DCT

1:21-cv-01015

Nippon Shinyaku Ltd v. Sarepta Therap Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:21-cv-01015, D. Del., 01/14/2022
  • Venue Allegations: Venue is alleged to be proper as Defendant is a Delaware corporation that resides in the District and has contractually consented to venue in the District.
  • Core Dispute: Plaintiff alleges that Defendant’s Duchenne Muscular Dystrophy drug, VYONDYS 53, infringes seven U.S. patents related to antisense oligonucleotide compositions, methods of use, and manufacturing processes for inducing skipping of exon 53 in the human dystrophin gene.
  • Technical Context: The technology concerns antisense oligonucleotides (ASOs), which are synthetic molecules designed to bind to specific RNA sequences to alter protein production, used here as a targeted therapy for the genetic disorder Duchenne Muscular Dystrophy (DMD).
  • Key Procedural History: The complaint notes that Defendant filed seven petitions for Inter Partes Review (IPR) at the Patent Trial and Appeal Board seeking to invalidate the patents-in-suit. Plaintiff alleges that these filings breach a Mutual Confidentiality Agreement (MCA) between the parties that designated the District of Delaware as the exclusive forum for patent validity challenges.

Case Timeline

Date Event
2010-09-01 Earliest Patent Priority Date (JP App. 2010-196032)
2017-07-18 U.S. Patent No. 9,708,361 Issues
2019-08-20 U.S. Patent No. 10,385,092 Issues
2019-09-10 U.S. Patent No. 10,407,461 Issues
2019-11-26 U.S. Patent No. 10,487,106 Issues
2019-12-12 FDA grants accelerated approval for VYONDYS 53
2020-05-12 U.S. Patent No. 10,647,741 Issues
2020-05-26 U.S. Patent No. 10,662,217 Issues
2020-06-16 U.S. Patent No. 10,683,322 Issues
2021-06-21 Defendant files seven IPR petitions against patents-in-suit
2022-01-14 Complaint Filing Date

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 9,708,361 - “Antisense Nucleic Acids”

The Invention Explained

  • Problem Addressed: The patent addresses the need for an effective therapy for Duchenne Muscular Dystrophy (DMD), a severe genetic disorder caused by mutations in the dystrophin gene (Compl. ¶27-28; ’361 Patent, col. 1:35-44). Specifically, it targets the subset of DMD patients whose condition can be treated by "skipping" exon 53 of the gene, noting that previous techniques for inducing this skipping lacked high efficiency ('361 Patent, col. 2:55-57).
  • The Patented Solution: The invention is an antisense oligomer designed to bind to a specific region of the pre-mRNA transcript of the human dystrophin gene. This binding interferes with the cellular splicing machinery, causing it to exclude, or "skip," exon 53 when assembling the final mRNA molecule (Compl. ¶34-35). This process restores the proper reading frame, allowing the patient's cells to produce a shortened but partially functional dystrophin protein, thereby converting the severe DMD phenotype to a milder form ('361 Patent, col. 2:15-27). The inventors identified a specific nucleotide sequence that induces this skipping with high efficiency ('361 Patent, col. 3:15-21).
  • Technical Importance: The technology provides a targeted molecular therapy for approximately 8% of all DMD patients for whom exon 53 skipping is a viable treatment strategy (Compl. ¶36).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶97).
  • Claim 1 requires:
    • An antisense oligomer
    • which causes skipping of the 53rd exon in the human dystrophin gene,
    • consisting of the nucleotide sequence of SEQ ID NO: 57,
    • wherein the antisense oligomer is an oligonucleotide in which the sugar moiety and/or the phosphate-binding region is modified, or a morpholino oligomer.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 10,385,092 - “Antisense Nucleic Acids”

