US Patent 10,723,730: Palbociclib Crystalline Free-Base Claims and Patent Landscape
US Patent 10,723,730 protects specific crystalline and particle-size-defined forms of palbociclib free base, not palbociclib as a chemical entity generally. The independent claim architecture requires both the identified palbociclib free base and a defined solid-state or particle-size characteristic. Claims 1-12 protect crystalline material identified by powder X-ray diffraction (PXRD), solid-state carbon-13 nuclear magnetic resonance (13C ssNMR), and particle-size parameters. Claims 13-14 and 21 extend protection to pharmaceutical compositions containing the claimed material.
The patent is commercially relevant to generic manufacturers because a palbociclib product can infringe even where the active pharmaceutical ingredient (API) is chemically identical to palbociclib described in earlier patents, if the manufactured API falls within the claimed crystal and particle-size ranges.
What drug and molecular form does US 10,723,730 protect?
The claimed compound is palbociclib, the active ingredient in Pfizer’s Ibrance product. The chemical name in the claims is:
6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one.
The patent claims the crystalline free base rather than a salt, solvate, hydrate, amorphous form, or broad genus of CDK4/6 inhibitors.
| Claim characteristic |
Scope |
| Active ingredient |
Palbociclib |
| Chemical form |
Crystalline free base |
| Solid-state identification |
PXRD peaks and, in dependent claims, 13C ssNMR resonances |
| Particle-size limitation |
D90 of about 30-65 μm or D[4,3] of about 15-40 μm |
| Narrower D[4,3] limitation |
About 15-30 μm |
| Dosage-form coverage |
Pharmaceutical compositions containing the claimed free base |
| Covered product type |
Palbociclib API and formulations containing that API |
The claims do not cover every palbociclib product. They require the accused material to meet the relevant analytical limitations.
How are the US 10,723,730 claims structured?
The patent contains three principal claim groups.
Claims 1-6: D90-defined crystalline palbociclib
Claim 1 requires:
- Crystalline palbociclib free base;
- PXRD peaks at approximately 8.0°, 10.1°, and 11.5° 2θ; and
- A primary particle-size distribution with a D90 of approximately 30-65 μm.
Claims 2-3 add more specific PXRD limitations. Claim 2 adds the 10.3° peak, while claim 3 refers to a PXRD pattern essentially the same as Figure 1.
Claims 4-6 add 13C ssNMR limitations. The specified resonances are:
- 12.5 ppm;
- 112.4 ppm; and
- 143.2 ppm.
The claim hierarchy progressively narrows the analytical fingerprint.
Claims 7-12: D[4,3]-defined crystalline palbociclib
Claim 7 requires the same core PXRD peaks but replaces the D90 requirement with a volume mean diameter, D[4,3], of approximately 15-40 μm.
Claims 8-9 add the 10.3° PXRD peak or the Figure 1 pattern. Claims 10-12 add the same sequence of 13C ssNMR limitations found in claims 4-6.
D[4,3] is a volume-weighted mean particle diameter. It is not interchangeable with D90. A product can satisfy one metric without satisfying the other, depending on the particle-size distribution.
Claims 13-14 and 21: Pharmaceutical compositions
Claims 13 and 14 cover pharmaceutical compositions containing the material of claim 1 or claim 7. Claim 21 covers a composition containing the material of claim 15.
These claims require more than the presence of palbociclib. The palbociclib must satisfy the applicable crystal and particle-size limitations, and the composition must contain a pharmaceutically acceptable carrier, diluent, or excipient.
What solid-state features are required for infringement?
A product accused under the broadest independent claims would generally need to satisfy both a structural identity and a measurable physical characteristic.
For claims 1 and 7, the core PXRD requirements are:
| Required PXRD peak |
Claimed range |
| First peak |
8.0° ± 0.2° 2θ |
| Second peak |
10.1° ± 0.2° 2θ |
| Third peak |
11.5° ± 0.2° 2θ |
The dependent claims add a fourth peak at 10.3° ± 0.2° 2θ or require a pattern essentially the same as Figure 1.
