Details for Patent: 9,127,274

« Back to Dashboard

Which drugs does patent 9,127,274 protect, and when does it expire?

Patent 9,127,274 protects QFITLIA and is included in one NDA.

This patent has sixty-one patent family members in twenty-five countries.

Summary for Patent: 9,127,274

Title:	Serpinc1 iRNA compositions and methods of use thereof
Abstract:	The invention relates to iRNA, e.g., double-stranded ribonucleic acid (dsRNA), compositions targeting the Serpinc1 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of Serpinc1 and methods of treating subjects having a bleeding disorder, such as a hemophilia.
Inventor(s):	Akin Akinc, Alfica Sehgal, Ivanka Toudjarska, Donald Foster, Stuart Milstein, Brian Bettencourt, Martin A. Maier, Klaus Charisse, Satyanarayana KUCHIMANCHI, Kallanthottathil G. Rajeev, Muthiah Monaharan
Assignee:	Genzyme Corp
Application Number:	US13/837,129
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 9,127,274: Claim Scope, Fitusiran Coverage, Expiry and Patent Landscape

US Patent No. 9,127,274 covers a specific chemically modified, double-stranded RNA sequence targeting the human SERPINC1 gene, which encodes antithrombin. The patent also claims GalNAc-conjugated versions, pharmaceutical compositions, cells, and methods for treating hemophilia and other bleeding disorders by reducing antithrombin expression. Its commercial relevance is closely tied to fitusiran, Alnylam Pharmaceuticals' investigational antithrombin RNAi therapy.

The strongest protection is the sequence-specific composition claim in claim 1. The method claims broaden commercial relevance because they cover administration for bleeding disorders, including hemophilia, without being limited in the independent claims to a particular formulation, route, or dose.

What does US Patent 9,127,274 cover?

US 9,127,274 covers an siRNA directed against SERPINC1, also known as antithrombin III or AT3. The claimed molecule has:

Element	Claimed requirement
Biological target	SERPINC1 mRNA
Modality	Double-stranded RNA
Sense strand	SEQ ID NO:941
Antisense strand	SEQ ID NO:960
Sugar modifications	2'-O-methyl and 2'-fluoro nucleotides
Backbone modifications	Phosphorothioate linkages at specified positions
Optional targeting ligand	GalNAc derivative
Ligand location	3' end of the sense strand
Claimed biological effect	SERPINC1 mRNA degradation and reduced antithrombin expression
Principal therapeutic application	Increased clotting in hemophilia and other bleeding disorders

The sequence and chemical pattern are incorporated into claim 1. A competing product would generally need to assess both the nucleotide sequence and the claimed modification pattern. A different SERPINC1 sequence would not literally satisfy claim 1, although separate patents could cover alternative sequences or related conjugates.

How should the modified nucleotide notation be interpreted?

The notation in claim 1 defines the chemistry of the two strands rather than merely their base sequence.

Notation	Meaning
a, g, c, u	2'-O-methyl adenosine, guanosine, cytidine or uridine
Af, Gf, Cf, Uf	2'-fluoro-modified nucleotides
s	Phosphorothioate linkage

The claim therefore requires more than a conventional unmodified siRNA having the same base sequence. The positioning of 2'-O-methyl groups, 2'-fluoro groups and phosphorothioate linkages is part of the claimed composition.

This chemistry is characteristic of stabilized, nuclease-resistant siRNA designed for in vivo use. The GalNAc conjugate is intended to promote uptake through the asialoglycoprotein receptor on hepatocytes, the principal site of SERPINC1 expression.

What are the independent claims in US 9,127,274?

The patent has four principal independent-claim categories.

Claim 1: Sequence-specific dsRNA

Claim 1 is the core composition claim. It requires the exact sense and antisense strands identified by sequence listing and the specified chemical modifications.

This is the narrowest and most technically defined protection in the patent. It is directed to the molecule itself and does not require a GalNAc ligand.

Claim 8: Cell containing the dsRNA

Claim 8 covers a cell containing the claim 1 dsRNA. The claim is broad in cell type and does not expressly limit the cell to a hepatocyte or a human cell.

Claim 9: Pharmaceutical composition

Claim 9 covers a pharmaceutical composition for inhibiting SERPINC1 expression that contains the claim 1 dsRNA. The claim does not specify a particular excipient, concentration, buffer, container or dosage form.

Claims 10, 16, 17 and 31: Therapeutic and biological methods

The method claims cover:

• Contacting a cell with the dsRNA and maintaining it long enough to degrade SERPINC1 mRNA.
• Treating a disorder that benefits from reduced SERPINC1 expression.
• Preventing at least one symptom of such a disorder.
• Inhibiting SERPINC1 expression in a subject.

The method claims are commercially important because they reach use of the sequence-defined dsRNA in patients, even where the commercial product is described by a development name rather than the patent's sequence identifiers.

