DCT
1:17-cv-00423
Millennium Pharma Inc v. Zydus Pharma USA Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Millennium Pharmaceuticals, Inc. (Delaware)
- Defendant: Zydus Pharmaceuticals (USA) Inc. (New Jersey) and Cadila Healthcare Ltd. (India)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:17-cv-00423, D. Del., 04/13/2017
- Venue Allegations: Venue is based on Defendants' business activities within Delaware, the location of foreseeable harm to Plaintiff (a Delaware corporation), and Defendant Zydus's alleged consent to jurisdiction by filing counterclaims in prior Delaware cases.
- Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the cancer drug VELCADE® constitutes an act of infringement of two patents covering stable, lyophilized formulations of bortezomib.
- Technical Context: The technology concerns pharmaceutical formulations that solve the problem of boronic acid compounds' inherent instability by forming a stable, reversible mannitol boronate ester through lyophilization (freeze-drying).
- Key Procedural History: Plaintiff is the exclusive licensee of the patents-in-suit. In a prior case against a different defendant (Millennium v. Sandoz), certain other claims of one of the patents-in-suit were found invalid for obviousness; Plaintiff notes the claims asserted here were not among those invalidated. The current action was triggered by a "Notice Letter" from Defendants regarding their ANDA filing, in which Defendants allegedly did not contest infringement of numerous asserted claims.
Case Timeline
| Date | Event |
|---|---|
| 2001-01-25 | Priority Date for '446 and '319 Patents |
| 2002-12-02 | Plaintiff Millennium obtains exclusive license to patents-in-suit |
| 2003 | FDA first approves New Drug Application for VELCADE® |
| 2004-03-30 | U.S. Patent No. 6,713,446 Issues |
| 2005-10-25 | U.S. Patent No. 6,958,319 Issues |
| 2015-08-20 | Court holds certain other claims of the '446 Patent invalid in prior litigation |
| 2017-03-03 | Defendants send Plaintiff a Notice Letter of their ANDA filing |
| 2017-04-13 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 6,713,446 - "Formulation of Boronic Acid Compounds"
- Patent Identification: U.S. Patent No. 6,713,446, "Formulation of Boronic Acid Compounds", issued March 30, 2004.
The Invention Explained
- Problem Addressed: The patent describes that boronic acid compounds, while pharmaceutically useful, are often difficult to prepare in pure form and are unstable, readily degrading and forming anhydrides, which limits their pharmaceutical utility and shelf life (ʼ446 Patent, col. 2:50–62).
- The Patented Solution: The invention addresses this stability issue by lyophilizing (freeze-drying) an aqueous mixture of the boronic acid compound with mannitol. This process forms a stable D-mannitol boronate ester, which protects the active drug. The resulting lyophilized cake can be stored for long periods and, upon reconstitution with an aqueous solvent, rapidly releases the active boronic acid compound for administration (ʼ446 Patent, Abstract; col. 2:7–14).
- Technical Importance: This formulation strategy provided a way to produce a stable, solid dosage form of a promising class of drugs, thereby enabling their practical development and commercialization for clinical use (ʼ446 Patent, col. 2:62–68).
Key Claims at a Glance
- The complaint asserts direct infringement of claims including independent claims 1 and 23.
- Independent Claim 1 (Compound Claim): A compound having a specific chemical structure (formula (1)) that is a boronate ester, further limited by the following elements:
- Z¹ and Z² together form a moiety derived from a sugar;
- The atom attached to boron in each case is an oxygen atom; and
- The sugar is mannitol.
- Independent Claim 23 (Method Claim): A method of preparing a lyophilized compound of formula (1), the method comprising:
- Preparing a mixture comprising water, a boronic acid compound (formula (3)), and mannitol; and
- Lyophilizing the mixture.
- The complaint reserves the right to assert additional claims (Compl. ¶47).
U.S. Patent No. 6,958,319 - "Formulation of Boronic Acid Compounds"
- Patent Identification: U.S. Patent No. 6,958,319, "Formulation of Boronic Acid Compounds", issued October 25, 2005.
The Invention Explained
- Problem Addressed: As a continuation of the application leading to the '446 Patent, the '319 patent addresses the same technical problem of the instability of boronic acid compounds for pharmaceutical use (ʼ319 Patent, col. 2:55–64).
- The Patented Solution: The '319 Patent describes the same solution: creating a stable, lyophilized boronate ester by freeze-drying the active boronic acid compound with a sugar. Upon reconstitution, this formulation releases the active drug (ʼ319 Patent, col. 2:8–16).
- Technical Importance: The invention provides a stable formulation that exhibits a longer shelf-life compared to the free boronic acid compound, making it suitable for pharmaceutical use (ʼ319 Patent, col. 2:1-4).
Key Claims at a Glance
- The complaint asserts direct infringement of claims including independent claims 14 and 29.
- Independent Claim 14 (Compound Claim): A lyophilized compound of formula (1) where:
- Z¹ and Z² together form a moiety derived from a sugar; and
- The atom attached to boron in each case is an oxygen atom.
- Independent Claim 29 (Method Claim): A method of preparing a lyophilized compound of formula (1), the method comprising:
- Preparing a mixture comprising water, a boronic acid compound (formula (3)), and a sugar; and
- Lyophilizing the mixture.
- The complaint reserves the right to assert additional claims (Compl. ¶56).
III. The Accused Instrumentality
- Product Identification: The accused instrumentality is "Defendants' ANDA Product," a generic bortezomib for injection (3.5 mg/vial) for which Defendants seek FDA approval via ANDA No. 210204 (Compl. ¶33).
