DCT
1:19-cv-00264
Genzyme Corp v. Zenara Pharma Pvt Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Genzyme Corp. (Massachusetts) and The Regents of the University of Michigan (Michigan)
- Defendant: Zenara Pharma Private Limited (India)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:19-cv-00264, D. Del., 02/07/2019
- Venue Allegations: Venue is alleged to be proper because the Defendant is a foreign corporation, which may be sued in any judicial district.
- Core Dispute: Plaintiffs allege that Defendant's submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of the drug CERDELGA® (eliglustat) constitutes an act of infringement of four patents covering the eliglustat compound and its therapeutic use.
- Technical Context: The technology relates to small molecule inhibitors of the glucosylceramide synthase enzyme, used as a substrate reduction therapy for the long-term treatment of Gaucher disease type 1, a rare genetic disorder.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a notification letter from Defendant, dated December 27, 2018. The letter included a Paragraph IV Certification alleging that Plaintiffs' patents are invalid and/or would not be infringed by the manufacture, use, or sale of Defendant's proposed generic product.
Case Timeline
| Date | Event |
|---|---|
| 2001-07-16 | Priority Date for ’205 and ’573 Patents |
| 2002-04-29 | Priority Date for ’802 and ’185 Patents |
| 2005-07-12 | ’802 Patent Issued |
| 2007-03-27 | ’205 Patent Issued |
| 2007-08-07 | ’185 Patent Issued |
| 2009-11-10 | ’573 Patent Issued |
| 2014-08-19 | FDA Approves Genzyme's CERDELGA® (eliglustat) NDA |
| 2018-12-27 | Zenara Notifies Plaintiffs of ANDA Filing with Paragraph IV Certification |
| 2019-02-07 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 6,916,802 - Amino Ceramide-Like Compounds and Therapeutic Methods of Use
- Issued: July 12, 2005
The Invention Explained
- Problem Addressed: The patent describes genetic disorders known as glycosphingolipidoses (e.g., Gaucher’s disease), which result from defects in enzymes that metabolize glycosphingolipids (GSLs). This enzymatic defect leads to the harmful accumulation of GSLs in the patient, causing severe clinical manifestations. At the time, the only available treatment was enzyme replacement therapy, which is noted to be extremely expensive and carries risks associated with drugs isolated from human tissues ('802 Patent, col. 1:34-60).
- The Patented Solution: The invention provides "ceramide-like compounds" that inhibit the GlcCer synthase enzyme, which is responsible for forming glucosylceramide (GlcCer), the precursor for hundreds of GSLs. By slowing the synthesis of GlcCer, the compounds are intended to lower the levels of all derived GSLs, allowing the patient's defective enzymes to gradually reduce the accumulation of the toxic substrate ('802 Patent, Abstract; col. 2:61-67). This approach is known as substrate reduction therapy.
- Technical Importance: This technology provided an alternative therapeutic strategy to enzyme replacement, offering the potential for an orally administered small molecule drug to manage GSL storage disorders ('802 Patent, col. 2:47-60).
Key Claims at a Glance
- The complaint asserts independent claims 1 and 6, among others (Compl. ¶36).
- Independent Claim 1 recites:
- A compound of a specific chemical formula (Formula I), a stereoisomer, or a pharmaceutically acceptable salt thereof
- Wherein R¹ is a phenyl, a substituted phenyl group, a branched aliphatic group, or a 7-15 carbon alkyl or alkenyl chain
- Wherein R² is an alkyl group of 2 to 18 carbons
- Wherein R³ is a pyrrolidine, azetidine, morpholine, or piperidine group
U.S. Patent No. 7,196,205 - Synthesis of UDP-Glucose: N-Acylsphingosine Glucosyltransferase Inhibitors
- Issued: March 27, 2007
The Invention Explained
- Problem Addressed: The patent explains that known methods for preparing the amino ceramide-like inhibitor compounds are "poorly suited for manufacturing on an industrial scale" ('205 Patent, col. 2:1-3). Because the target compounds have two chiral centers, prior syntheses produced a mixture of four diastereoisomers, requiring difficult and expensive purification processes not amenable to large-scale production ('205 Patent, col. 2:3-12).
