DCT
1:18-cv-01934
Sanofi v. Fresenius Kabi
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Genzyme Corporation (Massachusetts) and sanofi-aventis U.S. LLC (Delaware)
- Defendant: Fresenius Kabi USA, LLC (Delaware)
- Plaintiff’s Counsel: RatnerPrestia; McDonnell Boehnen Hulbert & Berghoff LLP
- Case Identification: 1:18-cv-01934, D. Del., 12/06/2018
- Venue Allegations: Venue is alleged to be proper in the District of Delaware based on Defendant’s incorporation in Delaware, its continuous business contacts within the state, and the fact that Plaintiff Sanofi is a Delaware entity allegedly harmed in the state.
- Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic version of Plaintiffs' Mozobil® product constitutes an act of infringement of two patents covering methods of using plerixafor to mobilize hematopoietic stem cells.
- Technical Context: The technology concerns small-molecule drugs that mobilize hematopoietic stem cells from bone marrow into the bloodstream, facilitating their collection for subsequent autologous transplantation in patients with certain cancers.
- Key Procedural History: The complaint alleges that the patents-in-suit have been the subject of prior litigation against other generic drug manufacturers. It specifically notes that district court decisions, affirmed by the Federal Circuit in one instance, found certain asserted claims not invalid and infringed, a fact alleged to be known by the Defendant and central to the willfulness allegations.
Case Timeline
| Date | Event |
|---|---|
| 2001-07-31 | Earliest Priority Date for '102 and '590 Patents |
| 2006-01-17 | '102 Patent Issue Date |
| 2008-12-15 | FDA Approval of Mozobil® (NDA No. 022311) |
| 2011-03-01 | '590 Patent Issue Date |
| 2016-05-11 | D. Del. decision in Genzyme v. Dr. Reddy's |
| 2017-12-18 | Federal Circuit affirmance in Genzyme v. Dr. Reddy's |
| 2018-08-08 | D. Del. decision in Genzyme v. Zydus Pharma |
| 2018-10-25 | Date of Defendant's Notice Letter to Plaintiffs |
| 2018-12-06 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,897,590 - "Methods to Mobilize Progenitor/Stem Cells," issued March 1, 2011
The Invention Explained
- Problem Addressed: The patent's background describes the need for therapeutic agents that can mobilize progenitor and stem cells from the bone marrow into the peripheral blood, particularly to counteract the damaging effects of chemotherapy on a patient's hematopoietic system. It notes the disadvantages associated with then-existing protein and peptide-based pharmaceuticals used for this purpose. (’590 Patent, col. 1:24-41, col. 2:56-62).
- The Patented Solution: The invention is a method that uses specific polyamine compounds which act as antagonists to the chemokine receptor CXCR4. By inhibiting the binding of the natural ligand SDF-1 to this receptor, the patented method disrupts the mechanism that retains stem cells in the bone marrow, causing them to be released (mobilized) into the peripheral blood where they can be collected for transplantation. (’590 Patent, Abstract; col. 4:51-67).
- Technical Importance: This technology provided a small-molecule-based method for mobilizing stem cells, offering a different therapeutic approach compared to larger, protein-based growth factors. (’590 Patent, col. 2:56-62).
Key Claims at a Glance
- The complaint asserts claims 8 and 19. Claim 19 depends from claim 8, which in turn depends from independent claim 1.
- The essential elements of independent claim 1 are:
- A method to obtain progenitor and/or stem cells from a subject
- comprising: (a) administering to the subject a compound of the formula Z-linker-Z' or a pharmaceutically acceptable salt thereof
- in an amount effective to mobilize said progenitor and/or stem cells into the peripheral blood;
- followed by (b) harvesting said progenitor and/or stem cells.
- Claim 8 specifies the compound as 1,1'-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane (plerixafor).
- Claim 19 further requires administering G-CSF prior to the plerixafor and specifies the subject has non-Hodgkin's lymphoma or multiple myeloma.
- The complaint does not explicitly reserve the right to assert other claims, but infringement is broadly alleged for "one or more claims" (Compl. ¶42).
