DCT

1:21-cv-01736

Genzyme Corp v. Novartis Gene Therapies Inc

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Key Events
Amended Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:21-cv-01736, D. Del., 02/23/2022
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware as two of the defendant corporations, Novartis Gene Therapies, Inc. and Novartis Pharmaceuticals Corporation, are incorporated in and reside in the district.
  • Core Dispute: Plaintiff alleges that Defendant’s gene therapy drug Zolgensma® infringes six patents related to the creation, preparation, use, and formulation of recombinant adeno-associated virus (rAAV) vectors.
  • Technical Context: The lawsuit concerns foundational technologies in the field of gene therapy, specifically the use of engineered viral vectors to deliver therapeutic genes into a patient's cells.
  • Key Procedural History: The complaint alleges a licensing history that may be central to the allegations of knowledge and willfulness. Plaintiff Genzyme licensed certain patents to AskBio but expressly excluded rights for treating spinal muscular atrophy (SMA). AskBio subsequently licensed its "self-complementary" patent portfolio to AveXis (now Novartis Gene Therapies, Inc.). Plaintiff alleges this chain of agreements put Defendants on notice of the asserted patents before they began marketing Zolgensma® for the treatment of SMA. Additionally, five of the six asserted patents expired on August 8, 2020; infringement is alleged to have occurred prior to their expiration.

Case Timeline

Date Event
1999-08-09 Priority Date for ’535, ’717, ’888, ’729, and ’054 Patents
2003-07-22 ’535 Patent Issued
2004-06-01 Priority Date for ’542 Patent
2006-10-24 ’717 Patent Issued
2008-08-28 ’729 Patent Issued
2010-08-31 ’888 Patent Issued
2012-01-10 ’054 Patent Issued
2015-05-29 AskBio licenses technology to AveXis, Inc.
2015-06-09 ’542 Patent Issued
2018-04-09 Novartis AG announces agreement to acquire AveXis, Inc.
2019-05-24 FDA approves Zolgensma®
2020-08-08 ’535, ’888, ’729, and ’054 Patents Expire
2022-02-23 First Amended Complaint Filed

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

U.S. Patent No. 6,596,535 - "Metabolically Activated Recombinant Viral Vectors and Methods for the Preparation and Use"

The Invention Explained

  • Problem Addressed: The patent addresses the problem that gene therapy using recombinant adeno-associated virus (rAAV) vectors can be inefficient. This inefficiency stems from the fact that rAAV vectors deliver a single-stranded DNA (ssDNA) genome, which must be converted into a double-stranded DNA (dsDNA) molecule by the host cell's machinery before the therapeutic gene can be expressed. This conversion is described as a key "rate-limiting step." (Compl. ¶16; ’535 Patent, col. 2:18-24).
  • The Patented Solution: The invention is an rAAV vector engineered to bypass this rate-limiting step. The vector's single-stranded genome is designed to contain regions of self-complementarity, described as "intrastrand base pairing," which allow the ssDNA to rapidly fold back on itself to form a dsDNA-like structure upon entering a cell. This "self-complementary" or "metabolically activated" vector serves as a ready template for gene expression without relying on the host cell's slower ssDNA-to-dsDNA conversion process. (Compl. ¶17; ’535 Patent, Abstract; col. 4:50-59).
  • Technical Importance: This technology allows for faster onset and higher levels of gene expression, which could enable lower, potentially safer, doses of a gene therapy drug to be effective. (Compl. ¶17).

Key Claims at a Glance

  • The complaint asserts independent claim 1. (Compl. ¶44).
  • The essential elements of independent claim 1 are:
    • A recombinant adeno-associated virus (rAAV) vector comprising a single-stranded heterologous nucleotide sequence;
    • The sequence comprises a region which forms intrastrand base pairs;
    • This base pairing enhances the expression of a coding region relative to a vector lacking such pairing; and
    • The region that forms intrastrand base pairs is located within a coding region.

