Details for Patent: 8,222,222

Which drugs does patent 8,222,222 protect, and when does it expire?

Patent 8,222,222 protects LEQVIO and is included in one NDA.

This patent has forty-two patent family members in fourteen countries.

Summary for Patent: 8,222,222

Title:	Compositions and methods for inhibiting expression of the PCSK9 gene
Abstract:	The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of the PCSK9 gene (PCSK9 gene), comprising an antisense strand having a nucleotide sequence which is less that 30 nucleotides in length, generally 19-25 nucleotides in length, and which is substantially complementary to at least a part of the PCSK9 gene. The invention also relates to a pharmaceutical composition comprising the dsRNA together with a pharmaceutically acceptable carrier; methods for treating diseases caused by PCSK9 gene expression and the expression of the PCSK9 gene using the pharmaceutical composition; and methods for inhibiting expression of a PCSK9 gene in a cell.
Inventor(s):	Pamela Tan, Birgit Bramlage, Maria Frank-Kamenetsky, Kevin Fitzgerald, Akin Akinc, Victor E. Kotelianski
Assignee:	Alnylam Pharmaceuticals Inc
Application Number:	US12/554,231
Patent Claim Types: see list of patent claims	Use;

United States Patent 8,222,222: PCSK9 siRNA Claims, Scope, Expiration, and Competitive Patent Landscape

US 8,222,222 is an Alnylam patent directed to suppressing PCSK9 expression with double-stranded RNA. Its broadest claims cover PCSK9-targeting siRNA methods using an antisense strand containing at least 15 contiguous nucleotides of SEQ ID NO:1228. Narrower claims require the full SEQ ID NO:1227/1228 duplex, defined chemical modifications, lipid formulation, or LNP-01 formulation. The patent is potentially relevant to PCSK9 siRNA products, including products using the claimed target sequence, but it does not cover PCSK9 antibodies such as Repatha or Praluent.

The patent’s expected 20-year term runs from the relevant nonprovisional filing date and is generally expected to expire on or about May 1, 2029, subject to any patent-term adjustment or terminal-disclaimer data recorded by the USPTO.[1]

What does US Patent 8,222,222 protect?

US 8,222,222 protects methods of inhibiting PCSK9 gene expression and treating PCSK9-associated disorders with a specified class of siRNA molecules.[1]

Claim group	Subject matter	Principal limitation
Claims 1-14	PCSK9 gene-expression inhibition	Cell contacted with dsRNA; antisense strand includes at least 15 contiguous nucleotides of SEQ ID NO:1228
Claims 2-5	In vitro and in vivo activity	HepG2 inhibition of at least 20%; animal treatment resulting in lower total serum cholesterol
Claims 6-8	Defined sequence duplex	Sense SEQ ID NO:1227 and antisense SEQ ID NO:1228
Claims 9-12	Chemical modification	2'-O-methyl, phosphorothioate, 2'-fluoro, locked, morpholino, phosphoramidate and other modified nucleotides
Claims 13-14	Formulation	Lipid formulation or LNP-01
Claims 15-20	Treatment methods	Administration to treat or manage pathological processes or PCSK9-associated disorders
Claims 21-23	Specifically modified duplex	SEQ ID NO:1229 sense strand and SEQ ID NO:1230 antisense strand
Claims 24-27	Formulation-dependent treatment	Lipid formulation or LNP-01

The patent is a method patent. It does not principally claim a composition of matter in isolation. A commercial product could avoid direct literal infringement of a composition claim because the patent’s asserted claims require use, administration, expression inhibition, or treatment. Commercial manufacture and sale could still create infringement exposure through induced or contributory infringement theories if the product is supplied for a claimed use.

How broad is claim 1 of US 8,222,222?

Claim 1 has a broad sequence-based scope, but it is limited by functional and structural requirements.

The accused method must include:

1. A cell.
2. Contact with a double-stranded RNA.
3. A sense strand and an antisense strand.
4. An antisense strand containing at least 15 contiguous nucleotides of SEQ ID NO:1228.
5. Maintenance of the cell for sufficient time to produce degradation of PCSK9 mRNA.
6. Resulting inhibition of PCSK9 expression.

The phrase “comprising at least 15 contiguous nucleotides” creates a substantial sequence genus. It can cover antisense strands longer than 15 nucleotides and duplexes that contain additional nucleotides, chemical modifications, overhangs, or other structural elements, provided the claimed sequence relationship and functional requirements are satisfied.

The claim does not require:

• A particular dose.
• A particular route of administration.
• A particular cell type.
• A particular disease.
• A particular delivery vehicle.
• A particular cholesterol reduction threshold.
• LNP-01 formulation.
• The complete SEQ ID NO:1228 sequence.

