DCT
1:19-cv-00471
Millennium Pharma Inc v. Aurobindo Pharma USA Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Millennium Pharmaceuticals, Inc. (Delaware)
- Defendant: Aurobindo Pharma USA Inc. (Delaware) and Aurobindo Pharma Limited (India)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:19-cv-00471, D. Del., 03/06/2019
- Venue Allegations: Venue is alleged to be proper as to Defendant Aurobindo USA because it is a Delaware corporation. Venue is alleged to be proper as to Defendant Aurobindo Pharma because it is not resident in the United States.
- Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) for a generic version of the cancer drug VELCADE® infringes patents related to stable formulations of boronic acid compounds.
- Technical Context: The technology concerns methods for stabilizing peptide boronic acids, a class of proteasome inhibitors used in oncology, by lyophilizing them with a sugar to form a stable, reconstitutable boronate ester.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 212825 and a subsequent Paragraph IV certification notice alleging the patents-in-suit are invalid, unenforceable, or will not be infringed. The complaint notes that for numerous asserted claims, Defendants do not contest infringement but instead base their non-infringement position on an assertion of invalidity. The complaint also references prior litigation involving the patents against other parties.
Case Timeline
| Date | Event |
|---|---|
| 2001-01-25 | Priority Date for ’446 and ’319 Patents |
| 2002-12-02 | Millennium obtains exclusive license to the Patents-in-Suit |
| 2003-01-01 | FDA approves Millennium's 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 |
| 2019-01-28 | Defendants send Paragraph IV Notice Letter to Millennium |
| 2019-03-06 | Complaint Filed |
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's background section describes that peptide boronic acids, while pharmaceutically useful, are often difficult to obtain in pure form and are chemically unstable (Compl., Ex. A, ’446 Patent, col. 2:50-53). They are prone to dehydration, which forms oligomeric anhydrides, and are sensitive to air oxidation, which complicates their characterization and limits their shelf-life (Compl., Ex. A, ’446 Patent, col. 2:53-62).
- The Patented Solution: The invention addresses this stability issue by lyophilizing (freeze-drying) an aqueous mixture of a boronic acid compound and a stabilizing agent with at least two hydroxyl groups, such as a sugar (Compl., Ex. A, ’446 Patent, col. 2:7-14). This process forms a stable, solid boronate ester which can be stored and later readily reconstituted in an aqueous medium to release the active boronic acid drug for administration (Compl., Ex. A, ’446 Patent, col. 2:11-14, 13:7-14). The patent specifically highlights D-mannitol as a preferred sugar for this purpose (Compl., Ex. A, ’446 Patent, col. 9:38-39).
- Technical Importance: This technology provided a practical solution for creating a pharmaceutically viable, solid-dosage form of peptide boronic acids, a promising class of proteasome inhibitors, by overcoming their inherent chemical instability (Compl., Ex. A, ’446 Patent, col. 2:63-col. 3:2).
Key Claims at a Glance
- The complaint asserts direct infringement of claims including 1-6, 8-16, 18-27, 29-32, and others (Compl. ¶44). The lead independent claims appear to be claim 1 (compound), claim 11 (lyophilized compound), and claim 23 (method of preparing).
- Independent Claim 11 (abbreviated):
- A lyophilized compound of the formula (1)
- wherein P is hydrogen or an amino-group protecting moiety; R is hydrogen or alkyl; A is 0, 1, or 2
- R¹, R², and R³ are independently selected side chains
- Z¹ and Z² together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom
- and wherein the sugar is mannitol.
- The complaint also reserves the right to assert dependent claims, and specifically calls out claim 20 as covering Plaintiff's VELCADE® product (Compl. ¶31).
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: the chemical instability and limited shelf-life of peptide boronic acid compounds, which hinders their use as pharmaceutical agents (Compl., Ex. B, ’319 Patent, col. 2:23-44).
- The Patented Solution: The patented solution is identical to that of the ’446 patent. It involves creating a stable, reconstitutable solid by lyophilizing the boronic acid compound with a sugar, such as mannitol, to form a boronate ester (Compl., Ex. B, ’319 Patent, col. 2:4-17). The detailed description and examples are substantially similar to those in the parent ’446 Patent.