The Invention Explained

  • Problem Addressed: As with its parent, the ’361 Patent, the ’092 Patent addresses the need for a highly efficient method of inducing exon 53 skipping to treat a specific subset of DMD patients ('092 Patent, col. 2:40-57).
  • The Patented Solution: The patent claims a specific type of antisense oligomer—a phosphorodiamidate morpholino oligomer (PMO)—of a precise length (25-mer) that is 100% complementary to a specific target site: the 36th to 60th nucleotides of the human dystrophin gene's 53rd exon ('092 Patent, col. 9:55-64, Abstract). This defined structure and target sequence are disclosed as enabling highly efficient exon skipping.
  • Technical Importance: This patent narrows the claimed invention to a specific chemical structure (PMO) and binding site, providing a more defined therapeutic agent for the relevant DMD patient population (Compl. ¶36).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶111).
  • Claim 1 requires:
    • A phosphorodiamidate morpholino oligomer (PMO) antisense oligomer
    • that causes skipping of the 53rd exon in a human dystrophin pre-mRNA,
    • consisting of a 25-mer oligomer
    • that is 100% complementary to the 36th to the 60th nucleotides from the 5' end of the 53rd exon,
    • wherein the PMO antisense oligomer hybridizes to said pre-mRNA with Watson-Crick base pairing under physiological conditions.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 10,407,461 (“’461 Patent”) - “Antisense Nucleic Acids”

  • Patent Identification: U.S. Patent No. 10,407,461, entitled “Antisense Nucleic Acids,” issued September 10, 2019.
  • Technology Synopsis: This patent claims a PMO with a specific 25-mer nucleotide sequence for causing exon 53 skipping, and further defines the precise chemical structure of the PMO's constituent monomers, specifying methyl groups at particular locations (R² and R³) on the morpholino ring structure (Compl. ¶120).
  • Asserted Claims: Independent claim 1 (Compl. ¶123).
  • Accused Features: The specific chemical structure of the accused product, golodirsen, which allegedly contains the claimed monomer structure with methyl groups at the specified locations (Compl. ¶122).

U.S. Patent No. 10,487,106 (“’106 Patent”) - “Antisense Nucleic Acids”

  • Patent Identification: U.S. Patent No. 10,487,106, entitled “Antisense Nucleic Acids,” issued November 26, 2019.
  • Technology Synopsis: This patent claims a PMO with a specific 25-mer sequence that is complementary to the 36th to 60th nucleotides of exon 53. The claims further recite a specific chemical formula for a group attached to the 5' end of the PMO oligomer (Compl. ¶130).
  • Asserted Claims: Independent claim 1 (Compl. ¶132).
  • Accused Features: The chemical structure of the 5' end of the accused product, golodirsen, is alleged to meet the claimed formula (Compl. ¶131).

U.S. Patent No. 10,647,741 (“’741 Patent”) - “Antisense Nucleic Acids”

  • Patent Identification: U.S. Patent No. 10647741, entitled “Antisense Nucleic Acids,” issued May 12, 2020.
  • Technology Synopsis: This patent claims a method of treating a DMD patient. The method comprises administering a PMO consisting of a specific 25-mer oligomer that is 100% complementary to the 36th to 60th nucleotides of exon 53, thereby inducing the skipping of that exon in the patient (Compl. ¶139).
  • Asserted Claims: Independent claim 1 (Compl. ¶142).
  • Accused Features: The administration of VYONDYS 53 to DMD patients, which is alleged to result in the exclusion of exon 53 during mRNA processing, as encouraged by Defendant’s product label (Compl. ¶140, 141).

U.S. Patent No. 10,662,217 (“’217 Patent”) - “Antisense Nucleic Acids”

  • Patent Identification: U.S. Patent No. 10662217, entitled “Antisense Nucleic Acids,” issued May 26, 2020.
  • Technology Synopsis: This patent claims a method of treating a DMD patient by intravenously administering a PMO. The claim recites specific chemical formulas for both the PMO monomers and a group at the 5' end of the oligomer (Compl. ¶147).
  • Asserted Claims: Independent claim 1 (Compl. ¶150).
  • Accused Features: The intravenous administration of VYONDYS 53, which allegedly has the claimed chemical structures, as specifically instructed on Defendant’s product label (Compl. ¶148, 149).

