Details for Patent: 8,148,333

Which drugs does patent 8,148,333 protect, and when does it expire?

Patent 8,148,333 protects TYMLOS and is included in one NDA.

This patent has forty-two patent family members in twenty-eight countries.

Summary for Patent: 8,148,333

Title:	Stable composition comprising a PTHrP analogue
Abstract:	The present invention provides a storage-stable composition containing a parathyroid hormone-related protein (PTHrP) analogue and methods of using a PTHrP analogue and the PTHrP compositions described herein to treat osteoporosis, to increase bone mass or to increase bone quality. The composition is storage stable, in sterile form, and in general may be stored at room temperature for at least several weeks to allow convenient parenteral administration to human patients.
Inventor(s):	Michael J. Dey, Nathalie Mondoly, Benedicte Rigaud, Bart Henderson, C. Richard Lyttle
Assignee:	Ipsen Pharma SAS , Radius Health Inc
Application Number:	US12/311,418
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,148,333
Patent Claim Types: see list of patent claims	Composition;

United States Patent 8,148,333: Abaloparatide Formulation Scope, Expiration, and Patent Landscape

US 8,148,333 protects storage-stable formulations of the PTHrP analogue abaloparatide at an acidic pH, principally around pH 5.1. The patent is formulation-specific. It does not, based on the supplied claims, broadly protect abaloparatide as a molecule, its therapeutic use, or every injectable formulation containing the peptide.

The commercial formulation most closely aligned with the claims is Radius Health’s Tymlos (abaloparatide) injection, supplied as a 2 mg/mL multidose solution containing an acetate buffer and phenol. The patent’s earliest priority date appears to place its ordinary 20-year term in late 2027, subject to any patent-term adjustment, disclaimer, or correction recorded by the USPTO.

What does US Patent 8,148,333 protect?

US 8,148,333 protects a storage-stable composition containing:

1. The specific amidated PTHrP analogue identified in SEQ ID NO. 2; and
2. An effective amount of a pH buffer maintaining the formulation at approximately pH 4.5 to 5.6.

The claimed analogue is:

[Glu22,25, Leu23,28,31, Aib29, Lys26,30] hPTHrP(1-34)NH2

This molecule is abaloparatide, also known as ABL or BIM-44058. The claims do not cover every PTHrP analogue. They require the particular amino-acid substitutions and the C-terminal amidation recited in the claim.

Claim architecture

Claim	Subject matter	Practical scope
1	Abaloparatide plus buffer maintaining pH at about 4.5-5.6	Independent formulation claim
2	Claim 1 at about pH 5.1	Narrow pH limitation
3	Acetate, tartrate, phosphate, or citrate buffer	Closed buffer-selection limitation
4	Acetate buffer	Narrows claim 3
5	Acetic acid and sodium acetate	Specific acetate system
6	Buffer concentration of about 1-10 mM	Concentration range
7	Buffer concentration of about 6 mM	Preferred concentration
8	Addition of antimicrobial agent	Additional formulation limitation
9	Phenol as antimicrobial agent	Specific antimicrobial
10	Phenol at about 0.25-5 mg/mL	Phenol range
11	Phenol at about 5 mg/mL	Preferred phenol concentration
12	Abaloparatide at about 2 mg/mL	Commercially significant concentration
13	No chemical stabilizer	Negative formulation limitation

Claim 1 is open-ended because it uses “comprising.” A formulation can contain additional excipients and still fall within the claim if it contains the specified peptide and buffer and maintains the required pH.

How narrow is the independent claim?

Claim 1 is narrower than a conventional composition-of-matter claim but broader than the dependent claims. It requires four central elements:

• The specific abaloparatide sequence;
• An administrable composition;
• Storage stability;
• A buffer maintaining pH at approximately 4.5 to 5.6.

A product that contains abaloparatide at pH 5.1 with an acetate buffer will present a strong literal-infringement profile under claim 1, even if it uses excipients not expressly identified in the dependent claims.

The claim does not expressly require:

• Phenol;
• Acetate;
• A 2 mg/mL peptide concentration;
• A multidose pen;
• A particular container;
• Subcutaneous administration;
• A particular manufacturing process; or
• The absence of all excipients.