- Functionality and Market Context: The product is a generic version of Plaintiff's VELCADE®, a proteasome inhibitor used to treat multiple myeloma and mantle cell lymphoma (Compl. ¶¶1, 28). The complaint alleges that the ANDA product is, like VELCADE®, a "lyophilized mannitol ester of bortezomib" (Compl. ¶¶31, 49). It is intended to be reconstituted from its lyophilized form into a solution for intravenous or subcutaneous administration (Compl. ¶28). The filing of the ANDA signifies a commercial intent to market a lower-cost generic alternative to the branded drug upon approval (Compl. ¶¶1, 10).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint alleges that the filing of ANDA No. 210204 is a statutory act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶¶45, 54). The complaint also states that in a pre-suit Notice Letter, Defendants did not contest infringement of a large number of the asserted claims (Compl. ¶¶35-36).
'446 Patent Infringement Allegations
The infringement theory is that the Defendants' ANDA Product is a generic equivalent to VELCADE®, which Plaintiff asserts is an embodiment of the patent claims. The complaint specifically identifies VELCADE® as the "lyophilized mannitol ester of bortezomib" covered by at least claim 20 (Compl. ¶31).
| Claim Element (from Dependent Claim 20) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| The lyophilized compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate. | The Defendants' ANDA Product is alleged to be a generic version of VELCADE® and is, or contains, the lyophilized mannitol ester of bortezomib, which is the compound specified in the claim. | ¶¶31, 33, 47 | col. 9:20-28 |
'319 Patent Infringement Allegations
Similarly, the complaint alleges the ANDA product infringes the '319 Patent, specifically noting that VELCADE® is covered by claim 26 (Compl. ¶32).
| Claim Element (from Dependent Claim 26) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| The lyophilized compound of claim 20, wherein said compound is a sugar ester of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid. | The Defendants' ANDA Product is alleged to be a lyophilized product containing the mannitol ester of bortezomib. Mannitol is a sugar, and the product is thus alleged to be the claimed "sugar ester." | ¶¶32, 56 | col. 12:45-50 |
- Identified Points of Contention:
- Validity vs. Infringement: The complaint's repeated assertion that Defendants have not contested infringement of numerous claims suggests the central dispute may not be over infringement, but rather over the validity and/or enforceability of the patents-in-suit (Compl. ¶¶35-36, 48, 57).
- Technical Questions on Validity: A key technical question for the court will likely be whether the asserted claims are patentably distinct from the claims of the '446 Patent that were previously invalidated for obviousness in the Sandoz litigation (Compl. ¶41). The analysis will likely focus on whether the specific limitations of the asserted claims render them non-obvious over the prior art.
V. Key Claim Terms for Construction
While the central dispute may be validity, the construction of certain terms could be relevant to both validity and infringement analyses.
The Term: "lyophilized compound" ('319 Patent, claim 14)
Context and Importance: This term defines the physical state of the claimed invention. Its scope is critical for determining what products infringe and what prior art is relevant. Practitioners may focus on this term to argue whether a product with a different physical appearance or residual moisture content, or a prior art reference describing a different type of dried product, falls within the claim's scope.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent does not provide an explicit definition, which may support an interpretation covering any solid material obtained through a lyophilization process containing the claimed chemical entity.
- Evidence for a Narrower Interpretation: The specification describes a specific embodiment as a "lyophilized cake" and provides an example with a specific residual water content of 0.88% by weight, which a party could argue implicitly limits the term's scope (ʼ446 Patent, col. 13:34, 51–53).
The Term: "a moiety derived from a sugar" ('446 Patent, claim 1; '319 Patent, claim 14)
Context and Importance: This term defines the stabilizing agent that forms the boronate ester. The breadth of "sugar" is central to the scope of the invention and its patentability over prior art that may teach stabilization with other polyhydroxy compounds.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification defines the term broadly as a moiety "formed by removing the hydrogen atoms from two hydroxyl groups of any sugar moiety," and lists "glucose, sucrose, fructose, trehalose, xylitol, mannitol, and sorbitol" as non-limiting examples ('446 Patent, col. 6:32-43).
- Evidence for a Narrower Interpretation: A party might argue that the term should be limited by the specific examples and preferred embodiments, which heavily feature mannitol and the formation of 5- or 6-membered boronate ester rings ('446 Patent, col. 6:35-39; col. 6:44).
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Defendants will induce infringement because their proposed product labeling will instruct medical professionals to reconstitute and administer the ANDA product in a manner that directly infringes method claims of the patents-in-suit. Contributory infringement is also alleged on the basis that the ANDA product is specially made for an infringing use and has no substantial non-infringing use (Compl. ¶¶49-50, 58-59).
- Willful Infringement: Willfulness is alleged based on Defendants' pre-suit knowledge of the patents. The complaint cites the patents' listing in the FDA's Orange Book, prior litigation involving the patents, and the Defendants' own Notice Letter (which allegedly concedes infringement of many claims) as evidence of knowledge and a lack of a reasonable basis to believe they would not be liable (Compl. ¶¶48, 51, 57, 60).
VII. Analyst’s Conclusion: Key Questions for the Case
Given that this is an ANDA case where infringement appears to be a secondary issue, the litigation will likely center on the following key questions:
- A core issue will be one of patent validity: Are the asserted claims of the '446 and '319 patents, which were not invalidated in the prior Sandoz litigation, non-obvious over the prior art? The court's determination may depend on whether the limitations in the current set of asserted claims are sufficient to render them patentably distinct from the previously invalidated claims.
- A key question for willfulness will be one of objective reasonableness: Did Defendants possess a good-faith, objectively reasonable basis for challenging the validity of these specific patents at the time they filed their ANDA, particularly in light of the prior litigation history and their alleged pre-suit concessions regarding infringement?