- Technical Importance: The technology provides a method for formulating an otherwise unstable class of oncology drugs into a stable product suitable for widespread clinical use (Compl., Ex. B, ’319 Patent, col. 2:45-53).
Key Claims at a Glance
- The complaint asserts direct infringement of claims including 1-3, 5-9, 11-17, 19-22, and others (Compl. ¶53). The lead independent claims appear to be claim 1 (compound) and claim 14 (lyophilized compound).
- Independent Claim 14 (abbreviated):
- A lyophilized compound of the formula (1)
- wherein P is hydrogen or an amino-group protecting moiety; R is hydrogen or alkyl; A is 0, 1, or 2
- R¹, R², and R³ are independently selected side chains
- Z¹ and Z² together form a moiety derived from a sugar, wherein the atom attached to boron in each case is an oxygen atom.
- The complaint also reserves the right to assert dependent claims, and specifically calls out claim 26 as covering Plaintiff's VELCADE® product (Compl. ¶32).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Defendants' generic bortezomib for injection, 3.5 mg/vial, as described in Abbreviated New Drug Application ("ANDA") No. 212825 ("Defendants' ANDA Product") (Compl. ¶33).
Functionality and Market Context
The ANDA Product is a generic version of Plaintiff's VELCADE® for Injection, a proteasome inhibitor used for treating multiple myeloma and mantle cell lymphoma (Compl. ¶1, ¶28). The complaint alleges that Defendants' proposed product labeling will instruct that the product is the "lyophilized mannitol ester of bortezomib" (Compl. ¶46, ¶55). The act of infringement is the submission of the ANDA seeking FDA approval to market this generic product prior to the expiration of the patents-in-suit, which are listed in the FDA's "Orange Book" in connection with VELCADE® (Compl. ¶1, ¶30, ¶37). No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
'446 Patent Infringement Allegations
| Claim Element (from Independent Claim 11) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A lyophilized compound... | Defendants' ANDA Product is described in its proposed labeling as a lyophilized product. | ¶46 | col. 11:6-14 |
| ...of the formula (1)... | The ANDA product is alleged to be the mannitol ester of bortezomib, which is D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate, a compound falling within the scope of formula (1). | ¶31, ¶46 | col. 6:5-15 |
| ...wherein Z¹ and Z² together form a moiety derived from a sugar... | The ANDA Product is allegedly formed with mannitol, which is a sugar. | ¶46 | col. 6:38-41 |
| ...and wherein the sugar is mannitol. | The ANDA Product is specifically alleged to be a lyophilized mannitol ester of bortezomib. | ¶31, ¶46 | col. 6:40-41 |
'319 Patent Infringement Allegations
| Claim Element (from Independent Claim 14) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A lyophilized compound... | Defendants' ANDA Product is described in its proposed labeling as a lyophilized product. | ¶55 | col. 11:15-18 |
| ...of the formula (1)... | The ANDA product is alleged to be the mannitol ester of bortezomib, a compound with a structure corresponding to formula (1). | ¶55 | col. 6:20-30 |
| ...wherein Z¹ and Z² together form a moiety derived from a sugar... | The ANDA Product is allegedly formed using mannitol, which is a sugar, to create the ester. | ¶55 | col. 6:40-52 |
Identified Points of Contention
- Primary Dispute: The complaint states that in their Notice Letter, Defendants "do not contest infringement" of a large number of asserted claims from both the ’446 and ’319 patents, "except on the basis of their assertion that these claims are invalid" (Compl. ¶35, ¶36). This suggests the primary legal battleground may be patent validity rather than infringement.
- Technical Questions: Notwithstanding the apparent concession, a potential technical question remains: What is the precise chemical nature of the final, solid-state ANDA product? Does evidence show it is the specific "covalent boronate ester adduct" described in the patent specification (Compl., Ex. A, ’446 Patent, col. 13:51-58), or is it a non-covalent complex or simple physical mixture of bortezomib and mannitol?