Those limitations appear only in dependent claims or are not recited at all.

Effect of the “about” language

The patent repeatedly uses “about,” including for:

• pH 4.5 to 5.6;
• pH 5.1;
• 1 to 10 mM buffer;
• 0.25 to 5 mg/mL phenol; and
• 2 mg/mL peptide.

The scope of “about” would depend on intrinsic evidence, specification examples, prosecution history, analytical precision, and the ordinary technical meaning in peptide formulation science. A product at pH 5.7 is not automatically outside the claim. The relevant question would be whether pH 5.7 falls within the technically supported meaning of “about 5.6.”

For a freedom-to-operate analysis, pH should be assessed using the same measurement conditions and product state used for the patent’s stability data. Small differences caused by calibration, temperature, dilution, or sampling could affect the analysis.

What formulations are protected by the dependent claims?

The strongest commercial formulation position is the combination of claims 1, 5, 7, 9, 11, 12, and 13:

• Abaloparatide;
• Acetic acid and sodium acetate;
• Approximately 6 mM buffer;
• Approximately pH 5.1;
• Phenol at approximately 5 mg/mL;
• Abaloparatide at approximately 2 mg/mL; and
• No chemical stabilizer.

This combination closely corresponds to the basic formulation profile publicly associated with Tymlos.

Formulation claim map

Formulation characteristic	Claim coverage
Abaloparatide at acidic pH	Claim 1
pH around 5.1	Claim 2
Acetate, tartrate, phosphate, or citrate	Claim 3
Acetate buffer	Claim 4
Acetic acid plus sodium acetate	Claim 5
Buffer at 1-10 mM	Claim 6
Buffer at approximately 6 mM	Claim 7
Antimicrobial agent	Claim 8
Phenol	Claim 9
Phenol at 0.25-5 mg/mL	Claim 10
Phenol at approximately 5 mg/mL	Claim 11
Abaloparatide at approximately 2 mg/mL	Claim 12
No chemical stabilizer	Claim 13

A competitor using citrate rather than acetate could avoid claims 4-7, but it would remain exposed to claim 1 if the formulation still contains the specified peptide and maintains pH within the claimed range. A competitor using acetate at pH 5.1 would likely remain exposed to claims 1-5 even if it changed the buffer concentration or antimicrobial agent.

Does the patent cover Tymlos?

Tymlos is abaloparatide injection approved by the FDA for postmenopausal women with osteoporosis at high risk for fracture. The approved product is administered subcutaneously using a multidose pen. The labeled dose is 80 micrograms once daily, and the product is supplied as a 2 mg/mL solution in a multidose cartridge.[1]

The publicly described Tymlos formulation includes elements that track the patent claims, including:

• Abaloparatide;
• An acetate-based pH system;
• Acidic formulation conditions;
• Phenol as an antimicrobial preservative; and
• Approximately 2 mg/mL peptide concentration.

FDA-approved labeling identifies the formulation components and concentration. The Orange Book identifies patents associated with approved drug products, including formulation patents when properly listed by the sponsor.[2]

Tymlos and US 8,148,333

Issue	Assessment
Active ingredient	Abaloparatide
Dosage form	Injectable solution
Route	Subcutaneous
Commercial concentration	Approximately 2 mg/mL
Claimed pH	About 4.5-5.6, with pH 5.1 preferred
Commercially relevant buffer	Acetate
Preservative	Phenol
Patent relevance	Direct formulation overlap
Patent type	Formulation and stability patent
Molecule protection	Not established by the supplied claims

A product can practice the claimed formulation even if it is sold under a different device, container, label, or trade name. The claims are directed principally to the composition, not the pen device.

When does US 8,148,333 lose exclusivity?

The patent’s ordinary expiration date is expected to fall in 2027, based on the patent family’s priority and filing history. The controlling date should be taken from the USPTO patent record and any applicable patent-term-adjustment calculation.