U.S. Patent No. 7,125,717 - "Metabolically Activated Recombinant Viral Vectors and Methods for the Preparation and Use"

The Invention Explained

  • Problem Addressed: As a continuation of the ’535 Patent, the ’717 Patent addresses the same technical challenge: the slow and inefficient expression from conventional rAAV vectors due to the rate-limiting conversion from ssDNA to dsDNA. (’717 Patent, col. 1:30-40).
  • The Patented Solution: The ’717 Patent claims methods of using the self-complementary vector technology. The invention covers the methods of introducing a polynucleotide into a cell (claim 1) and expressing a polynucleotide in a cell (claim 2) by contacting the cell with an rAAV particle containing the self-complementary vector. The method is specified to be performed "essentially in the absence of an AAV helper virus." (’717 Patent, Claims 1, 2).
  • Technical Importance: This patent extends protection from the vector composition itself to the therapeutic methods of its use, securing rights over the application of the self-complementary rAAV technology for delivering and expressing genes in cells. (’717 Patent, col. 8:1-15).

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 2. (Compl. ¶52).
  • The essential elements of independent claim 1 include:
    • A method for introducing a polynucleotide into a cell;
    • Comprising contacting the cell (in the absence of helper virus) with an rAAV particle containing an rAAV vector;
    • The vector comprises a single-stranded heterologous sequence with a coding region that forms intrastrand base pairs for enhanced expression; and
    • The vector comprises one or more inverted terminal repeat (ITR) sequences flanking the heterologous sequence.
  • Independent claim 2 recites a similar method for expressing a polynucleotide coding region in a cell using the same self-complementary rAAV vector technology.

U.S. Patent No. 7,785,888 - "Metabolically Activated Recombinant Viral Vectors and Methods for the Preparation and Use"

  • Technology Synopsis: The ’888 Patent claims a recombinant AAV preparation that is essentially free of helper virus. The preparation comprises rAAV particles containing a self-complementary genome where the total amount of unique sequence is about one-half of the total length, allowing it to form "intrastrand base pairs along most or all of its length" to enhance expression. (Compl. ¶¶ 17, 65; ’888 Patent, Claim 1).
  • Asserted Claims: Independent claim 1. (Compl. ¶62).
  • Accused Features: The Zolgensma® drug product is alleged to be an rAAV preparation that is free of helper virus and contains self-complementary rAAV genomes. (Compl. ¶¶ 66-67).

U.S. Patent No. 7,846,729 - "Metabolically Activated Recombinant Viral Vectors and Methods for the Preparation and Use"

  • Technology Synopsis: The ’729 Patent claims a method for preparing rAAV. The method comprises incubating a host cell that contains the necessary components for AAV replication (a rAAV vector less than ~2.5 kb, AAV rep and cap functions, and helper virus function) and then purifying the resulting rAAV particles, which comprise a self-complementary genome. (Compl. ¶74; ’729 Patent, Claim 1).
  • Asserted Claims: Independent claim 1. (Compl. ¶71).
  • Accused Features: The complaint alleges that the process used to manufacture Zolgensma® follows the claimed method of preparing self-complementary rAAV particles. (Compl. ¶75).

U.S. Patent No. 8,093,054 - "Metabolically Activated Recombinant Viral Vectors and Methods for the Preparation and Use"

  • Technology Synopsis: The ’054 Patent claims a composition comprising a purified rAAV particle with a specific self-complementary genome structure. This structure is defined as containing, in 5' to 3' order: a 5' ITR, a first heterologous sequence, an internal AAV ITR, a second heterologous sequence, and a 3' ITR, where the first and second sequences can form intrastrand base pairs. (Compl. ¶85; ’054 Patent, Claim 1).
  • Asserted Claims: Independent claims 1 and 19. (Compl. ¶81).
  • Accused Features: Zolgensma® is alleged to be a composition comprising purified rAAV particles containing a self-complementary genome that embodies the claimed structure. (Compl. ¶87).

