Details for Patent: 8,828,356

Summary for Patent: 8,828,356

Title:	Farnesyltransferase inhibitors for treatment of laminopathies, cellular aging and atherosclerosis
Abstract:	Although it can be farnesylated, the mutant lamin A protein expressed in Hutchinson Gilford Progeria Syndrome (HGPS) cannot be defarnesylated because the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein (called “progerin”) that alters normal lamin A function as a dominant negative, as well as assuming its own aberrant function through its association with the nuclear membrane. The retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) (both direct effectors and indirect inhibitors) will inhibit the formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression. Similarly, treatment with FTIs should improve disease status in progeria and other laminopathies. In addition, elements of atherosclerosis and aging in non-laminopathy individuals will improve after treatment with farnesyltransferase inhibitors.
Inventor(s):	Leslie B. Gordon, Francis S. Collins, Thomas Glover, Michael W. Glynn, Brian C. Capell, Adrienne D. Cox, Channing J. Der
Assignee:	University of North Carolina at Chapel Hill , University of Michigan System , Progeria Research Foundation Inc , US Department of Health and Human Services
Application Number:	US13/857,052
Patent Claim Types: see list of patent claims	Use;

United States Patent 8,828,356: Scope, Claims, Expiration, and Lonafarnib Patent Landscape

US Patent 8,828,356 covers methods of treating Hutchinson-Gilford Progeria Syndrome, or HGPS, by administering a farnesyltransferase inhibitor. The broadest claim reaches any therapeutically effective FTI used to reduce at least one HGPS symptom, prevent disease progression, or slow progression. Dependent claims narrow the protection to specified symptoms, FTIs, doses, combination therapy, and lonafarnib, also known as SCH66336.

The patent is important because it claims the therapeutic use of an FTI in HGPS rather than the chemical composition of lonafarnib itself. Its commercial relevance is tied primarily to Zokinvy, the FDA-approved lonafarnib product for HGPS and certain progeroid laminopathies.

What does US Patent 8,828,356 protect?

The patent protects a treatment method with four core elements:

1. The patient has HGPS.
2. The patient receives a therapeutically effective dose of an FTI.
3. The treatment reduces at least one clinical symptom of HGPS.
4. The treatment may prevent or retard disease progression.

Claim 1 is the principal broad claim:

A method of reducing at least one clinical symptom of HGPS in a subject having HGPS by administering a therapeutically effective dose of an FTI.

The claim does not limit the treatment to lonafarnib. It covers the therapeutic use of the FTI class, subject to the other limitations in the claim.

The claim also does not require a specific symptom, dose, administration schedule, route, formulation, biomarker, or genotype. A treatment can potentially fall within claim 1 if it uses an FTI in an HGPS patient and produces a clinical symptom reduction.

Claim structure and practical scope

Claim	Subject matter	Scope
1	FTI treatment of HGPS	Broad independent method claim
2	Specified HGPS symptoms	Failure to thrive, maldevelopment, cardiovascular disease, abnormal bone density, distal bone resorption, osteoporosis, or decreased adipose tissue
3	Cardiovascular manifestations	Atherosclerosis, plaques, interstitial fibrosis, stenosis, or paucity of medial smooth muscle cells
4	Disease progression	Prevention or retardation of HGPS progression
5	Specific FTIs	PD169541, R115777, SCH66336, L-744832, FTI-2153, or active derivatives
6	Combination treatment	FTI plus a second therapeutic compound
7	Non-FTI combination agent	The second compound cannot be another FTI
8	Dose range	About 0.1 nM/kg to about 1 µM/kg
9	Weight-based dose	0.1 to 200 mg/kg
10	Specific weight-based doses	1, 10, 25, 50, or 100 mg/kg
11	Lonafarnib	SCH66336 specifically
12	Lonafarnib dose	At least 115 mg/m² twice daily
13	Alternative concentration range	About 1 to 500 nM/kg
14	Narrow concentration range	About 5 to 50 nM/kg

How broad is claim 1 of US 8,828,356?

Claim 1 is broad in drug identity and clinical outcome but narrow in disease indication. It requires HGPS, not merely a progeroid disorder, laminopathy, cardiovascular disease, or a mutation affecting lamin A processing.

The principal breadth points are:

• Any FTI may satisfy the drug limitation.
• The claim does not require lonafarnib.
• Any clinical symptom reduction may satisfy the outcome limitation.
• The claim does not specify a minimum duration of therapy.
• The claim does not require a particular route of administration.
• The claim does not limit treatment to a particular age group.
• The claim does not require a specific LMNA mutation in the patient.
• The claim does not require a particular formulation or dosage form.