- The Patented Solution: The invention provides an efficient and "highly enantioselective synthesis" that produces the desired ceramide-like compound in only five steps from known starting materials ('205 Patent, col. 2:27-30). This process, illustrated in the patent's Figure 2, results in an enantiomeric excess of at least 99.6%, thereby avoiding the problematic and costly purification steps of prior methods ('205 Patent, col. 2:30-34).
- Technical Importance: The invention provides a commercially viable and economical manufacturing route for these therapeutic compounds, making the substrate reduction therapy a practical alternative to other treatments ('205 Patent, col. 2:20-24).
Key Claims at a Glance
- The complaint asserts independent claim 1, among others (Compl. ¶56).
- Independent Claim 1 recites:
- A compound represented by a specific structural formula, which corresponds to the compound N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide, also known as eliglustat.
- The claim also covers a physiologically acceptable salt thereof.
U.S. Patent No. 7,253,185 - Amino Ceramide-Like Compounds and Therapeutic Methods of Use
- Issued: August 7, 2007 (Compl. ¶18)
- Technology Synopsis: Belonging to the same family as the ’802 Patent, this patent also discloses amino ceramide-like compounds that function as inhibitors of the GlcCer synthase enzyme. The technology is directed at providing a substrate reduction therapy for disorders caused by the accumulation of glycosphingolipids ('185 Patent, Abstract).
- Asserted Claims: Claims 1-4 are asserted (Compl. ¶76). Claim 1 is independent.
- Accused Features: The active ingredient, eliglustat, contained within Zenara's proposed ANDA product, is alleged to be a compound covered by the claims of the ’185 Patent (Compl. ¶¶71, 73).
U.S. Patent No. 7,615,573 - Synthesis of UDP-Glucose: N-Acylsphingosine Glucosyltransferase Inhibitors
- Issued: November 10, 2009 (Compl. ¶19)
- Technology Synopsis: Belonging to the same family as the ’205 Patent, this patent claims methods of using ceramide-like compounds for therapeutic purposes. The claimed methods involve administering an effective amount of a compound like eliglustat to a subject to inhibit glucosylceramide synthase, lower glycosphingolipid concentrations, or treat Gaucher disease ('573 Patent, Abstract).
- Asserted Claims: Claims 1-5 and 21-25 are asserted (Compl. ¶94). Claims 1 and 21 are independent method claims.
- Accused Features: The proposed use of Zenara's generic product for the long-term treatment of Gaucher disease is alleged to infringe the patent's method claims (Compl. ¶94).
III. The Accused Instrumentality
Product Identification
- Defendant Zenara's ANDA No. 212420 product, which is a generic version of CERDELGA® (eliglustat) in 84 mg capsules for oral use (Compl. ¶¶1, 30).
Functionality and Market Context
- The accused product contains the active ingredient eliglustat, which is a small molecule inhibitor of glucosylceramide synthase (Compl. ¶¶13, 32). The complaint provides the chemical structure of the eliglustat hemitartrate salt contained in the CERDELGA® product (Compl. ¶14). The product is intended for the long-term treatment of adult patients with Gaucher disease type 1 (Compl. ¶23). Zenara seeks to market this product as a generic equivalent to Genzyme's branded CERDELGA®, which was granted Orphan Drug Exclusivity for this indication (Compl. ¶15).
