protection
• Pricing after generic entry

A compound patent covering the active ingredient generally has greater revenue importance than a narrow formulation patent, but its commercial effect ends when the compound claim expires or is successfully invalidated.

Geographic coverage and international patent risk

US 8,785,632 provides rights only in the United States. International protection must be assessed country by country.

Key jurisdictions for a crizotinib freedom-to-operate review include:

• European Patent Office member states
• Japan
• China
• Canada
• South Korea
• Australia
• Brazil
• India

Foreign family members may differ in:

• Claim scope
• Grant status
• Patent-term adjustment
• Supplementary protection certificate eligibility
• Opposition history
• Litigation outcome
• Regulatory linkage

The US patent does not create automatic protection in any foreign jurisdiction.

Key Takeaways

• US 8,785,632 is a Pfizer compound patent covering enantiomerically pure substituted 2-aminopyridines.
• Claim 4 expressly covers crizotinib, the active ingredient in Xalkori.
• Claim 1 is a broad heteroaryl genus claim with extensive substituent definitions.
• Claim 3 narrows the scope to pyrazole-containing compounds with heteroalicyclic substituents.
• The patent claims compounds and salts, not an identified formulation, manufacturing process or treatment method.
• Crizotinib is a small molecule, so biosimilar law does not apply.
• The ordinary patent-term baseline is approximately December 2027, subject to USPTO patent-term adjustment and any other term modifications.
• A generic containing the R enantiomer of crizotinib would face the clearest infringement risk under claim 4.
• The complete generic-entry analysis requires review of all Orange Book-listed patents and related continuation, formulation, method-of-use and litigation records.
• The commercial strength of the patent is highest against direct crizotinib copies and lower against next-generation ALK or ROS1 inhibitors.

Frequently Asked Questions

Is crizotinib explicitly claimed in US Patent 8,785,632?

Yes. Claim 4 expressly lists the crizotinib molecule by chemical name, together with two related compounds and pharmaceutically acceptable salts.

Does US 8,785,632 cover Xalkori tablets?

It covers the crizotinib active ingredient in the tablets. The supplied claims do not independently claim the Xalkori tablet formulation or its excipients.

Can a generic company avoid this patent by using a different crizotinib salt?

Not necessarily. Claim 4 expressly includes pharmaceutically acceptable salts. The specific salt, claim construction and any separate solid-form patents would determine the infringement analysis.

Does a Paragraph IV challenge automatically allow generic crizotinib launch?

No. A Paragraph IV certification can trigger patent litigation and an FDA approval stay. Launch depends on the patent claims, litigation outcome, settlement terms and other listed patents.

Does this patent block competing ALK inhibitors such as alectinib or lorlatinib?

Generally, no. The patent is directed to specified 2-aminopyridine compounds and expressly listed species. Alectinib and lorlatinib have different chemical structures and separate patent estates.

References

1. Food and Drug Administration. (2011). Xalkori (crizotinib) prescribing information. U.S. Department of Health and Human Services.

2. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.

3. Pfizer Inc. (2014). US Patent No. 8,785,632: Enantiomerically pure compounds. United States Patent and Trademark Office.

4. United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term information. U.S. Department of Commerce.

5. United States Patent and Trademark Office. (n.d.). Manual of Patent Examining Procedure. U.S. Department of Commerce.

Drugs Protected by US Patent 8,785,632

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 8,785,632

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1786785		PA2013005	Lithuania
European Patent Office	1786785		CA 2013 00009	Denmark
European Patent Office	1786785		92155	Luxembourg
European Patent Office	1786785		C300587	Netherlands
European Patent Office	1786785		C20130007 00075	Estonia