DCT

1:17-cv-00389

Novartis Pharma Corp v. Mylan Pharma Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-00389, D. Del., 04/07/2017
  • Venue Allegations: Venue is alleged to be proper based on Defendant being registered to do business in Delaware, maintaining a designated agent for service of process in the state, holding Delaware state licenses for pharmaceutical distribution, and its Abbreviated New Drug Application (ANDA) filing indicating an intent to market the accused products in Delaware.
  • Core Dispute: Plaintiff alleges that Defendant’s submission of an ANDA to the FDA seeking approval to market generic everolimus tablets constitutes an act of infringement of three patents covering the active compound, a method of its use for treating certain brain tumors, and a specific dispersible tablet formulation.
  • Technical Context: The technology relates to the pharmaceutical compound everolimus, a derivative of rapamycin, which functions as an immunosuppressant and is used to treat certain non-malignant tumors.
  • Key Procedural History: This is a Hatch-Waxman action initiated after Plaintiff received a Notice Letter dated February 24, 2017, in which Defendant Mylan certified that its proposed generic product would not infringe or that the patents-in-suit were invalid. The action was filed within the 45-day statutory window. Subsequent to the filing of the complaint, U.S. Patent No. 5,665,772 underwent inter partes review (IPR) proceedings, resulting in a certificate confirming the patentability of claims 1-3 and 8-10. This outcome may create an estoppel, preventing the defendant from re-litigating certain invalidity grounds against those claims.

Case Timeline

Date Event
1992-10-09 Priority Date for U.S. Patent No. 5,665,772
1997-09-09 Issue Date for U.S. Patent No. 5,665,772
2001-02-19 Priority Date for U.S. Patent No. 8,778,962
2001-09-28 Priority Date for U.S. Patent No. 8,617,598
2012-08-29 FDA Approval for AFINITOR Disperz® (Reference Listed Drug)
2013-12-31 Issue Date for U.S. Patent No. 8,617,598
2014-07-15 Issue Date for U.S. Patent No. 8,778,962
2017-02-24 Date of Mylan's Notice Letter with Paragraph IV certification
2017-04-07 Complaint Filing Date
2019-05-17 IPR Certificate issued for U.S. Patent No. 5,665,772

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

U.S. Patent No. 5,665,772, “O-ALKYLATED RAPAMYCIN DERIVATIVES AND THEIR USE, PARTICULARLY AS IMMUNOSUPPRESSANTS,” issued September 9, 1997

The Invention Explained

  • Problem Addressed: The patent describes the naturally occurring antibiotic rapamycin as a potent immunosuppressant whose pharmaceutical utility is constrained by its "very low and variable bioavailability," high toxicity, and poor solubility, which complicates the creation of stable pharmaceutical formulations (’772 Patent, col. 1:35-40).
  • The Patented Solution: The invention provides novel alkylated derivatives of rapamycin, specifically 40-O-substituted compounds like 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), that are designed to possess an "improved pharmacologic profile," including greater stability and bioavailability, thereby facilitating the production of effective galenic formulations (’772 Patent, col. 1:41-47; col. 2:55-62). The general structure of these novel compounds is depicted in Formula I (’772 Patent, col. 1:48-col. 2:10).
  • Technical Importance: These derivatives offered a path to harness the therapeutic potential of rapamycin by overcoming critical drug delivery and pharmacokinetic hurdles that limited the original compound’s clinical application (’772 Patent, col. 1:41-47).

Key Claims at a Glance

  • The complaint alleges infringement of claims 1-3 and 7-10, noting that Defendant did not contest infringement of these claims in its Notice Letter (Compl. ¶26). Independent claims in this range are Claim 1 and Claim 8.
  • Independent Claim 1 recites:
    • A compound of the formula [depicted in Formula I]
    • wherein R¹ is hydroxy(C₁-₆)alkyl or hydroxy(C₁-₃)alkoxy(C₁-₃)alkyl.
  • Independent Claim 8 recites:
    • A method of inducing an immunosuppressant effect in a subject in need of immunosuppression,
    • which comprises administering to said subject an immunosuppressant effective amount of a compound according to claim 1.