The main limiting feature is the requirement that the subject have HGPS. A product used exclusively for oncology, viral disease, or another non-HGPS indication would not infringe merely because it is an FTI.

What symptoms are covered?

Claims 2 and 3 provide a nonexclusive list of protected clinical manifestations. The listed symptoms include:

• Failure to thrive
• Maldevelopment
• Cardiovascular disease
• Abnormal bone density
• Distal bone resorption
• Osteoporosis
• Decreased adipose tissue
• Atherosclerosis
• Atherosclerotic plaques
• Interstitial fibrosis
• Stenosis
• Paucity of medial smooth muscle cells

Because claim 1 refers to “at least one clinical symptom,” the dependent symptom claims do not exhaust the potential symptom scope of claim 1. Claim 1 can reach a symptom not expressly listed in claim 2 if the other claim elements are met.

Which farnesyltransferase inhibitors are named in the patent?

Claim 5 identifies six FTI categories or compounds:

FTI named in claim 5	Other identifier or commercial relevance
PD169541	Research FTI
R115777	Tipifarnib
SCH66336	Lonafarnib
L-744832	Research FTI
FTI-2153	Research FTI
Derivatives maintaining FTI activity	Functional derivative coverage

Claim 11 separately narrows the invention to lonafarnib, identified as SCH66336. Lonafarnib is the compound used in Zokinvy.

The derivative language in claim 5 is potentially significant. It does not cover every chemical analog automatically. A derivative must maintain farnesyltransferase inhibitory activity and must also satisfy the method-of-treatment limitations. A compound with a different mechanism, such as a geranylgeranyl transferase inhibitor without FTI activity, would fall outside the literal scope of that limitation.

What dose of lonafarnib is covered?

Claim 12 covers:

At least 115 mg/m² twice daily.

The claim is broader than a single commercial dose because it establishes a floor rather than a fixed upper limit. A lonafarnib regimen of 115 mg/m² twice daily or higher can satisfy the dose limitation, assuming the treatment otherwise meets claim 11 and the underlying claim 1 requirements.

The FDA-approved Zokinvy regimen uses body-surface-area dosing. FDA labeling describes an initial dosage of 115 mg/m² twice daily with food, followed by an increase to 150 mg/m² twice daily after an initial treatment period, subject to product-specific maximum doses and patient factors (FDA, 2020).

This creates a direct overlap between claim 12 and the commercial treatment regimen. The patent claim, however, is not limited to the exact Zokinvy label. It does not require a specific capsule strength, treatment duration, food instruction, or maximum dose.

Dose-related claim construction issues

Claims 8, 9, 13, and 14 use different dose units:

• nM/kg
• µM/kg
• mg/kg
• mg/m²

These units are not interchangeable without molecular-weight and dosing-context calculations. A court would ordinarily construe each limitation according to its stated unit. Claims 8, 13, and 14 appear to describe concentration-normalized amounts, while claims 9 and 10 use mass per body weight. Claim 12 uses body-surface-area dosing, which is the format used in the Zokinvy label.

The coexistence of these ranges may create claim-construction and enablement issues if the specification does not provide adequate support across the full breadth of each range. The strongest commercial claim is likely claim 11 in combination with claim 12 because it tracks the approved active ingredient and the FDA-recognized dosing framework.

Does the patent cover combination treatment?

Yes. Claim 6 covers administration of an FTI together with a second therapeutic compound. Claim 7 specifies that the second compound is not another FTI.

The claims therefore reach combination regimens involving lonafarnib and a non-FTI agent, provided that:

• The patient has HGPS.
• The FTI is administered.
• The method reduces a clinical symptom or meets the progression limitation.
• The second compound is therapeutic.
• The regimen otherwise satisfies the selected claim.

The combination claims may be relevant to future HGPS regimens involving cardiovascular, bone, metabolic, or supportive treatments. They do not necessarily cover the second compound as a standalone product or monotherapy.

What is the FDA status of lonafarnib and Zokinvy?

FDA approved Zokinvy capsules on November 20, 2020, for reducing the risk of mortality in patients one year of age and older with genetically confirmed HGPS or certain processing-deficient progeroid laminopathies with a body-surface area of at least 0.39 m² (FDA, 2020).

Regulatory item	Status
Product	Zokinvy
Active ingredient	Lonafarnib
Sponsor at approval	Eiger BioPharmaceuticals, Inc.
FDA approval date	November 20, 2020
Dosage form	Oral capsules
Initial indication	HGPS and qualifying processing-deficient progeroid laminopathies
Patient population	One year of age and older, subject to labeling criteria
Regulatory designation	Orphan-drug product
Dose framework	Body-surface-area-based twice-daily dosing

The approved indication is narrower and more precisely defined than claim 1 of US 8,828,356. The patent claims symptom reduction and disease progression in HGPS, while the FDA indication focuses on mortality-risk reduction and includes specified progeroid laminopathies beyond classic HGPS.