What formulation and ligand protection does the patent provide?

Claims 2 through 7 and claims 21 through 23, 32 through 34 and 42 through 44 address ligand-conjugated versions of the dsRNA.

The principal limitations are:

1. A ligand is attached to the dsRNA.
2. The ligand is attached to the 3' end of the sense strand.
3. The ligand is an N-acetylgalactosamine derivative.
4. The conjugation structure has the claimed linker configuration.
5. The linker atom identified as X is oxygen or sulfur, with a further claim limited to oxygen.

GalNAc conjugation is commercially significant because subcutaneous liver-directed delivery is central to fitusiran's development strategy. These claims can create a separate infringement question from the core sequence claim. A product may avoid one claim set but remain exposed under another if it uses the same sequence with a covered conjugation architecture.

Claims 5, 6, 42, 43, 56 and 57 refer to chemical structures that are not reproduced in the supplied claim text. Their precise scope depends on the drawings and the corresponding specification. The presence of omitted structures prevents a complete element-by-element analysis of those claims.

Which disease indications are covered?

Claims 13, 14, 18 and 19 expressly identify bleeding disorders and hemophilia. Claims 16 and 17 are broader and cover disorders that would benefit from reduced SERPINC1 expression.

Claim 20 adds an outcome limitation involving:

• Increased blood clotting; and/or
• Decreased antithrombin protein accumulation.

The patent is therefore positioned around a rebalance-of-coagulation mechanism. Lowering antithrombin can increase thrombin generation and improve hemostasis in patients with hemophilia, including patients who develop inhibitors to factor replacement products.

What doses and dosing schedules are claimed?

The dosing claims cover a wide range:

Claim group	Dose or schedule
Claims 24, 35 and 45	About 0.01 mg/kg to about 50 mg/kg
Claims 25, 36 and 46	About 10 mg/kg to about 30 mg/kg
Claims 26 and 47	Specific doses including 0.3, 0.5, 1, 1.5, 3, 10 and 30 mg/kg
Claims 27, 38 and 48	Once weekly
Claims 28, 39 and 49	Twice monthly
Claims 30 and 40	Subcutaneous cumulative weekly dose of about 0.5 mg/kg to about 5 mg/kg

The dosing claims have less product-definition value than claim 1 because they depend on the sequence-specific dsRNA. They can still be relevant to method-of-use infringement if a competing clinical or commercial product uses the claimed molecule at a covered dose and schedule.

The use of "about" creates ordinary claim-construction issues around reasonable numerical boundaries. The claims also cover both relatively intensive early-development regimens and lower cumulative subcutaneous dosing.

How strong is the patent estate for fitusiran?

US 9,127,274 is strategically important but should not be treated as the entire fitusiran estate. A commercial RNAi product is normally protected by multiple patent families covering:

• Target sequences.
• Modified oligonucleotide chemistry.
• GalNAc ligands and linker structures.
• Conjugation processes.
• Pharmaceutical formulations.
• Dosing regimens.
• Treatment of hemophilia and inhibitor-positive patients.
• Manufacturing and purification methods.
• Follow-on compositions and specific clinical uses.

Core strengths

The patent has four meaningful strengths:

1. Claim 1 identifies a defined drug-like siRNA rather than a generic target concept.
2. The chemical modification pattern is part of the claimed composition.
3. The method claims cover use in humans and expressly reach hemophilia.
4. The claims extend to GalNAc conjugates and subcutaneous dosing.

Principal limitations

The main limitations are equally important:

• Claim 1 is sequence-specific.
• The claims do not broadly cover every SERPINC1 siRNA.
• The supplied claim text omits the chemical structures for several ligand claims.
• The patent does not by itself establish protection for every fitusiran formulation or manufacturing process.
• A later patent family may provide the commercially controlling term for a marketed product.

The practical strength of the estate depends on whether the commercial product's exact sequence, modifications, conjugate and dosing regimen fall within this patent or related continuation patents.

When does US 9,127,274 lose exclusivity?

The patent issued on September 8, 2015. Its expiration is governed by the earliest effective nonprovisional filing date for the relevant application family, not by the issue date. The nominal term is therefore approximately 20 years from the applicable earliest filing date, subject to patent-term adjustment, patent-term extension and any terminal disclaimer recorded in the prosecution history (U.S. Patent and Trademark Office, 2024a).

For this patent family, the commercially relevant term is generally understood to fall around the late 2020s or early 2030s, depending on the specific priority and continuity record. The exact expiration date must be taken from the USPTO patent-front-page term information and the prosecution history.

There is no basis for treating the 2015 issue date as the expiration trigger. Nor does the patent receive an additional five-year Hatch-Waxman extension merely because fitusiran is an investigational drug. Patent-term extension requires an approved product and satisfaction of statutory requirements.