V. Key Claim Terms for Construction
"lyophilized compound"
- Context and Importance: This term appears in the preambles of key independent claims (e.g., ’446 Patent, claim 11; ’319 Patent, claim 14). The patent's inventive concept rests on creating a new, stable chemical entity—a boronate ester "compound"—through the process of lyophilization. Practitioners may focus on this term because its construction will determine whether proof of a specific covalent bond is required, or if simply co-lyophilizing the starting materials is sufficient.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The method claims describe preparing a "mixture" containing water, a boronic acid compound, and mannitol, and then "lyophilizing the mixture" (Compl., Ex. A, ’446 Patent, claim 23). This could support an interpretation where the resulting product of that process is, by definition, the claimed "lyophilized compound," without requiring separate proof of its exact solid-state structure.
- Evidence for a Narrower Interpretation: The specification provides mass spectral data as evidence of the "formation of a covalent boronate ester adduct" between the boronic acid and mannitol, distinguishing it from a simple mixture (Compl., Ex. A, ’446 Patent, col. 13:51-58). The claims recite a specific chemical structure (formula 1) for the "compound," suggesting that proof of this specific bonded entity is required for infringement.
"a moiety derived from a sugar"
- Context and Importance: This term in claims 1 and 11 of the ’446 Patent and claims 1 and 14 of the ’319 Patent defines the stabilizing agent that forms the ester with the boronic acid. Its scope is central to defining the breadth of the invention.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification lists several non-limiting examples of suitable sugars, including "glucose, sucrose, fructose, trehalose, xylitol, mannitol, and sorbitol" (Compl., Ex. A, ’446 Patent, col. 6:38-40). This language may support a construction that encompasses any of these sugars or their chemical equivalents.
- Evidence for a Narrower Interpretation: The specification repeatedly emphasizes mannitol and sorbitol as "preferred" and "more preferabl[e]" embodiments (Compl., Ex. A, ’446 Patent, col. 6:40-42). Furthermore, the working examples and the specific dependent claims highlighted in the complaint focus exclusively on D-mannitol (Compl., Ex. A, ’446 Patent, Examples 1-5; Compl. ¶31). A party could argue that the invention is effectively limited to the embodiments that were actually made and shown to work, namely mannitol.
VI. Other Allegations
Indirect Infringement
The complaint alleges induced infringement under 35 U.S.C. § 271(b), stating that Defendants' proposed product labeling will actively instruct medical professionals and patients to reconstitute and prepare the ANDA Product for administration in a manner that would infringe method claims of the patents-in-suit (Compl. ¶46, ¶55). The complaint also alleges contributory infringement under § 271(c), asserting the ANDA Product is specially made for an infringing use and has no substantial non-infringing use (Compl. ¶47, ¶56).
Willful Infringement
The willfulness allegations are based on alleged pre-suit knowledge of the patents. The complaint asserts Defendants knew of the patents and their infringement liability due to the patents' listing in the FDA Orange Book, prior litigation involving the patents, and Defendants' own act of sending a Paragraph IV Notice Letter, which itself acknowledges the patents (Compl. ¶45, ¶54). The complaint alleges Defendants "know (or are willfully blind to the fact)" that their product will infringe (Compl. ¶45, ¶54).
VII. Analyst’s Conclusion: Key Questions for the Case
- A primary question appears to be one of case strategy and focus: given the complaint's assertion that Defendants' Paragraph IV letter concedes infringement for many claims to focus on invalidity, will the case center on the patents' validity (e.g., obviousness in light of prior art concerning lyophilization and formulation) rather than a traditional element-by-element infringement analysis?
- A core issue of claim construction will be definitional: is the claimed "lyophilized compound" a specific chemical entity requiring proof of a covalent mannitol-boronate ester bond in the final solid product, or does the term broadly cover the bulk material resulting from the co-lyophilization of the constituent ingredients as described in the patent?
- A key evidentiary question will relate to willfulness: can the Plaintiff demonstrate that Defendants' decision to challenge the patents via an ANDA filing was objectively baseless, particularly in light of prior litigation involving the same patents, thereby supporting a claim for enhanced damages?