Milestone	Date or period
Earliest priority period	2006-2007 patent-family period
US patent grant	April 3, 2012
Ordinary 20-year term	Expected in late 2027
FDA approval of Tymlos	April 28, 2017
Five-year NCE exclusivity	Expired in April 2022
Formulation patent protection	Expected to continue into 2027, subject to term adjustments

Patent expiration and FDA exclusivity are separate. The five-year new chemical entity exclusivity associated with abaloparatide expired before the anticipated expiration of the formulation patent. NCE exclusivity prevented FDA approval of an ANDA or certain 505(b)(2) applications during its statutory period, while the patent can block commercial activity after regulatory exclusivity ends.

What is the Orange Book status of US 8,148,333?

US 8,148,333 has been associated with the Tymlos patent estate and is relevant to Orange Book-based generic litigation analysis. An Orange Book listing can require an ANDA applicant to make a patent certification, including a Paragraph IV certification asserting that the patent is invalid, unenforceable, or not infringed.[2]

The key distinction is that Orange Book listing does not establish patent validity or infringement. It creates a regulatory notice and litigation mechanism.

For an ANDA applicant, a Paragraph IV certification concerning a listed patent can trigger:

• Notice to the patent owner and NDA holder;
• A 45-day period for suit;
• A potential 30-month FDA approval stay if a timely infringement action is filed;
• Patent litigation over claim construction, validity, enforceability, and infringement.

The formulation nature of US 8,148,333 makes claim construction central. Litigation would likely focus on “storage-stable,” “effective amount,” “about,” “maintain the pH,” and “chemical stabilizer.”

Which companies are challenging the Tymlos patent estate?

Public generic competition analysis should distinguish between:

• Companies that have publicly disclosed an ANDA or Paragraph IV challenge;
• Companies that have been sued after serving a Paragraph IV notice; and
• Companies that may be developing an injectable abaloparatide product without a public patent challenge.

A definitive competitor list requires current FDA Orange Book and PACER records. The relevant defendants, if sued, would be identified in federal complaints brought by the NDA holder or patent owner. The existence of an ANDA filing alone does not establish that a Paragraph IV notice was served or that litigation was initiated.

The commercial threat is structurally different from a conventional small-molecule tablet. Abaloparatide is a synthetic peptide administered by injection. Generic developers must address:

• Peptide identity and purity;
• Potency and degradation profile;
• Preservative content;
• Container-closure compatibility;
• Multidose-device performance;
• Sterility and microbiological controls;
• In-use stability; and
• FDA requirements for pharmaceutical equivalence and bioequivalence.

These factors can delay commercial launch even after a patent challenge succeeds.

Is there biosimilar risk for abaloparatide?

Abaloparatide is generally analyzed through the generic and 505(b)(2) frameworks rather than the biosimilar pathway. The biologics license application framework under section 351 does not ordinarily apply to a synthetic peptide approved as a drug under section 505.

The principal regulatory pathways are therefore:

Pathway	Relevance
ANDA under section 505(j)	Potential pathway for a therapeutically equivalent injectable product
505(b)(2) NDA	Possible pathway where reliance on FDA findings is combined with new clinical or formulation data
Biosimilar BLA under section 351(k)	Generally not the expected pathway for synthetic abaloparatide

The formulation patent can affect either an ANDA or a 505(b)(2) product if the proposed product uses the claimed composition. A 505(b)(2) applicant may seek a different formulation, route, device, or dosing presentation, but those changes can increase development and regulatory costs.

What patent rights are outside US 8,148,333?

The patent should be separated from other potential rights in the abaloparatide estate.

Composition-of-matter rights

A composition-of-matter patent covering the abaloparatide sequence would present a broader barrier than US 8,148,333. Such a patent could cover the analogue independent of pH, buffer, preservative, concentration, or dosage form.

The supplied claims do not establish that US 8,148,333 is a composition-of-matter patent. They are expressly directed to storage-stable compositions containing the analogue and a buffer.

Method-of-use patents

Separate patents may cover:

• Treatment of osteoporosis;
• Reduction of vertebral or nonvertebral fracture risk;
• Dosing schedules;
• Duration of treatment;
• Use in postmenopausal women;
• Sequential therapy with antiresorptive agents; or
• Use in patients with particular fracture-risk profiles.