The functional requirement for degradation of the PCSK9 mRNA is important. A sequence that contains 15 contiguous nucleotides but does not produce the claimed PCSK9 mRNA degradation may present a non-infringement position. That position would depend on claim construction, laboratory evidence, and the accused product’s actual mechanism.

Why the 15-nucleotide limitation matters

A 15-nucleotide contiguous match is materially broader than a full-length 20- or 21-nucleotide siRNA match. It can reach sequence variants and modified duplexes that preserve a core region of the claimed antisense sequence.

The breadth is constrained by the requirement that the sequence function in a dsRNA method directed to PCSK9. The claim is therefore broader than a claim limited to one exact siRNA, but narrower than a claim covering every PCSK9-targeting oligonucleotide.

What do claims 6 through 12 add?

Claims 6-8 narrow the invention to the named duplex:

• Sense strand: SEQ ID NO:1227.
• Antisense strand: SEQ ID NO:1228.

The progression is:

• Claim 6: each strand comprises the relevant sequence.
• Claim 7: each strand comprises the relevant sequence in the claimed duplex.
• Claim 8: each strand consists of the exact sequence.

Claims 9-12 address chemical modifications. The listed modifications include:

• 2'-O-methyl ribonucleotides.
• 5'-phosphorothioate groups.
• 2'-deoxy-2'-fluoro nucleotides.
• Locked nucleotides.
• Abasic nucleotides.
• 2'-amino and 2'-alkyl modifications.
• Morpholino nucleotides.
• Phosphoramidates.
• Non-natural bases.
• Cholesteryl derivatives.
• Dodecanoic acid bisdecylamide groups.

Claim 12 specifically requires both at least one 2'-O-methyl modification and at least one nucleotide with a 5'-phosphorothioate group.

These claims are commercially relevant because therapeutic siRNAs commonly use chemical modifications to increase nuclease stability, reduce immune activation, improve pharmacokinetics, and control strand selection. A product using the exact duplex but a different modification pattern may fall outside claims 10-12 while remaining potentially relevant to claims 1, 6, 7, 15, or 16.

What sequences are claimed in claims 21 through 23?

Claims 21-23 identify a specific chemically modified duplex:

Strand	Sequence as stated in the claims
Sense	5'-uucuAGAccuGuuuuGcuuTsT-3'
Antisense	5'-AAGcAAAAcAGGUCuAGAATsT-3'

The patent identifies lower-case “c” and “u” positions as 2'-O-methyl ribonucleotides and lower-case “s” as phosphorothioate linkages or positions, depending on the patent’s sequence notation.[1]

These claims are narrower than claim 1 because they require the exact modified strand architecture. They can be important in litigation because a plaintiff may assert an exact-sequence claim when the accused product uses the named duplex, while a defendant may challenge whether the product’s chemical configuration corresponds precisely to the patent’s notation.

Claims 21, 22, and 23 cover:

• PCSK9 expression inhibition.
• Treatment or management of pathological processes.
• Treatment of a PCSK9-associated disorder.

Do the claims cover lipid nanoparticles and LNP-01?

Yes. Claims 13, 14, and 24-27 expressly recite lipid formulation or LNP-01 lipid formulation.

The formulation claims are dependent claims. They require the underlying sequence and method limitations of the claims from which they depend. They do not independently cover every LNP containing every PCSK9 siRNA.

LNP-01 is a formulation designation used in the patent family. The scope of the LNP-01 claims depends on how the term is construed from the specification, including its lipid components, ratios, particle characteristics, and preparation methods. A formulation using a different lipid system may avoid the LNP-01 limitation while still implicating broader sequence or treatment claims.

The presence of a formulation limitation also creates a potential design-around path. A company could use:

• GalNAc conjugation.
• A different lipid nanoparticle.
• A polymeric delivery system.
• An antibody-oligonucleotide conjugate.
• A formulation that does not meet the technical definition of LNP-01.

Avoiding the LNP-01 claims would not necessarily avoid claims 1 or 15-20.

When does US 8,222,222 lose exclusivity?

The patent is generally expected to expire around May 1, 2029, based on the relevant nonprovisional filing date.[1]

Milestone	Date or status
Earliest priority period	2008-era priority chain identified for the PCSK9 siRNA invention
Nonprovisional filing	Approximately May 1, 2009
US publication	Published application corresponding to the issued patent
Grant	July 17, 2012
Expected base expiration	Approximately May 1, 2029
Patent-term adjustment	Must be confirmed in the USPTO Patent Center record
Patent-term extension	No extension should be assumed without a recorded regulatory term-extension order

The patent’s term is not calculated from the issue date. The 2012 grant date does not provide a new 20-year period.