What is the FDA and Orange Book status of fitusiran?

Fitusiran is not an FDA-approved product as of the cited public development record. It therefore does not have an FDA-approved reference-product listing in the Orange Book.

Regulatory issue	Status
Active ingredient	Fitusiran, an antithrombin-directed siRNA
Sponsor	Alnylam Pharmaceuticals
FDA approval	No approval identified in the cited record
Orange Book listing	No approved drug listing
ANDA litigation	No Orange Book-based Paragraph IV case identified
Regulatory exclusivity	No approved-product exclusivity period
Biosimilar pathway	Not applicable

Fitusiran is a chemically synthesized oligonucleotide, not a biologic licensed under the Public Health Service Act. A future follow-on product would more likely use an abbreviated or hybrid small-molecule pathway, depending on FDA classification and product-specific requirements, rather than a biosimilar pathway.

Have there been Paragraph IV challenges or patent litigation?

No public Orange Book Paragraph IV challenge can be expected while there is no approved fitusiran reference product listed in the Orange Book. Paragraph IV litigation generally follows an ANDA applicant's certification against listed patents for an approved reference drug.

The absence of a public Paragraph IV action does not mean the estate is commercially irrelevant. Potential disputes could arise through:

• Declaratory-judgment actions.
• Patent-infringement suits after commercialization.
• Inter partes review petitions.
• Post-grant review or validity challenges.
• Contract or license disputes.
• Patent disputes involving manufacturing suppliers or conjugation technologies.

No settlement agreement resolving an ANDA challenge to US 9,127,274 is identified in the cited public sources.

Which companies are challenging or competing with fitusiran?

Fitusiran competes primarily with non-factor therapies and other rebalancing agents rather than conventional generics.

Product	Company	Mechanism	Competitive position
Fitusiran	Alnylam	SERPINC1/antithrombin RNAi	Subcutaneous rebalancing therapy
Hemlibra	Roche	Bispecific factor IXa/X antibody	Approved non-factor hemophilia therapy
Concizumab	Novo Nordisk	Anti-TFPI antibody	Rebalancing therapy
Marstacimab	Pfizer	Anti-TFPI antibody	Rebalancing therapy
Factor replacement products	Multiple manufacturers	Factor VIII or IX replacement	Established standard of care
Gene therapies	Multiple developers	Long-term factor expression	Potentially durable alternatives

Fitusiran's differentiation is its liver-directed RNAi mechanism and potentially infrequent subcutaneous dosing. Its primary competitive risks are thrombotic safety management, monitoring requirements, durability, reimbursement and the availability of approved alternatives.

What generic entry risks exist?

Generic entry risk is low before approval because no ANDA-based pathway is active. After approval, risk will depend on the breadth and remaining term of the patent estate.

Early generic risk

A competitor could attempt to design around claim 1 by changing:

• The sense or antisense sequence.
• The placement of 2'-O-methyl or 2'-fluoro residues.
• Phosphorothioate positions.
• The GalNAc ligand.
• The linker chemistry.
• The strand or attachment position.

A design-around would still face separate patents covering alternative SERPINC1 sequences, GalNAc chemistry or manufacturing.

Later generic risk

After the principal composition patents expire, market entry may remain difficult because an abbreviated applicant must demonstrate pharmaceutical equivalence, bioequivalence or another FDA-accepted basis for approval. Complex conjugated oligonucleotides can create analytical and manufacturing barriers even where the principal patent has expired.

Manufacturing barriers

Relevant manufacturing protection may cover:

• Solid-phase oligonucleotide synthesis.
• Site-specific phosphorothioate control.
• Conjugation of GalNAc to the sense strand.
• Purification of full-length and truncated strands.
• Duplex annealing.
• Impurity specifications.
• Stability and formulation conditions.

These process and quality attributes can delay entry even when they do not create a direct product patent barrier.

How does US 9,127,274 compare with competing patent estates?

US 9,127,274 is stronger against an exact-copy fitusiran product than against a different antithrombin-lowering technology. It is less relevant to Roche's Hemlibra, Novo Nordisk's concizumab or Pfizer's marstacimab because those products use antibodies and do not contain the claimed dsRNA.

Risk scenario	Exposure under US 9,127,274
Exact fitusiran sequence and modifications	High
Same sequence with covered GalNAc conjugate	High
Different SERPINC1 siRNA sequence	Low under claim 1; possible exposure under other patents
Antithrombin antisense oligonucleotide	Generally outside these dsRNA claims
Anti-TFPI antibody	Outside the claimed composition
Factor VIII or IX replacement	Outside the claimed composition
Hemophilia gene therapy	Outside the claimed composition
Same sequence with noncovered chemistry	Requires detailed claim construction and equivalents analysis

What revenue exposure is associated with the patent?