Those rights would raise different infringement questions from the formulation claims. A generic label that omits a patented indication can reduce, but not necessarily eliminate, method-of-use risk.

Device and container patents

Tymlos is delivered through a multidose injection device. Separate patents could cover:

• Pen architecture;
• Cartridge configuration;
• Dose-setting mechanisms;
• Needle interfaces;
• Priming or dose-delivery controls; and
• Container-closure systems.

US 8,148,333 does not require the Tymlos pen. A competitor can avoid device claims while still practicing the formulation claims, or design around the formulation while using a similar device.

Manufacturing and process rights

The patent claims supplied do not recite:

• Peptide synthesis;
• Purification;
• Lyophilization;
• Sterile filtration;
• Filling;
• Container sealing;
• Stability testing; or
• Manufacturing equipment.

A different manufacturing process does not avoid composition claims if the resulting product has the claimed composition. Process patents matter separately where the accused process itself is claimed.

How strong is the patent estate for generic-entry purposes?

US 8,148,333 has moderate commercial importance and a narrower legal perimeter than a molecule patent.

Strength factors

• The claims target the commercial injectable concentration.
• Claim 1 covers any buffer capable of maintaining the claimed pH range.
• The peptide sequence is specifically identified, reducing ambiguity about the active ingredient.
• The patent reaches formulations with added excipients because claim 1 uses “comprising.”
• Dependent claims provide multiple fallback positions around acetate, phenol, pH, and concentration.

Weakness factors

• The claims are limited to a formulation architecture.
• A competitor may attempt a different pH range or buffer system.
• “Storage-stable” can create an evidentiary issue if the specification does not define the required stability period or test conditions with precision.
• “About” creates boundary disputes.
• The absence of a chemical stabilizer in claim 13 may be difficult to apply if the parties disagree over what qualifies as a chemical stabilizer.
• The patent term is expected to end in 2027, limiting the value of prolonged litigation.

The practical risk is highest for a product that reproduces Tymlos closely. It is lower for a formulation using a materially different pH, buffer system, preservative, concentration, or stability strategy.

What generic launch scenarios exist?

Scenario	Likely result
Generic copies acetate-buffered formulation at pH about 5.1	High exposure to claims 1-7
Generic uses phenol and approximately 2 mg/mL abaloparatide	Increased exposure to claims 8-12
Generic uses citrate at pH 5.1	Potentially avoids acetate-dependent claims, but not claim 1
Generic uses pH above the claimed range	Possible design-around, subject to “about” and equivalents
Generic removes phenol	Avoids claims 8-11 but not claims 1-7 or 12
Generic changes peptide concentration	May avoid claim 12 but not claim 1
Generic adds a chemical stabilizer	May avoid claim 13 while remaining exposed to claim 1
505(b)(2) product with a different formulation	Lower direct formulation exposure, higher development burden
Product launched after patent expiry	Patent-based launch risk materially reduced

A Paragraph IV challenge would have the greatest value if supported by a design-around formulation. A validity-only challenge would likely focus on anticipation or obviousness based on earlier PTHrP formulations, peptide stability data, buffer selection, and the claimed pH range.

What litigation and settlement issues matter?

A dispute involving this patent would likely address:

1. Whether the accused formulation contains the claimed abaloparatide analogue;
2. Whether the product is “storage-stable” under the patent’s construction;
3. Whether the measured pH is within the range implied by “about 4.5 to about 5.6”;
4. Whether the buffer maintains the pH during storage;
5. Whether the product contains a chemical stabilizer;
6. Whether the asserted claims are enabled across the full claimed range;
7. Whether the claimed formulation would have been obvious; and
8. Whether any settlement permits a date-certain generic launch before patent expiry.

A settlement could specify a launch date, supply arrangement, license, or authorized-generic structure. The existence and terms of any settlement should be verified against court filings and FTC settlement disclosures before being used in valuation or launch forecasting.

What is the geographic scope of the patent estate?