U.S. Patent No. 10,683,322 (“’322 Patent”) - “Antisense Nucleic Acids”

  • Patent Identification: U.S. Patent No. 10683322, entitled “Antisense Nucleic Acids,” issued June 16, 2020.
  • Technology Synopsis: This patent claims a manufacturing process. The complaint alleges the process includes iteratively reacting specific chemical compounds in the presence of an acid, a base, and a solvent to add phosphorodiamidate morpholino monomers to a growing oligomer chain (Compl. ¶155-156).
  • Asserted Claims: Independent claim 1 (Compl. ¶159, 161).
  • Accused Features: Defendant’s alleged manufacturing process for VYONDYS 53 (Compl. ¶155, 158).

III. The Accused Instrumentality

  • Product Identification: The accused product is Sarepta’s VYONDYS 53, also known by its generic name, golodirsen (Compl. ¶3). The infringement allegations also implicate methods of using and manufacturing the product (Compl. ¶139, 155).
  • Functionality and Market Context:
    • VYONDYS 53 is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass, identified as a 25-mer containing 25 linked subunits (Compl. ¶52, 94, 107). Its function is to bind to exon 53 of the human dystrophin pre-mRNA, which results in the exclusion of this exon during mRNA processing in patients with specific genetic mutations (Compl. ¶95, 110). This mechanism is intended to treat DMD in patients with a confirmed mutation amenable to exon 53 skipping (Compl. ¶99).
    • The complaint alleges that Sarepta and Nippon Shinyaku are direct competitors and are the only companies with FDA clearance to market oligonucleotide therapies that induce exon 53-skipping for the treatment of DMD (Compl. ¶11). Sarepta received accelerated FDA approval for VYONDYS 53 on December 12, 2019, and began commercial distribution in the U.S. immediately thereafter (Compl. ¶57, 58).

IV. Analysis of Infringement Allegations

'361 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
An antisense oligomer... Sarepta's product, golodirsen, is identified as an antisense oligonucleotide. ¶94 col. 3:24-25
which causes skipping of the 53rd exon in the human dystrophin gene, Golodirsen is designed to bind to exon 53 of dystrophin pre-mRNA, resulting in the exclusion of this exon during mRNA processing. ¶95 col. 3:24-25
consisting of the nucleotide sequence of SEQ ID NO: 57, The complaint alleges "The sequence of bases from the 5' end to 3' end [of golodirsen] is GTTGCCTCCGGTTCTGAAGGTGTTC." ¶96 col. 9:35-36
wherein the antisense oligomer is an oligonucleotide in which the sugar moiety and/or the phosphate-binding region...is modified, or a morpholino oligomer. Golodirsen is identified as a phosphorodiamidate morpholino oligomer (PMO), which is a type of morpholino oligomer. ¶94 col. 4:60-63

'092 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A phosphorodiamidate morpholino oligomer (PMO) antisense oligomer that causes skipping of the 53rd exon... Golodirsen is a PMO designed to bind to exon 53 and cause its exclusion during mRNA processing. ¶107, 110 col. 10:29-32
consisting of a 25-mer oligomer Golodirsen is alleged to contain 25 linked subunits. ¶107 col. 3:24-29
that is 100% complementary to the 36th to the 60th nucleotides from the 5' end of the 53rd exon in said human dystrophin pre-mRNA... The complaint alleges the sequence of golodirsen is 100% complementary to the specified target nucleotides and provides a visual alignment chart. This visual shows the base-by-base Watson-Crick pairing between the golodirsen sequence and the target pre-mRNA sequence. ¶109 col. 10:55-64
wherein said PMO antisense oligomer hybridizes to said pre-mRNA with Watson-Crick base pairing under physiological conditions. Golodirsen's alleged complementarity and intended function of binding to pre-mRNA to induce exon skipping suggest it hybridizes under physiological conditions. ¶110 col. 10:64-67