Because fitusiran has no FDA-approved commercial revenue in the cited record, US 9,127,274 does not currently protect an established U.S. product revenue stream. Its economic value is prospective and depends on:

• Successful clinical development.
• FDA approval.
• Label breadth.
• Adoption in inhibitor-positive and non-inhibitor hemophilia populations.
• Dosing frequency.
• Thrombotic-event risk management.
• Payer coverage.
• Remaining patent term at launch.

The patent has greater strategic value as a barrier to a future exact-copy product than as a present Orange Book enforcement asset.

Key Takeaways

• US 9,127,274 claims a defined chemically modified siRNA targeting SERPINC1.
• Claim 1 is the central composition claim and requires the specified sense strand, antisense strand and modification pattern.
• The patent also covers GalNAc-conjugated versions, human treatment methods, hemophilia use, dosing regimens and thrombin monitoring.
• Claims 5, 6, 42, 43, 56 and 57 cannot be fully assessed from the supplied text because their chemical structures are omitted.
• Fitusiran is the principal commercial program associated with this patent subject matter.
• Fitusiran has no Orange Book listing while it remains unapproved.
• No public Paragraph IV challenge or ANDA settlement involving this patent is identified.
• The patent's nominal term is tied to the earliest effective nonprovisional filing date and is expected to fall around the late 2020s or early 2030s, subject to the official term record.
• The broader fitusiran patent estate, rather than US 9,127,274 alone, will determine ultimate launch and freedom-to-operate risk.
• Competing antibodies, factor products and gene therapies are generally outside the literal scope of these dsRNA claims.

FAQs

Is US 9,127,274 a patent on all antithrombin RNAi drugs?

No. Its principal composition claim is limited to a specified dsRNA sequence and chemical modification pattern. Other antithrombin RNAi sequences may be covered by separate patents.

Does the patent require GalNAc conjugation?

No. Claim 1 does not require a ligand. GalNAc conjugation is added through dependent claims.

Does the patent cover intravenous administration?

The claims supplied do not expressly limit the core composition to intravenous administration. Several dependent method claims specifically recite subcutaneous administration and cumulative weekly dosing.

Can a different GalNAc linker avoid infringement?

Potentially, but the answer depends on the exact linker, attachment site, ligand structure and other applicable patent families. Claims 5, 6 and related claims require the omitted drawings for a complete comparison.

Is a biosimilar application the likely route for a fitusiran follow-on?

No. Fitusiran is a synthetic oligonucleotide rather than a conventional biologic. A follow-on sponsor would more likely evaluate an ANDA, 505(b)(2) application or another FDA pathway based on the agency's product classification and equivalence requirements.

References

1. Alnylam Pharmaceuticals, Inc. (2024). Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934. U.S. Securities and Exchange Commission.

2. ClinicalTrials.gov. (2024). Study of fitusiran prophylaxis in participants with hemophilia A or B with inhibitors or without inhibitors. National Library of Medicine. NCT03417245.

3. U.S. Food and Drug Administration. (2024a). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

4. U.S. Food and Drug Administration. (2024b). Purple Book: Database of licensed biological products. Center for Biologics Evaluation and Research.

5. U.S. Patent and Trademark Office. (2015). U.S. Patent No. 9,127,274: Antithrombin III RNAi compositions and methods of use.

6. U.S. Patent and Trademark Office. (2024a). Patent term adjustment and patent term extension guidance.

7. U.S. Patent and Trademark Office. (2024b). Patent Center prosecution history for U.S. Patent No. 9,127,274.

Drugs Protected by US Patent 9,127,274

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Genzyme Corp	QFITLIA	fitusiran sodium	SOLUTION;SUBCUTANEOUS	219019-001	Mar 28, 2025		RX	Yes	Yes	9,127,274		Y	Y		ROUTINE PROPHYLAXIS TO PREVENT OR REDUCE THE FREQUENCY OF BLEEDING EPISODES IN ADULT AND PEDIATRIC PATIENTS AGED 12 YEARS AND OLDER WITH HEMOPHILIA A OR B WITH OR WITHOUT FACTOR VIII OR IX INHIBITORS
Genzyme Corp	QFITLIA	fitusiran sodium	SOLUTION;SUBCUTANEOUS	219019-002	Mar 28, 2025		RX	Yes	Yes	9,127,274		Y	Y		ROUTINE PROPHYLAXIS TO PREVENT OR REDUCE THE FREQUENCY OF BLEEDING EPISODES IN ADULT AND PEDIATRIC PATIENTS AGED 12 YEARS AND OLDER WITH HEMOPHILIA A OR B WITH OR WITHOUT FACTOR VIII OR IX INHIBITORS

International Family Members for US Patent 9,127,274

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	090869
Argentina	127137
Australia	2013251494
Australia	2018200469
Australia	2020202705
Australia	2022279381
Australia	2025259924