IV. Analysis of Infringement Allegations
U.S. Patent No. 6,916,802 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A compound of formula I ... wherein R¹ is a ... substituted phenyl group | Zenara's product contains eliglustat, which has a 2,3-dihydrobenzo[b][1,4]dioxin-6-yl moiety, alleged to be a substituted phenyl group. The complaint provides a diagram of this chemical structure. | ¶¶32, 36, 14 | col. 4:41-46 |
| R² is an alkyl group 2 to 18 carbons long | Eliglustat contains an octanamide group, derived from an 8-carbon acid, which corresponds to a 7-carbon alkyl residue for R². | ¶¶32, 36, 14 | col. 4:51-57 |
| and R³ is a pyrrolidine ... in which the nitrogen atom is attached to the kernel | Eliglustat contains a pyrrolidin-1-yl group attached to the core structure, which is an enumerated R³ group. | ¶¶32, 36, 14 | col. 4:58-62 |
U.S. Patent No. 7,196,205 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A compound represented by the following structural formula: [structure of eliglustat] ... or a physiologically acceptable salt thereof. | The active ingredient in Zenara's ANDA product is alleged to be eliglustat, the specific compound recited in the claim. The complaint provides a diagram of this chemical structure. | ¶¶53, 56, 14 | col. 11:1-25 |
Identified Points of Contention
- Scope Questions: The complaint's infringement theory appears direct: Zenara’s product allegedly contains the exact compound claimed in the ’205 Patent, which is also alleged to fall within the genus of compounds claimed in the ’802 Patent. A potential dispute, though not raised in the complaint, could involve whether a different salt form or polymorph in Zenara's ANDA product might fall outside the scope of the asserted claims.
- Technical Questions: For the method claims (e.g., in the ’802 and ’573 patents), a central question will be whether the instructions for use in Zenara’s proposed product label direct physicians and patients to perform the steps of the claimed methods (Compl. ¶¶33, 94). The content of this label and its interpretation will be a key factual issue for allegations of induced infringement.
V. Key Claim Terms for Construction
- The Term: "a substituted phenyl group" (from Claim 1 of the ’802 Patent)
- Context and Importance: The construction of this term is central to determining whether eliglustat, which contains a 2,3-dihydrobenzo[b][1,4]dioxin-6-yl moiety, literally infringes Claim 1 of the ’802 Patent. Its scope will also be critical to the patent's validity analysis over the prior art. Practitioners may focus on this term because the infringement allegation requires this specific chemical moiety to be classified as a "substituted phenyl group."
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent specification provides an explicit list of exemplary substitutions, including "dioxane substitutions such as methylenedioxy, ethylenedioxy, and trimethylenedioxy" ('802 Patent, col. 4:43-46). This language may support a construction broad enough to encompass the fused dioxin ring structure present in eliglustat.
- Evidence for a Narrower Interpretation: A party seeking a narrower construction might point to the specific chemical structures depicted in the patent's figures, arguing that the term should be limited to substitutions that do not involve a fused ring system if such examples are absent. However, Figure 9 explicitly depicts a D-threo-1-(3’,4’-ethylenedioxy)phenyl structure, which corresponds to the moiety in eliglustat, suggesting the patent contemplates such structures ('802 Patent, Fig. 9).
VI. Other Allegations
- Indirect Infringement: The complaint alleges both induced and contributory infringement of the asserted method claims. The factual basis for these allegations is that Zenara's ANDA product, if approved, will be accompanied by a product label that will instruct physicians and patients to use the product to treat Gaucher disease, which is the patented method (Compl. ¶¶33, 94). The complaint also asserts that there are no substantial non-infringing uses for the product (Compl. ¶¶33, 94).
- Willful Infringement: The complaint alleges that Zenara had actual knowledge of the patents-in-suit prior to submitting its ANDA, as evidenced by its Paragraph IV notification letter (Compl. ¶¶37, 57, 77, 98). It further alleges that Zenara's invalidity and non-infringement positions lack an objective good faith basis, which may support a claim for willful infringement (Compl. ¶¶39, 59, 79, 100).
VII. Analyst’s Conclusion: Key Questions for the Case
As is typical in ANDA litigation, the central dispute will likely concern the validity of the asserted patents, with infringement of the composition claims being a less contentious issue. The case appears poised to turn on the following key questions:
- A primary issue will be one of validity: can the Defendant prove by clear and convincing evidence that the asserted claims covering the eliglustat compound and its method of use for treating Gaucher disease would have been obvious to a person of ordinary skill in the art at the time the inventions were made, as alleged in its Paragraph IV certification?
- A secondary, but critical, question will be one of inducement: assuming the method claims are found valid, does the language of the Defendant's proposed product label provide sufficient instruction and encouragement to physicians to prescribe the drug for treating Gaucher disease, thereby meeting the legal standard for inducing infringement?