U.S. Patent No. 9,051,542 - "Compositions and Methods to Prevent AAV Vector Aggregation"

  • Technology Synopsis: This patent addresses the problem of rAAV particles clumping together (aggregating) at high concentrations, which can reduce stability and safety. The patented solution is a storage composition for purified rAAV vector particles that uses a high ionic strength (greater than 200 mM) and a specific pH range (7.5 to 8.0), including one or more specified multivalent ions, to keep the particles from aggregating. (Compl. ¶¶ 18, 95; ’542 Patent, Abstract).
  • Asserted Claims: Independent claim 1. (Compl. ¶93).
  • Accused Features: The liquid formulation of Zolgensma® is alleged to be a storage composition meeting the claim's requirements for concentration, pH, excipients (multivalent ions), and high ionic strength, and is alleged to be stored without significant aggregation. (Compl. ¶¶ 96-97).

III. The Accused Instrumentality

Product Identification

  • The accused product is the gene therapy drug Zolgensma® (onasemnogene abeparvovec-xioi), including its manufacture, use, and sale. (Compl. ¶1).

Functionality and Market Context

  • Zolgensma® is an FDA-approved therapy for spinal muscular atrophy (SMA) in children under two years old. (Compl. ¶25). It functions by using an adeno-associated virus (AAV) vector to deliver a functional copy of the human survival motor neuron (SMN) gene to the patient's motor neuron cells. (Compl. ¶26). The complaint alleges Zolgensma® is specifically designed as a "recombinant self-complementary AAV9" product to enhance its efficacy. (Compl. ¶¶ 48, Compl. Ex. A at ¶11). The complaint further describes the drug's formulation as a suspension with a nominal concentration of 2.0 × 10¹³ vector genomes/mL, a pH of 8.0, and excipients including magnesium chloride and sodium chloride. (Compl. ¶96).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

U.S. Patent No. 6,596,535 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A recombinant adeno-associated virus (rAAV) vector comprising a single-stranded heterologous nucleotide sequence... Zolgensma® contains an rAAV vector that comprises the SMN gene, which is a heterologous sequence. (Compl. ¶48). ¶48 col. 4:45-48
...comprising a region which forms intrastrand base pairs such that expression of a coding region...is enhanced relative to a second rAAV vector that lacks sufficient...pairing... Zolgensma® is described as a "recombinant self-complementary AAV9" and is alleged to utilize "intrastrand base pairing vector technology" to increase the drug's efficacy. (Compl. ¶48). ¶48 col. 4:50-59
...wherein the region which forms intrastrand base pairs is in a coding region. The rAAV vector in Zolgensma® allegedly "comprises a coding region of the SMN gene...that forms intrastrand base pairs." (Compl. ¶48). ¶48 col. 10:57-61

U.S. Patent No. 7,125,717 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for introducing a polynucleotide into a cell, comprising contacting the cell essentially in the absence of an AAV helper virus with a recombinant... (rAAV) particle... Zolgensma® is administered to patients as an rAAV particle without a co-administered helper virus. (Compl. ¶58). ¶58 col. 5:32-35
...wherein the rAAV vector comprises a single-stranded heterologous nucleotide sequence comprising a coding region which forms intrastrand base pairs... The vector within Zolgensma® allegedly contains a coding region of the SMN gene that forms intrastrand base pairs, utilizing self-complementary technology. (Compl. ¶57). ¶57 col. 4:50-59
...wherein the rAAV vector comprises one or more inverted terminal repeat (ITR) sequence flanking said heterologous sequence The rAAV vector in Zolgensma® allegedly contains one or more ITR sequences that flank the SMN gene sequence. (Compl. ¶57). ¶57 col. 2:62-65

Identified Points of Contention

  • Evidentiary Questions: For the Carter patents (’535, ’717, ’888, ’729, ’054), the central dispute may be factual. The complaint relies on the Zolgensma® product insert describing the vector as "self-complementary" to allege it meets the "intrastrand base pairs" limitations. (Compl. ¶48). A key question will be whether the actual molecular structure of the vector used in Zolgensma® corresponds to the claimed structures. This raises the evidentiary question: What technical proof beyond product literature will be required to demonstrate that the accused vector's genome forms intrastrand base pairs in its coding region to an extent that enhances expression?
  • Scope Questions: For the ’542 patent, the analysis may turn on claim construction. The claim requires storage "without significant aggregation." (Compl. ¶95). The complaint alleges this is met by the product insert's description of the thawed product as a "clear to slightly opaque...liquid, free of particles." (Compl. ¶97). This raises the question of definitional scope: Does the qualitative description "free of particles" in a product insert meet the legal and technical threshold of "without significant aggregation," or will the court require quantitative data (e.g., from dynamic light scattering) to prove this limitation is met?