FDA approval does not establish patent validity or infringement. It establishes the approved regulatory use and labeling framework.

What is the Orange Book status of US 8,828,356?

US Patent 8,828,356 is a method-of-use patent associated with the therapeutic use of lonafarnib in HGPS. Its commercial significance depends on whether it is listed in the FDA Orange Book for the relevant Zokinvy NDA and whether any listed-use patent remains enforceable at the time of an ANDA filing.

Orange Book listing is legally important because an ANDA applicant must address listed patents through one of four certifications:

• Paragraph I: no patent information has been submitted.
• Paragraph II: the patent has expired.
• Paragraph III: the applicant will wait until patent expiration.
• Paragraph IV: the patent is invalid, unenforceable, or will not be infringed.

An Orange Book-listed method-of-use patent generally does not block every generic use of the active ingredient. The practical scope depends on the use code submitted by the NDA holder. A generic applicant may attempt a section viii statement seeking approval for indications or uses outside the patented method, subject to the FDA’s treatment of the use code.

The patent’s claims are directed to HGPS treatment. If the patent is listed with a corresponding HGPS use code, a Paragraph IV challenge could target the validity, enforceability, or noninfringement of the HGPS method claims.

When does US Patent 8,828,356 lose exclusivity?

The patent term is governed by the earliest effective nonprovisional or international filing date under the patent-term statute, subject to patent-term adjustment and other statutory modifications. The issuance date, September 9, 2014, does not determine the expiration date.

Public patent records identify the patent as an HGPS treatment patent with a mid-2000s priority and filing history. The enforceable expiration date should be taken from the USPTO Patent Center patent-term calculation and any later terminal disclaimer or adjustment record. The FDA Orange Book may display a different practical date if the patent is listed there and if pediatric exclusivity or other regulatory periods affect the blocking period.

The separate regulatory exclusivity timeline is more straightforward:

• Zokinvy approval date: November 20, 2020.
• Standard orphan-drug exclusivity period: seven years.
• Expected orphan exclusivity endpoint: November 20, 2027, subject to statutory exceptions and the specific FDA exclusivity record.

Orphan exclusivity and patent protection are separate. Orphan exclusivity can block approval of the same drug for the same disease or condition, while a patent can block covered use, manufacture, sale, or importation.

How strong is the patent estate for lonafarnib?

The estate has meaningful commercial strength for the original HGPS use because claim 11 identifies lonafarnib and claim 12 tracks the approved dose threshold. Its strength is lower for broader FTI research programs because the patent does not claim the FTI molecule itself and does not necessarily prevent non-HGPS uses.

Strengths

• Direct coverage of lonafarnib treatment.
• Direct alignment with the approved HGPS regimen.
• Coverage of disease progression and symptom reduction.
• Coverage of multiple FTI compounds.
• Combination-treatment claims.
• No requirement for a particular formulation in the principal claims.
• Potential application to both pediatric and adult HGPS patients if the disease and treatment limitations are met.

Vulnerabilities

• The broadest claims depend on the legal meaning of “clinical symptom” and “therapeutically effective dose.”
• The FTI class is broad relative to the named compounds.
• The disease limitation may restrict application to HGPS rather than all progeroid laminopathies.
• Dose claims using concentration units may face written-description, enablement, or claim-construction challenges.
• A later entrant could pursue a non-infringing indication, formulation, dosing schedule, or patient population if the approved use and patent claims permit it.
• A Paragraph IV challenger could contest anticipation, obviousness, written description, enablement, or indefiniteness.

The patent does not claim lonafarnib as a composition of matter. That distinction generally makes the estate less resistant to invalidity challenges than a new-molecule patent, but it can still provide substantial blocking power for the patented clinical use.

What patent litigation and Paragraph IV risks affect Zokinvy?

The key generic-entry risk is a method-of-use challenge directed to the HGPS indication. A potential ANDA filer could assert that:

1. The claims are invalid over earlier FTI research or progeria-treatment disclosures.
2. The patent does not adequately support the full breadth of the claimed FTI class, dose ranges, or symptom categories.
3. The proposed label omits the patented use.
4. The proposed product does not induce infringement of the HGPS treatment claims.
5. The claims are indefinite or lack sufficient written description.

The most difficult claim for a challenger to avoid may be claim 11 combined with claim 12 if the proposed label includes lonafarnib for HGPS at or above 115 mg/m² twice daily. A label that omits HGPS and is limited to a nonpatented indication would present a stronger noninfringement position, although FDA use-code treatment and induced-infringement principles would remain relevant.