The language "comprising peaks" generally permits additional peaks. It does not require that the three or four identified peaks be the only peaks in the diffraction pattern. The phrase "essentially the same as shown in FIG. 1" creates a pattern-comparison issue that may depend on the patent specification, experimental conditions, peak intensity, and accepted PXRD analytical practice.
The 13C ssNMR claims create a separate narrowing layer. A material that meets the PXRD limitations but lacks the specified NMR resonances may avoid the NMR-dependent claims while remaining potentially within claims 1 or 7.
What particle-size ranges does the patent protect?
The particle-size limitations are central to the patent’s commercial scope.
| Claim |
Particle-size test |
Range |
| 1 |
Primary particle D90 |
About 30-65 μm |
| 7 |
Volume mean diameter D[4,3] |
About 15-40 μm |
| 15 |
Volume mean diameter D[4,3] |
About 15-30 μm |
Claim 15 is narrower than claim 7 because the upper limit is reduced from approximately 40 μm to approximately 30 μm. Claims 16-20 further narrow claim 15 through PXRD and NMR characteristics. Claim 21 covers compositions containing the claim 15 material.
The patent therefore creates overlapping but distinct claim pathways:
- A D90 pathway under claim 1;
- A broader D[4,3] pathway under claim 7;
- A narrower D[4,3] pathway under claim 15;
- PXRD-narrowed versions of each pathway;
- NMR-narrowed versions of those pathways; and
- Composition claims tied to the relevant API form.
Particle-size testing is method-sensitive. Milling, crystallization, agglomeration, dispersion, sampling, laser-diffraction settings, and the distinction between primary particles and agglomerates can affect the result. A generic manufacturer would need a controlled analytical record covering both API lots and the final drug product.
Does the patent cover Ibrance itself?
The patent is directed to a solid form of the palbociclib active ingredient used in Ibrance. Whether a particular Ibrance batch practices every limitation of a particular claim requires comparison with the patent’s examples, Pfizer’s product specifications, and analytical testing.
The existence of the patent does not establish that every Ibrance dosage form falls within every claim. The composition claims may be more commercially important than the API claims because they can implicate tablets or capsules containing the relevant crystalline material.
Ibrance is marketed as palbociclib capsules and tablets for hormone-receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, generally in combination with an aromatase inhibitor or fulvestrant and, in some patients, an aromatase inhibitor plus a luteinizing hormone-releasing hormone agonist. FDA approved Ibrance in 2015 and expanded its labeling after the initial approval. (FDA, n.d.-a)
Is US 10,723,730 a compound patent, formulation patent, or method-of-use patent?
It is principally a crystalline-form and particle-size patent.
| Patent category |
Coverage under US 10,723,730 |
| Broad chemical compound |
No |
| Crystalline solid form |
Yes |
| Particle-size distribution |
Yes |
| Pharmaceutical composition |
Yes |
| Tablet or capsule architecture |
Only to the extent the composition contains the claimed material |
| Manufacturing process |
No express process claim in the provided claims |
| Method of treatment |
No |
| Dosage regimen |
No |
| CDK4/6 inhibition method |
No |
| Salt or solvate |
Not on the face of the provided claims |
This distinction matters in freedom-to-operate analysis. A manufacturer could avoid this patent by using a nonclaimed palbociclib solid form or particle-size profile, but other palbociclib patents could still cover the compound, formulation, treatment method, or manufacturing route.
What other patent categories affect generic palbociclib entry?
Palbociclib has a layered patent estate. The relevant categories include the following.
Compound and therapeutic-use patents
Earlier Pfizer patent families cover the palbociclib chemical series and the use of CDK4/6 inhibition in cancer treatment. These patents are separate from the crystalline-form claims in US 10,723,730.
Formulation patents
Formulation patents may cover palbociclib compositions, dosage forms, excipient systems, release characteristics, or solid-state control. A generic applicant can face formulation risk even if it designs around the crystalline API claims.
Method-of-use patents
Method-of-use patents may cover treatment of breast cancer subpopulations, combination treatment with endocrine therapies, dosing schedules, or use in patients with particular biomarker or disease characteristics. These patents can affect Paragraph IV strategy and labeling design.