U.S. Patent No. 8,778,962, “TREATMENT OF SOLID TUMORS WITH RAPAMYCIN DERIVATIVES,” issued July 15, 2014

The Invention Explained

  • Problem Addressed: The patent is directed at the general need to "expand the armamentarium of cancer treatment of solid tumors," particularly for advanced-stage diseases where existing treatments may not be sufficient (’962 Patent, col. 2:62-65).
  • The Patented Solution: The invention is a specific method of using a rapamycin derivative to treat a particular condition. It claims a method for inhibiting the growth of non-malignant solid tumors of the brain by administering a therapeutically effective amount of everolimus, identified as a compound of Formula I with specific substitutions (’962 Patent, Claim 1). The abstract highlights that these rapamycin derivatives have "interesting effects in the treatment of solid tumours" (’962 Patent, Abstract).
  • Technical Importance: This patent provides targeted protection for a specific clinical application of everolimus, distinct from its general immunosuppressive properties, by claiming its use against a defined type of tumor (’962 Patent, col. 2:25-34).

Key Claims at a Glance

  • The complaint alleges infringement of claims 1-6 and notes Defendant did not contest infringement of these claims (Compl. ¶29). Claim 1 is independent.
  • Independent Claim 1 recites:
    • A method for inhibiting growth of non-malignant solid tumors of the brain in a subject,
    • said method consisting of administering to said subject a therapeutically effective amount of a compound of formula I,
    • wherein R₁ is CH₃,
    • R₂ is -CH₂-CH₂-OH, and
    • X is =O.

U.S. Patent No. 8,617,598, “PHARMACEUTICAL COMPOSITIONS COMPRISING COLLOIDAL SILICON DIOXIDE,” issued December 31, 2013

Technology Synopsis

The patent addresses the challenge of formulating insoluble macrolide drugs into tablets that can be rapidly dispersed in liquid, a feature desirable for pediatric and elderly patients (’598 Patent, col. 2:20-28). The patented solution is a pharmaceutical composition that combines a macrolide solid dispersion with a disintegrant and a specific amount (1-5% by weight) of colloidal silicon dioxide. This combination is asserted to achieve rapid disintegration times without compromising the mechanical hardness and stability of the tablet (’598 Patent, col. 2:45-53; col. 3:1-12).

Asserted Claims

The complaint alleges infringement of one or more claims, referencing Defendant's challenge to claims 1-6 in its Notice Letter (Compl. ¶20). Claim 1 is the sole independent claim.

Accused Features

Defendant's ANDA Products are alleged to contain a "pharmaceutical composition in the form of a solid dispersion comprising everolimus, a disintegrant and colloidal silicon dioxide," thereby infringing the ’598 patent (Compl. ¶30).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are Defendant Mylan's "everolimus tablets for oral suspension in 2 mg, 3 mg and 5 mg dosage strengths," for which Mylan submitted an ANDA to the FDA (Compl. ¶19).

Functionality and Market Context

The accused products are generic versions of Plaintiff's AFINITOR Disperz® tablets (Compl. ¶¶ 11, 19). The complaint alleges these products contain the active ingredient everolimus and are formulated as tablets for oral suspension (Compl. ¶19). The proposed indication for use, which would be reflected on the product label, is for the treatment of patients with subependymal giant cell astrocytoma (a non-malignant brain tumor) associated with tuberous sclerosis complex (Compl. ¶¶ 11, 28). The complaint alleges Mylan seeks to manufacture and sell these generic products prior to the expiration of the patents-in-suit, thereby triggering this Hatch-Waxman litigation (Compl. ¶19).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

’772 Patent Infringement Allegations

Claim Element (from Independent Claim 8) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of inducing an immunosuppressant effect in a subject in need of immunosuppression, which comprises administering... The filing of an ANDA for a drug product is a statutory act of infringement. The product contains everolimus, an immunosuppressant, and is intended for a therapeutic use that relies on this effect. ¶22, ¶25 col. 4:22-29
...an immunosuppressant effective amount of a compound according to claim 1. The accused product contains everolimus, which the complaint alleges is a compound falling within the scope of claim 1 of the ’772 patent. The proposed product label will instruct administration of a therapeutically effective amount to achieve a clinical outcome. ¶25, ¶12, ¶14 col. 2:11-19

’962 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for inhibiting growth of non-malignant solid tumors of the brain in a subject... Mylan’s ANDA seeks approval for a product that will be "specifically labeled for use in a method for inhibiting growth of non-malignant solid tumors of the brain," mirroring the indication for the reference drug AFINITOR Disperz® in treating subependymal giant cell astrocytoma. ¶27, ¶28, ¶11 col. 2:25-34
...said method consisting of administering to said subject a therapeutically effective amount of a compound of formula I... Mylan's proposed product contains everolimus, which the complaint alleges is the specific compound recited in claim 1 of the ’962 patent (a Formula I compound where R₂ is -CH₂-CH₂-OH and X is =O). The product's label will instruct administration of a therapeutically effective dose. ¶27, ¶28, ¶12 col. 2:3-23