No litigation result can be inferred from the claim text alone. Patent litigation status must be determined from federal court dockets, ANDA notices, USPTO records, and FDA listing information.

How does US 8,828,356 compare with the Zokinvy product position?

Issue	US 8,828,356	Zokinvy
Legal right	Patent claims	FDA-approved product
Active ingredient	Any FTI in claim 1; lonafarnib in claim 11	Lonafarnib
Disease	HGPS	HGPS and specified progeroid laminopathies
Outcome	Symptom reduction or progression control	Mortality-risk reduction
Dose	Multiple ranges; claim 12 at least 115 mg/m² BID	Label-specific BSA dosing
Formulation	Not expressly limited in core claims	Oral capsules
Exclusivity	Patent term	Orphan-drug exclusivity and any listed patents
Commercial use	Potentially broader than label for HGPS symptoms	Limited by FDA-approved indication and labeling

What manufacturing and geographic barriers remain?

US 8,828,356 is a US method patent. It does not, by itself, establish patent protection in Europe, Japan, China, Canada, or other jurisdictions. Geographic protection must be assessed family-by-family.

The patent also does not necessarily block:

• Manufacture of lonafarnib for non-HGPS uses.
• Export of product from the US for an unprotected foreign market.
• Research use outside commercial treatment.
• A formulation or process patent held by another party.
• A noninfringing label that omits HGPS, subject to induced-infringement analysis.

Manufacturing barriers may arise from separate composition, formulation, process, or impurity-control patents. They may also arise from know-how, controlled supply chains, low-volume economics, and the limited patient population. Those commercial barriers are distinct from the claims of US 8,828,356.

Key Takeaways

• US 8,828,356 is a method-of-treatment patent for using FTIs to treat HGPS.
• Claim 1 is broad across FTI compounds, symptoms, doses, and treatment schedules.
• Claim 11 specifically covers lonafarnib, and claim 12 covers at least 115 mg/m² twice daily.
• The claims overlap materially with the FDA-approved Zokinvy treatment regimen.
• The patent does not claim lonafarnib as a chemical composition.
• The strongest commercial position is the combination of lonafarnib, HGPS, and the approved body-surface-area dosing regimen.
• Zokinvy received FDA approval on November 20, 2020, with seven years of orphan-drug exclusivity for the approved orphan indication.
• Generic risk would likely center on Paragraph IV validity challenges, section viii label carve-outs, and noninfringement arguments.
• Patent expiration must be determined from the USPTO term record, not the issuance date.
• US 8,828,356 does not establish foreign protection or block all non-HGPS uses of lonafarnib.

FAQs

Does US 8,828,356 cover tipifarnib for HGPS?

Potentially. Claim 5 names R115777, also known as tipifarnib, as an FTI covered by the patent when used in the claimed HGPS treatment method.

Does the patent cover treatment of mandibuloacral dysplasia?

Not expressly as a standalone disease. The central claims require a subject having HGPS. Coverage of another progeroid laminopathy would depend on claim construction, the factual diagnosis, and whether the disease falls within the claimed HGPS limitation.

Can a generic company sell lonafarnib for cancer without infringing this patent?

Possibly. The patent claims treatment of HGPS, not all uses of lonafarnib. A cancer-only product and label would require separate analysis of the proposed label, marketing conduct, and induced-infringement risk.

Is claim 12 limited to pediatric patients?

No express age limitation appears in claim 12. The claim requires lonafarnib treatment at a dose of at least 115 mg/m² twice daily in a subject covered by the underlying claims.

Does the patent protect the Zokinvy capsule formulation?

Not through the claims provided. The claims focus on the therapeutic method, active FTI, disease, symptom or progression outcome, and dose. A separate formulation patent would be required for specific capsule composition or delivery-system protection.

References

1. Food and Drug Administration. (2020, November 20). FDA approves first treatment for Hutchinson-Gilford Progeria Syndrome and some progeroid laminopathies. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-hutchinson-gilford-progeria-syndrome-and-some-progeroid

2. Food and Drug Administration. (2020). Zokinvy (lonafarnib) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213969s000lbl.pdf

3. United States Patent and Trademark Office. (2014). U.S. Patent No. 8,828,356, Methods of treating Hutchinson-Guilford Progeria Syndrome. https://patents.google.com/patent/US8828356

4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/

5. United States Code. (2023). 35 U.S.C. §§ 154, 271, and 282. https://uscode.house.gov/աթիվ

Drugs Protected by US Patent 8,828,356

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 8,828,356

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	547536
Australia	2003301446
Canada	2501464
European Patent Office	1552020
European Patent Office	1853265
Japan	2006507845