U.S. Patent No. 6,987,102 - "Methods to Mobilize Progenitor/Stem Cells," issued January 17, 2006
The Invention Explained
- Problem Addressed: The patent addresses the same technical problem as the ’590 Patent: the need for effective, non-protein-based agents to mobilize hematopoietic progenitor and stem cells from bone marrow to the periphery for collection and therapeutic use. (’102 Patent, col. 1:20-41).
- The Patented Solution: As a parent to the ’590 Patent, the ’102 Patent discloses a similar solution. The method involves administering polyamine compounds that bind to the CXCR4 receptor, thereby antagonizing its natural ligand SDF-1 and causing progenitor and stem cells to enter the circulation. (’102 Patent, Abstract; col. 4:34-45). The patent’s examples demonstrate this effect with the compound AMD3100 (plerixafor). (’102 Patent, Table 1).
- Technical Importance: The invention provided an early disclosure of a small-molecule approach for mobilizing stem cells by targeting the CXCR4/SDF-1 pathway. (’102 Patent, col. 2:56-62).
Key Claims at a Glance
- The complaint asserts claim 8, which depends from claims 7, 6, and ultimately independent claim 1.
- The essential elements of independent claim 1 are:
- A method to obtain progenitor and/or stem cells from a subject
- comprising: (a) administering to said subject a compound of the formula (1) Z-linker-Z'
- in an amount effective to mobilize said progenitor and/or stem cells into the peripheral blood;
- followed by (b) harvesting said progenitor and/or stem cells by apheresis.
- Claim 8 specifies the compound is 1,1'-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane (plerixafor).
- The complaint alleges infringement of "one or more of the claims of the '102 patent, including but not limited to Claim 8" (Compl. ¶55).
III. The Accused Instrumentality
Product Identification
Defendant’s proposed Plerixafor Injection, 24 mg / 1.2 mL, which is the subject of Abbreviated New Drug Application (ANDA) No. 212395 (Compl. ¶2).
Functionality and Market Context
- The product is a proposed generic version of Genzyme's Mozobil® and contains the same active ingredient, plerixafor (Compl. ¶¶ 2, 19).
- The complaint alleges that the Defendant is seeking FDA approval to market its ANDA product for the same indication as Mozobil®: "for use in combination with granulocyte-colony stimulating factor ('G-CSF') to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma" (Compl. ¶¶ 14, 21).
- The proposed prescribing information for the ANDA product will allegedly instruct medical professionals to administer the product to human patients to achieve mobilization of hematopoietic stem cells, including instructions for use after the patient has received G-CSF (Compl. ¶¶ 23, 24).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
'590 Patent Infringement Allegations
| Claim Element (from Independent Claim 1 and Dependent Claims 8 & 19) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| The method of claim 8 which further comprises administering G-CSF to said subject prior to administering the...compound... | The proposed product label instructs use in combination with G-CSF. | ¶24 | col. 29:6-12 |
| ...administering to said subject a compound [that] is 1,1'-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane or a pharmaceutically acceptable salt thereof... | The active ingredient in the Defendant's ANDA product is plerixafor, the compound specified in the claim. | ¶19 | col. 28:8-13 |
| ...in an amount effective to mobilize said progenitor and/or stem cells into the peripheral blood... | The proposed product label instructs use for the purpose of mobilizing hematopoietic stem cells into the peripheral blood. | ¶23 | col. 27:48-52 |
| ...followed by (b) harvesting said progenitor and/or stem cells. | The proposed product label directs use for mobilization "for collection and subsequent autologous transplantation," which necessitates harvesting. | ¶23 | col. 27:53-54 |
| ...wherein the subject is a human patient having non-Hodgkin's lymphoma or multiple myeloma. | The ANDA product seeks approval for the indication of treating patients with non-Hodgkin's lymphoma and multiple myeloma. | ¶14, ¶21 | col. 29:6-12 |
'102 Patent Infringement Allegations
| Claim Element (from Independent Claim 1 and Dependent Claim 8) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| ...administering to said subject a compound [that is] 1,1'-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. | The active ingredient in the Defendant's ANDA product is plerixafor, the specific compound required by the claim. | ¶19 | col. 28:8-11 |
| ...in an amount effective to mobilize said progenitor and/or stem cells into the peripheral blood... | The proposed product label instructs administering the drug for the purpose of mobilizing hematopoietic stem cells. | ¶23 | col. 27:20-24 |
| ...followed by (b) harvesting said progenitor and/or stem cells by apheresis. | The proposed label's instruction for "collection and subsequent autologous transplantation" implies harvesting, and apheresis is the standard method for such collection. | ¶23 | col. 27:25-27 |
Identified Points of Contention
- Infringement Scope: In this ANDA case, infringement is statutorily defined by the act of filing the ANDA for a patented use. The primary infringement question will be whether the use described in the Defendant's proposed product label falls within the scope of the asserted claims. The complaint alleges the label will be substantially similar to the Mozobil® label, suggesting a direct overlap.