The expected expiration date should be separated from regulatory exclusivity. A patent may remain enforceable after FDA exclusivity ends, and an FDA product may retain regulatory exclusivity after an individual patent expires.

What is the Orange Book status of this patent?

US 8,222,222 is not itself an FDA exclusivity period. Orange Book treatment depends on whether the patent is listed for a particular approved drug application and whether the patent meets FDA listing requirements.[2]

Inclisiran, marketed as Leqvio, was approved by FDA under NDA 214012 in December 2021.[3] Leqvio is an siRNA product, but its regulatory listing position must be assessed separately from the patent’s ownership and technical scope.

The key regulatory distinctions are:

• Orange Book listing attaches to an approved NDA and specific drug product.
• Patent issuance does not automatically create an Orange Book listing.
• A patent can be relevant to an approved product without being listed.
• Unlisted patent rights may still support infringement litigation.
• FDA approval does not resolve whether a product practices a patent claim.

The Orange Book inquiry for Leqvio should therefore focus on the current FDA patent-listing record for NDA 214012, not only on the face of US 8,222,222.[2,3]

Does US 8,222,222 create biosimilar risk?

No conventional biosimilar pathway applies to a chemically synthesized siRNA in the same manner as it applies to a therapeutic protein biologic.

Inclisiran is a synthetic double-stranded RNA medicine regulated through an NDA pathway. A competing PCSK9 siRNA would generally present a generic or hybrid regulatory strategy rather than a conventional biosimilar filing. The pathway would depend on product formulation, delivery chemistry, pharmacodynamic comparability, and FDA requirements.

The principal competitive risks are:

• A follow-on siRNA using the same or overlapping target sequence.
• A new siRNA with a non-overlapping PCSK9 sequence.
• A different conjugation or delivery platform.
• A PCSK9 antibody or alternative lipid-lowering mechanism.
• A product relying on non-infringement or invalidity positions against the patent estate.

Which companies compete with or challenge the PCSK9 patent landscape?

The competitive field divides into four categories.

Company or product	Modality	Relevance to US 8,222,222
Novartis, Leqvio/inclisiran	PCSK9 siRNA	Potentially relevant to sequence and treatment claims; marketed product uses a GalNAc delivery approach rather than the LNP-01 limitation
Amgen, Repatha/evolocumab	PCSK9 monoclonal antibody	Does not practice dsRNA claims
Regeneron and Sanofi, Praluent/alirocumab	PCSK9 monoclonal antibody	Does not practice dsRNA claims
Alnylam	Original PCSK9 siRNA developer and patent owner/licensor	Core originator of the relevant siRNA platform
Silence Therapeutics and other RNA companies	Investigational RNA therapeutics	May compete through different PCSK9 sequences or delivery systems

Alnylam licensed inclisiran-related rights to Novartis in 2019. The transaction transferred commercial development and commercialization responsibilities for inclisiran while Alnylam retained economic and intellectual-property interests under the agreement.[4]

How does Leqvio compare with the claimed subject matter?

Leqvio is the most commercially relevant comparator because it is an FDA-approved PCSK9-targeting siRNA.

Issue	US 8,222,222	Leqvio
Target	PCSK9	PCSK9
Modality	dsRNA/siRNA	Inclisiran siRNA
Claimed therapeutic effect	PCSK9 mRNA degradation and expression inhibition	PCSK9 expression reduction and LDL-C lowering
Exact sequence	SEQ ID NO:1227/1228 and related 15-nucleotide genus	Product-specific inclisiran sequence and chemical structure
Delivery	Broad claim 1 has no required delivery system; dependent claims recite lipid formulation or LNP-01	GalNAc-conjugated delivery system
Administration	In vivo administration claims	Subcutaneous administration
Regulatory status	Patent right	FDA-approved under NDA 214012

The critical freedom-to-operate question is whether inclisiran’s antisense strand contains at least 15 contiguous nucleotides of SEQ ID NO:1228 and whether the marketed treatment satisfies the remaining method limitations. If so, claims 1 and 15-20 could be more important than the LNP-01 claims, because those broader claims do not require LNP-01.

The GalNAc conjugate may avoid claims limited to lipid formulation or LNP-01. It does not automatically avoid the sequence and therapeutic-method claims.

What patent families surround US 8,222,222?