Identified Points of Contention

  • Scope Questions: A central question for the composition claims (e.g., in the ’092 and ’106 Patents) may be the interpretation of the term "consisting of." Practitioners may focus on whether the accused product as formulated and sold contains additional chemical moieties not recited in the claims, and if so, whether those moieties are considered part of the claimed "oligomer" or are merely excipients. For instance, the complaint alleges golodirsen "contains 25 linked subunits" (Compl. ¶107), which may or may not be coextensive with an oligomer "consisting of a 25-mer."
  • Technical Questions: For the ’361 Patent, a key evidentiary question is whether the sequence of golodirsen is identical to the sequence defined as SEQ ID NO: 57 in the patent, as the claim language "consisting of" provides very little scope. For the ’322 method of manufacturing patent, the allegations are made on "information and belief" (Compl. ¶155, 156, 157). A primary point of contention will be whether discovery reveals that Sarepta's actual, proprietary manufacturing process includes the specific sequence of reaction steps recited in the asserted claim.

V. Key Claim Terms for Construction

  • The Term: "consisting of" (as in "consisting of a 25-mer oligomer" from ’092 Patent, Claim 1 and similar phrasing in other patents).
  • Context and Importance: This term is a critical transition phrase in patent claiming that is presumed to be closed, meaning it excludes any elements not specified in the claim. Its interpretation is central because if the accused VYONDYS 53 product is found to contain additional, unrecited structural elements as part of the oligomer itself, it may not infringe claims using this language. Practitioners may focus on this term because it creates a very high bar for proving literal infringement.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A party might argue that in the context of the patent, "oligomer" refers to the core sequence of monomers and that other functional groups or delivery moieties are separate components not excluded by the "consisting of" language. For example, the patent describes various 5' end modifications as optional features, which might suggest the core oligomer is a distinct entity ('092 Patent, col. 4:64-67).
    • Evidence for a Narrower Interpretation: The use of "consisting of" is a strong indicator of a narrow scope, intended to distinguish the invention from prior art that may have included additional elements. The patent specification's description of specific embodiments that show only the 25-mer PMO without additional components could be used to argue that the invention is limited to that precise structure ('092 Patent, Examples 1-12).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement for the asserted patents (e.g., Compl. ¶100, 102, 114, 116). Induced infringement is primarily based on Sarepta’s product labels, which allegedly encourage and instruct physicians and patients to administer VYONDYS 53 in a manner that performs the steps of the method claims (Compl. ¶101, 140, 149). Contributory infringement is based on the allegation that VYONDYS 53 is a material part of the invention, is known to be specially adapted for an infringing use, and is not a staple article of commerce suitable for substantial non-infringing use (Compl. ¶99, 113).
  • Willful Infringement: Willfulness is alleged for all asserted patents. The complaint alleges that Sarepta had knowledge of the patents and, despite this knowledge, has continued to "knowingly, willfully, deliberately, maliciously, and in bad faith" infringe the patents (Compl. ¶103, 117, 127). The complaint's reference to Sarepta's IPR filings against these same patents suggests Sarepta had pre-suit knowledge of the patents (Compl. ¶1).

VII. Analyst’s Conclusion: Key Questions for the Case

  • A core issue will be one of contractual obligation versus patent law procedure: does the forum selection clause in the parties' MCA prevent Sarepta from challenging the patents' validity via IPR proceedings at the USPTO, or do the statutory provisions for IPR preempt such a private contractual agreement?
  • A second central issue will be one of definitional scope: can the highly restrictive "consisting of" language used in the composition claims be read to cover the accused VYONDYS 53 product as commercially formulated? The resolution will depend on whether the product contains any additional structural elements and how the court construes the term "oligomer."
  • For the method and process patents, a key evidentiary question will be one of factual correspondence: will discovery confirm the complaint's "information and belief" allegations that Sarepta's proprietary manufacturing methods and specific instructions for patient administration directly map onto the steps recited in the asserted method claims?