US 8,148,333 has effect only in the United States. Parallel rights may exist in other jurisdictions through the same international patent family, but foreign claim scope, prosecution history, term, validity, and regulatory relevance must be assessed separately.

Geographic exposure is especially important for abaloparatide because:

• US approval and Orange Book listing drive the US ANDA pathway;
• European and other markets use different regulatory and patent-linkage systems;
• Patent-term calculations may differ by jurisdiction;
• Supplementary protection certificates may affect European market timing; and
• A US design-around does not establish freedom to operate elsewhere.

Key Takeaways

• US 8,148,333 is principally a formulation and stability patent for abaloparatide.
• Claim 1 requires the specified PTHrP analogue and a buffer maintaining pH at approximately 4.5-5.6.
• Claims 2-12 progressively narrow the formulation toward pH 5.1, acetate, approximately 6 mM buffer, phenol, and 2 mg/mL abaloparatide.
• Claim 13 requires the absence of a chemical stabilizer.
• The claims closely track the commercial Tymlos formulation.
• The patent does not, from the supplied claims, broadly cover the abaloparatide molecule, all methods of treating osteoporosis, the Tymlos pen, or peptide manufacturing.
• Ordinary patent expiration is expected in late 2027, subject to the USPTO-recorded term calculation.
• NCE exclusivity for Tymlos expired in April 2022.
• Abaloparatide is more likely to face ANDA or 505(b)(2) competition than biosimilar competition.
• The strongest design-around options involve changing pH, buffer, preservative, concentration, or stabilizer strategy.
• A close Tymlos formulation presents the highest infringement risk until patent expiry.

FAQs

Does US 8,148,333 cover abaloparatide by itself?

No. The supplied claims require abaloparatide in a storage-stable buffered composition. They do not claim the peptide as an isolated molecule.

Can a generic avoid the patent by replacing acetate with citrate?

Replacing acetate may avoid claims 4-7, but it would not necessarily avoid claim 1, which broadly refers to an effective pH buffer.

Does removing phenol avoid all claims?

No. Removing phenol may avoid claims 8-11. It does not avoid the independent claim or the buffer and concentration claims.

Is a 2 mg/mL abaloparatide product automatically infringing?

No. Concentration alone is insufficient. Infringement depends on whether the product also contains the claimed analogue, falls within the pH-buffer limitations, and satisfies the relevant stability requirements.

Is Tymlos eligible for biosimilar competition?

Abaloparatide is generally treated as a synthetic peptide drug rather than a biologic subject to the section 351(k) biosimilar pathway. Generic or 505(b)(2) competition is the more relevant framework.

References

1. U.S. Food and Drug Administration. (2017). Tymlos (abaloparatide) injection prescribing information. https://www.accessdata.fda.gov
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
3. United States Patent and Trademark Office. (2012). U.S. Patent No. 8,148,333, stable formulations of PTHrP analogues. https://patents.google.com/patent/US8148333
4. U.S. Food and Drug Administration. (2017). Application number 208743: Tymlos approval package. https://www.accessdata.fda.gov/drugsatfda
5. Radius Health, Inc. (2022). Annual report on Form 10-K. U.S. Securities and Exchange Commission. https://www.sec.gov/edgar/browse//?CIK=1537908

Drugs Protected by US Patent 8,148,333

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Radius	TYMLOS	abaloparatide	SOLUTION;SUBCUTANEOUS	208743-001	Apr 28, 2017		RX	Yes	Yes	8,148,333		Y

Foreign Priority and PCT Information for Patent: 8,148,333

PCT Information
PCT Filed	October 03, 2007	PCT Application Number:	PCT/US2007/021216
PCT Publication Date:	May 29, 2008	PCT Publication Number:	WO2008/063279

International Family Members for US Patent 8,148,333

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2073789		301235	Netherlands
European Patent Office	2073789		CA 2023 00019	Denmark
European Patent Office	2073789		2023C/523	Belgium
European Patent Office	2073789		LUC00309	Luxembourg
European Patent Office	2073789		23/2023	Austria
European Patent Office	2073789		122023000031	Germany
European Patent Office	2073789		2390018-6	Sweden