Identified Points of Contention

  • Validity vs. Infringement: The primary point of contention for all three patents will be validity. The complaint states that Mylan's Notice Letter alleged invalidity of asserted claims in all three patents (Compl. ¶20). Conversely, the complaint notes that Mylan did not deny infringement of claims 1-3 and 7-10 of the ’772 patent or claims 1-6 of the ’962 patent, suggesting that for these patents, the dispute will focus almost exclusively on whether the claims are valid over the prior art (Compl. ¶¶ 26, 29).
  • Scope Questions (’598 Patent): For the ’598 patent, Mylan alleged both non-infringement and invalidity (Compl. ¶20). This raises the question of whether Mylan’s formulation technically meets every element of the asserted claims. The dispute may center on whether Mylan’s product constitutes a "solid dispersion" or if its excipients function as a "disintegrant" in the manner required by the claims.

V. Key Claim Terms for Construction

The Term: "solid dispersion" (’598 Patent, Claim 1)

  • Context and Importance: This term is the technological core of the ’598 patent. As Mylan has alleged non-infringement of the ’598 patent, the precise meaning of "solid dispersion" will be critical to determining if Mylan’s formulation falls within the claim scope. Practitioners may focus on this term because its construction will likely decide the infringement question for this patent.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a functional definition: "a preparation in which the macrolide is in an amorphous or substantially amorphous form and is dispersed in a carrier medium" (’598 Patent, col. 6:40-44).
    • Evidence for a Narrower Interpretation: Mylan may argue the term should be limited by the specific methods of preparation disclosed, such as co-precipitation, co-evaporation, spray-drying, or melt-granulation (’598 Patent, col. 6:47-col. 7:21). The specific parameters of the working examples could also be cited to support a more constrained definition.

The Term: "non-malignant solid tumors of the brain" (’962 Patent, Claim 1)

  • Context and Importance: This term defines the entire field of use for the method claimed in the ’962 patent. Infringement depends on Mylan's proposed product label instructing a use that falls within this definition.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides examples of "brain and other central nervous system tumors," including "glioblastomas or medulla blastomas," though it does not explicitly classify them as malignant or non-malignant in that passage (’962 Patent, col. 2:27-30).
    • Evidence for a Narrower Interpretation: A party could argue the term should be understood in the context of the specific indication for the reference drug, AFINITOR Disperz®, which is "subependymal giant cell astrocytoma" (SEGA), a specific type of low-grade, non-malignant tumor (Compl. ¶11). The patent itself does not provide an explicit definition or a list of other non-malignant brain tumors.

VI. Other Allegations

Indirect Infringement

The complaint alleges induced and contributory infringement of the ’962 patent. Inducement is based on the allegation that Mylan, with knowledge of the patent, will sell a product with a label that instructs medical professionals and patients to perform the patented method of treatment (Compl. ¶27). Contributory infringement is based on the allegation that Mylan's product is a material part of the invention, is especially adapted for an infringing use, and has no substantial non-infringing use (Compl. ¶28).

Willful Infringement

The complaint does not contain an explicit claim for willful infringement. However, it lays a foundation for such a claim by alleging that Mylan was "aware of the '772, '962 and '598 patents" at the time it filed its ANDA, which established knowledge (Compl. ¶23).

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

  • A central issue will be one of validity: Can Mylan prove by clear and convincing evidence that the asserted claims, particularly those covering the well-known compound everolimus and its use in a specific formulation, are invalid as obvious or anticipated by the prior art? This question is sharpened by the fact that several claims of the ’772 patent have already survived an IPR challenge.
  • The case will also turn on a question of technical infringement scope: For the ’598 patent, does Mylan's proposed generic formulation, as detailed in its confidential ANDA, technically embody a "solid dispersion" containing a "disintegrant" and "colloidal silicon dioxide" as those terms are construed from the patent's specification, or does its formulation differ in a way that places it outside the bounds of the claims?
  • Finally, a key procedural question will be the preclusive effect of the IPR proceeding: To what extent will the doctrine of statutory estoppel bar Mylan from raising invalidity arguments against claims 1-3 and 8-10 of the ’772 patent that it raised or reasonably could have raised during the prior inter partes review?