The patent should be evaluated as one member of a broader Alnylam PCSK9 and RNA-interference estate. The surrounding patent categories include:

PCSK9 target and sequence patents

These patents claim particular PCSK9 siRNA sequences, sequence families, or antisense regions. They may overlap with the 15-nucleotide genus in US 8,222,222 or cover different PCSK9 regions.

Chemical modification patents

These patents address 2'-O-methyl, 2'-fluoro, phosphorothioate, terminal conjugation, and other modifications. They can create separate infringement exposure even when a product avoids the exact sequence claims.

GalNAc conjugate patents

Inclisiran uses targeted delivery chemistry distinct from LNP-01. GalNAc conjugation, linker structures, and hepatocyte-targeting methods may be protected by separate patent families.

Lipid nanoparticle patents

LNP composition, ionizable lipids, helper lipids, cholesterol, PEG-lipids, particle size, encapsulation methods, and manufacturing processes can create additional barriers.

Method-of-use patents

Separate patents may cover PCSK9 suppression for hypercholesterolemia, cardiovascular-risk reduction, statin-intolerant patients, familial hypercholesterolemia, or dosing schedules.

A complete freedom-to-operate review therefore cannot rely on US 8,222,222 alone. The highest-risk product attributes are the exact antisense sequence, the therapeutic use, and the delivery chemistry.

What Paragraph IV challenges or patent litigation affect this patent?

A Paragraph IV certification would be relevant only if a generic applicant filed an ANDA referencing an NDA for a product to which the patent was listed. A 505(b)(2) applicant could also create patent-certification issues depending on the reference product and proposed labeling.

No Paragraph IV challenge or district-court litigation involving US 8,222,222 is identified in the cited public records. The absence of a reported challenge does not eliminate future litigation risk before patent expiry.

For Leqvio, the commercial pathway is more likely to involve:

• A patent-listing analysis for NDA 214012.
• A future generic or 505(b)(2) filing.
• Declaratory-judgment litigation.
• Contractual enforcement under the Alnylam-Novartis license.
• Separate challenges to composition, conjugate, formulation, or use patents.

Patent litigation risk should be ranked by claim category:

Risk area	Relative exposure
Exact claimed PCSK9 duplex	High if product sequence matches
15-nucleotide antisense genus	Potentially high, subject to sequence and functional proof
LNP-01 formulation	Lower for GalNAc products; higher for matching LNP systems
PCSK9 antibody products	Low under this patent
Non-overlapping PCSK9 siRNA	Lower under this patent, subject to other families
Treatment of hypercholesterolemia	Potentially high if sequence limitations are met

How strong is the patent estate for commercial enforcement?

US 8,222,222 has several characteristics that support enforcement:

• A broad 15-contiguous-nucleotide sequence limitation.
• Separate exact-sequence claims.
• In vitro and in vivo claims.
• Treatment claims.
• Chemical-modification claims.
• Formulation-dependent claims.
• PCSK9-specific therapeutic relevance.

Its principal weaknesses are structural:

• The claims are method claims rather than a standalone composition claim.
• The broad claims require functional PCSK9 mRNA degradation or expression inhibition.
• LNP-01 claims may not reach GalNAc-conjugated products.
• The patent approaches its expected 2029 expiration.
• A defendant may challenge written description, enablement, definiteness, anticipation, obviousness, or claim construction.
• A competing product may use a different PCSK9 sequence.

The strongest enforcement theory would generally involve a product using the exact or substantially overlapping antisense sequence for PCSK9 suppression in patients. The weakest theory would involve a PCSK9 antibody or a siRNA using a remote target site and a non-lipid delivery system.

What generic launch scenarios exist after patent expiration?

Three principal launch scenarios exist.

Exact-sequence siRNA launch

A competitor uses the same or overlapping siRNA sequence and challenges listed patents through Paragraph IV or a related regulatory route. This presents the highest litigation exposure but may provide the closest product to the reference drug.

Non-overlapping siRNA launch

A competitor uses a different PCSK9 target sequence. This can avoid US 8,222,222 but may encounter other sequence, chemistry, conjugate, formulation, and use patents.

Alternative modality launch

A competitor uses a PCSK9 antibody, gene-editing approach, antisense oligonucleotide, or another lipid-lowering mechanism. Such a product is outside the literal dsRNA claims but competes commercially with Leqvio.

The practical launch date will depend on the full patent estate, FDA exclusivity, regulatory pathway, litigation duration, settlement terms, and any patent-term adjustment. Expiration of US 8,222,222 alone would not guarantee market entry.

What manufacturing and geographic IP barriers remain?