- Technical Questions: A potential point of dispute could center on whether the instructions on the proposed label necessarily result in the performance of every claimed step. For example, a question may arise as to whether every administration according to the label is "followed by" harvesting, as required by the claims.
V. Key Claim Terms for Construction
Term for Construction: "progenitor and/or stem cells"
Context and Importance: The identity of the cells being mobilized and harvested is the object of the claimed method. Practitioners may focus on this term because its scope determines what the patented method achieves. A defendant could argue for a narrow construction limited to the specific cell types and assays described in the patent, seeking to create a distinction with the effects described on its proposed product label.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification defines "progenitor cells" by their ability to form various types of colony-forming units (e.g., CFU-GM, CFU-GEMM) and "stem cells" as typically being positive for the CD34 marker, suggesting the term encompasses a class of hematopoietic precursor cells. (’102 Patent, col. 5:2-24).
- Evidence for a Narrower Interpretation: The patent provides specific protocols for assaying these cells, such as culturing them in methylcellulose and scoring colonies after a set time. (’102 Patent, col. 19:20-33). A party could argue the claims are limited to cells that meet the criteria of these specific experimental definitions.
Term for Construction: "harvesting"
Context and Importance: This is the final active step of the method claim. Its definition is critical to determining what actions complete the infringing process. The '590 Patent uses the general term "harvesting," while the '102 Patent specifies "harvesting... by apheresis."
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation (for '590 Patent): The use of the general term "harvesting" in the ’590 Patent, without the "by apheresis" limitation present in the related ’102 Patent, could suggest the patentee intended a broader meaning covering any method of collection. (’590 Patent, col. 27:53-54).
- Evidence for a Narrower Interpretation: The specification of both patents consistently discusses mobilization to permit harvesting for transplantation, and the working examples describe standard collection techniques. A party might argue that "harvesting" in the context of the patent implies a specific set of clinical procedures, such as apheresis, even where not explicitly stated in the claim. (’102 Patent, col. 4:65-67).
VI. Other Allegations
Indirect Infringement
The complaint alleges induced infringement under 35 U.S.C. § 271(b). The basis for this allegation is that the Defendant, by seeking approval for its ANDA product, intends for physicians and patients to use the product in accordance with its prescribing information, which will allegedly instruct users to perform the steps of the patented methods (Compl. ¶¶ 46, 59).
Willful Infringement
The complaint alleges that the Defendant's infringement is and will be willful. This allegation is supported by the claims that the Defendant had pre-suit knowledge of the patents-in-suit via its Paragraph IV certification, and, significantly, had notice of prior court decisions in the District of Delaware and the Federal Circuit that upheld the validity of the asserted claims against challenges from other generic manufacturers (Compl. ¶¶ 51, 64).
VII. Analyst’s Conclusion: Key Questions for the Case
- A primary issue will be one of validity under heightened scrutiny: Given that the asserted claims have survived previous validity challenges, the central question is whether the Defendant can present new prior art or a sufficiently compelling new argument to meet the clear and convincing evidence standard required to invalidate the patents, particularly for obviousness.
- The case will also present a key question of willfulness in the face of established precedent: Will the Defendant’s asserted good-faith belief in its invalidity defense be considered objectively reasonable, or will its decision to proceed with its ANDA filing, despite being aware of prior court rulings upholding the patents, support a finding of willful infringement?