V. Key Claim Terms for Construction

"intrastrand base pairs"

  • Context and Importance: This term is the technological core of five of the six asserted patents. The definition of the extent, location, and character of this base pairing will be critical to determining infringement. Practitioners may focus on this term because its construction will dictate the structural evidence Plaintiff must produce regarding the Zolgensma® vector.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The ’535 patent specification states that the extent of pairing "need not be 100% of the sequence but may be at least about any of the following: 25%, 40%, 50%" or more. (’535 Patent, col. 10:65-67). This language may support a construction that does not require complete or near-complete self-complementarity.
    • Evidence for a Narrower Interpretation: The patent frequently analogizes the inventive vector to a native double-stranded replicative form (RF), which is described as "double-stranded along most or all of its length." (’535 Patent, col. 15:30-32). This could support a construction requiring a very high degree of base pairing across the length of the heterologous sequence.

"without significant aggregation"

  • Context and Importance: This term from the ’542 patent is a term of degree, and its construction will determine whether Zolgensma®'s formulation infringes. The dispute may turn on whether the normal, expected state of the commercial product constitutes "significant aggregation." Practitioners may focus on this term because it is not defined with a quantitative metric in the patent, making it a likely subject of expert testimony.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent's background explains that aggregation is a problem because it can "negatively impact virus biodistribution and transduction efficiency, and can also increase immunogenicity." (Compl. ¶18). This may support a functional definition where "significant" aggregation is a level that would cause these negative biological effects.
    • Evidence for a Narrower Interpretation: The patent does not provide an explicit quantitative definition. A defendant may argue that "significant" implies a threshold detectable by standard analytical techniques and that the absence of such a definition renders the claim indefinite. However, within the patent, the term is used to distinguish from prior art solutions where aggregation remains a problem, suggesting "significant" means a level of aggregation that the prior art was unable to solve.

VI. Other Allegations

Indirect Infringement

  • The complaint alleges induced infringement of the method claims of the ’717 and ’054 patents. The basis for inducement is the allegation that Defendants' Zolgensma® label and other communications instruct and encourage physicians and healthcare providers to administer the product to patients, thereby performing the steps of the patented methods. (Compl. ¶¶ 54, 84).

Willful Infringement

  • Willfulness is alleged for all asserted patents. The complaint bases this allegation on Defendants' alleged pre-suit knowledge of the patents, arising from due diligence related to the AskBio-AveXis, Inc. license agreement. The complaint alleges that Novartis was aware of the Carter patents and the specific exclusion of SMA treatment rights from the license chain before it began marketing Zolgensma®. (Compl. ¶¶ 21, 39, 50, 60, 69, 79, 91).

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

  • A core issue will be one of evidentiary proof: Will discovery into the precise molecular structure and formulation of Zolgensma® confirm the complaint’s allegations, which are primarily based on descriptions from the product’s FDA-approved label, that the product practices the "intrastrand base pairing" technology of the Carter patents and the "high ionic strength" formulation of the ’542 patent?
  • A key legal question will be one of claim scope: Can the term "without significant aggregation" in the ’542 patent, a term of degree not quantitatively defined in the specification, be construed with sufficient certainty? And can it be met by a qualitative product description, or will it require extrinsic technical evidence to establish a baseline for what is "significant"?
  • A central question for damages will be one of knowledge and intent: Does the licensing history detailed in the complaint, specifically the alleged awareness of an express carve-out for SMA-related rights, constitute pre-suit knowledge sufficient to support a finding of willful infringement, potentially leading to enhanced damages?