Manufacturing exposure can remain after sequence claims are cleared. Relevant manufacturing rights include:

• Synthesis of modified RNA strands.
• Duplex annealing and purification.
• Lipid or conjugate attachment.
• LNP encapsulation.
• GalNAc-linker coupling.
• Particle-size control.
• Sterile injectable production.
• Analytical release testing.
• Scale-up and impurity removal.

Geographic coverage must be reviewed country by country. US 8,222,222 has no direct legal effect outside the United States. Foreign counterparts, national-phase patents, continuations, divisionals, and country-specific term adjustments may produce different expiration dates and claim scopes.

Key Takeaways

• US 8,222,222 covers PCSK9 suppression methods using dsRNA with an antisense strand containing at least 15 contiguous nucleotides of SEQ ID NO:1228.
• Claims 6-8 narrow the scope to the SEQ ID NO:1227/1228 duplex.
• Claims 21-23 cover specifically modified versions identified as SEQ ID NO:1229 and SEQ ID NO:1230.
• Claims 13, 14, and 24-27 address lipid and LNP-01 formulations.
• The patent does not cover PCSK9 monoclonal antibodies such as Repatha or Praluent.
• Leqvio is the most relevant commercial comparator because it is an FDA-approved PCSK9 siRNA.
• Leqvio’s GalNAc delivery system may avoid LNP-01-specific claims but does not automatically avoid broader sequence and treatment claims.
• The expected base expiration is around May 1, 2029, subject to USPTO term adjustments.
• No Paragraph IV challenge or litigation involving this patent is identified in the cited sources.
• A complete freedom-to-operate analysis requires review of related sequence, chemical-modification, conjugate, formulation, manufacturing, and method-of-use families.

FAQs About US Patent 8,222,222

Does US 8,222,222 cover inclisiran?

It may, depending on whether inclisiran’s antisense strand contains at least 15 contiguous nucleotides of SEQ ID NO:1228 and whether the product’s use satisfies the remaining claim limitations. The LNP-01 claims are less likely to apply to a GalNAc-conjugated product.

Is US 8,222,222 a composition-of-matter patent?

No. The supplied claims are directed primarily to methods of using specified dsRNA molecules to inhibit PCSK9 expression or treat PCSK9-associated disorders.

Can a different PCSK9 siRNA avoid this patent?

Potentially. A non-overlapping target sequence may avoid the sequence limitations, but separate PCSK9 siRNA, chemical-modification, conjugate, formulation, manufacturing, and method-of-use patents may still apply.

Does the patent block PCSK9 antibody products?

No. The claims require double-stranded RNA. Monoclonal antibodies that bind PCSK9 do not fall within the literal scope of these claims.

What is the most important claim for a competing PCSK9 siRNA?

Claim 1 is the principal broad claim because it covers an antisense strand containing at least 15 contiguous nucleotides of SEQ ID NO:1228. Claims 15 and 16 are the principal therapeutic-use claims.

References

1. United States Patent No. 8,222,222. (2012). Methods and compositions for inhibiting expression of a PCSK9 gene. United States Patent and Trademark Office.

2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

3. U.S. Food and Drug Administration. (2021). Leqvio (inclisiran) prescribing information, NDA 214012. FDA.

4. Novartis AG. (2019). Annual report 2019. Novartis.

Drugs Protected by US Patent 8,222,222

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Novartis	LEQVIO	inclisiran sodium	SOLUTION;SUBCUTANEOUS	214012-001	Dec 22, 2021		RX	Yes	Yes	8,222,222					AS AN ADJUNCT TO DIET AND EXERCISE FOR THE TREATMENT OF ADULTS WITH HYPERCHOLESTEROLEMIA, INCLUDING HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HEFH), BY INHIBITING EXPRESSION OF THE PCSK9 GENE
Novartis	LEQVIO	inclisiran sodium	SOLUTION;SUBCUTANEOUS	214012-001	Dec 22, 2021		RX	Yes	Yes	8,222,222					AS AN ADJUNCT TO DIET AND EXERCISE FOR THE TREATMENT OF PEDIATRIC PATIENTS AGED 12 YEARS AND OLDER WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HEFH) BY INHIBITING EXPRESSION OF THE PCSK9 GENE
Novartis	LEQVIO	inclisiran sodium	SOLUTION;SUBCUTANEOUS	214012-001	Dec 22, 2021		RX	Yes	Yes	8,222,222					AS AN ADJUNCT TO DIET AND EXERCISE FOR THE TREATMENT OF PEDIATRIC PATIENTS AGED 12 YEARS AND OLDER WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HOFH), BY INHIBITING EXPRESSION OF THE PCSK9 GENE

International Family Members for US Patent 8,222,222

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2007249329
Australia	2010241357
Australia	2012261570
Australia	2016203687