Manufacturing and process patents
Process patents can cover crystallization, isolation, purification, milling, particle-size control, or conversion between solid forms. US 10,723,730 does not, based on the provided claims, require a particular manufacturing process, but its product claims can still capture the resulting API.
What is the Orange Book status of US 10,723,730?
The FDA Orange Book is the controlling source for patent listings submitted for approved drug products. An Orange Book listing can create a Paragraph IV certification obligation for an ANDA applicant, depending on the patent’s listing status, dosage-form relationship, and expiration information. (FDA, n.d.-b)
The provided claim text alone does not establish:
- Whether US 10,723,730 is listed for Ibrance;
- The listed product number;
- The FDA-listed expiration date;
- Whether the patent has been delisted;
- Whether a pediatric exclusivity period applies; or
- Whether a specific ANDA applicant has certified Paragraph IV against it.
Patent grant information and Orange Book listing information are separate records. A patent can be relevant to a product without appearing in the Orange Book, and an Orange Book-listed patent can have claims that are narrower than the marketed product.
When does palbociclib lose exclusivity?
Palbociclib exclusivity must be separated into regulatory exclusivity, patent exclusivity, and settlement-controlled generic entry.
| Exclusivity type |
Relevance |
| New chemical entity exclusivity |
Protected the initial FDA approval period |
| Patent term |
Depends on each patent family and any patent-term adjustment or extension |
| Pediatric exclusivity |
Can add six months to qualifying listed protections |
| Orphan exclusivity |
Not the principal exclusivity mechanism for Ibrance |
| ANDA litigation stay |
Can delay approval for up to 30 months after a qualifying Paragraph IV notice |
| Settlement restrictions |
May establish an agreed generic launch date before patent expiry |
The earliest loss of one protection does not necessarily permit unrestricted generic launch. A generic entrant must assess all enforceable patents, FDA exclusivity, litigation stays, settlements, and the applicant’s proposed label.
Which companies are challenging palbociclib patents?
Generic manufacturers have pursued or evaluated ANDA pathways for palbociclib. Public litigation and settlement records must be reviewed by patent number because a company may challenge one Pfizer patent family while accepting or settling claims involving another.
A company’s Paragraph IV filing is not equivalent to a final invalidity judgment. The key diligence questions are:
- Which patent numbers were challenged?
- Was the patent listed for the relevant Ibrance dosage form?
- Did Pfizer file a timely infringement action?
- Did the action trigger a 30-month stay?
- Was the case dismissed, settled, or adjudicated?
- Does the settlement authorize launch before patent expiry?
- Does the agreed launch date apply to all strengths and formulations?
No biosimilar pathway applies. Palbociclib is a chemically synthesized small-molecule drug, so generic competition proceeds through the ANDA framework rather than the biosimilar pathway under the Public Health Service Act.
How strong is the patent estate for US 10,723,730?
The patent has meaningful but technically bounded strength.
Strengths
- It targets a defined crystalline palbociclib form likely relevant to commercial API production.
- It uses multiple independent physical characteristics: PXRD and particle size.
- It includes alternative particle-size metrics, including D90 and D[4,3].
- It contains composition claims that may reach finished pharmaceutical products.
- The dependent claims create several fallback positions based on additional PXRD and NMR data.
Vulnerabilities
- The claims do not cover all palbociclib forms.
- Particle-size limitations can be designed around through controlled crystallization or milling.
- Analytical variability may create disputes over D90, D[4,3], and primary-particle measurement.
- Solid-form claims can face prior-art challenges based on public crystalline-form disclosures, inherent anticipation, obviousness, or inadequate written description.
- The NMR-dependent claims may be difficult to use if the claimed resonances are not consistently reproduced across instruments and sample preparations.
- Composition claims may depend on proof that the API in the finished product retains the claimed characteristics.
The strongest enforcement position would generally involve a generic product whose API has the claimed PXRD pattern and falls within one of the specified particle-size ranges. A product using a different crystal form or a particle-size distribution outside the claimed ranges would present a stronger design-around position, subject to other patent families.
What generic launch scenarios exist?
Scenario 1: Launch after all relevant patents expire
This is the lowest litigation-risk scenario but may postpone market entry and reduce first-mover value.
Scenario 2: Paragraph IV challenge
The applicant alleges that the relevant patent is invalid, unenforceable, or not infringed. The commercial outcome depends on litigation, the 30-month stay, and any settlement.
Scenario 3: Form or particle-size design-around
The applicant develops palbociclib API that does not meet the claimed PXRD or particle-size limitations. This approach requires analytical evidence across validation batches and commercial-scale manufacture.
Scenario 4: Authorized generic or settlement launch
A settlement may permit launch on a negotiated date before the latest asserted patent expiry. Terms can include launch timing, supply arrangements, or restrictions on dosage forms and indications.
Scenario 5: Label carve-out
A generic applicant may omit patented indications or methods of use from its label. A carve-out does not avoid product or formulation patent claims and may not eliminate infringement risk where the product is sold for the patented use.
What geographic coverage does the patent provide?
US 10,723,730 provides United States protection only. Related applications or international family members may protect corresponding palbociclib solid forms in Europe, Japan, China, Canada, and other jurisdictions, but the scope, prosecution history, validity, and expiry dates must be assessed separately.
A US design-around does not establish freedom to operate in Europe or other markets. Patent claims may differ materially after national-phase prosecution, and some jurisdictions may reject or narrow particle-size limitations differently from the United States.
Key Takeaways
- US 10,723,730 is a palbociclib crystalline free-base patent.
- It does not claim palbociclib broadly as a chemical compound.
- The core limitations are PXRD peaks at approximately 8.0°, 10.1°, and 11.5° 2θ, combined with defined particle-size parameters.
- Claims 1-6 use D90 of about 30-65 μm.
- Claims 7-12 use D[4,3] of about 15-40 μm.
- Claims 15-21 narrow D[4,3] to about 15-30 μm.
- Dependent claims add a 10.3° PXRD peak, Figure 1 pattern, and 13C ssNMR resonances at 12.5, 112.4, and 143.2 ppm.
- Claims 13, 14, and 21 extend protection to pharmaceutical compositions.
- The patent creates API, solid-form, particle-size, and formulation risk for generic palbociclib manufacturers.
- Palbociclib is a small molecule, so biosimilar analysis is not applicable.
- Orange Book status, terminal expiration, litigation, and settlement rights must be determined by patent-specific FDA, USPTO, and court records rather than from the claim text alone.
FAQs About US 10,723,730 and Palbociclib Patent Risk
Does US 10,723,730 cover amorphous palbociclib?
No. The provided claims require a crystalline free base with specified PXRD characteristics. An amorphous material would generally fall outside those limitations, although other patents could cover amorphous palbociclib or its manufacture.
Can a generic avoid the patent by changing the excipients?
Not necessarily. Claims 1, 7, and 15 are directed to the API itself. Changing excipients would not avoid an API claim if the palbociclib material still satisfies the claimed solid-state and particle-size limitations.
Is the D90 range the same as the D[4,3] range?
No. D90 identifies a percentile of the particle-size distribution. D[4,3] is a volume-weighted mean diameter. They are different measurements and must be analyzed separately.
Are the PXRD peaks alone enough to establish infringement?
Not for claims 1, 7, or 15. Those claims also require the relevant particle-size limitation. The PXRD peaks become sufficient for certain dependent-form limitations only when read together with all limitations inherited from the applicable independent claim.
Does a Paragraph IV filing automatically invalidate US 10,723,730?
No. Paragraph IV is an ANDA certification alleging invalidity, unenforceability, or noninfringement. The patent remains enforceable unless it expires, is disclaimed, is cancelled, or is held invalid or not infringed.
References
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U.S. Patent No. 10,723,730. (2020). Crystalline free base of palbociclib. United States Patent and Trademark Office.
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U.S. Food and Drug Administration. (n.d.-a). Ibrance (palbociclib) prescribing information. FDA.
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U.S. Food and Drug Administration. (n.d.-b). Approved drug products with therapeutic equivalence evaluations. FDA.
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United States Patent and Trademark Office. (n.d.). Patent Center. USPTO.
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United States Code, 35 U.S.C. §§ 154, 156, 271, and 355.
