DCT

3:18-cv-10952

Endo Pharma Inc v. Lupin Atlantis Holdings SA

Key Events

Complaint

I. Executive Summary and Procedural Information

Parties & Counsel:
- Plaintiff: Endo Pharmaceuticals Inc. (Delaware)
- Defendant: Lupin Atlantis Holdings SA (Switzerland)
- Plaintiff’s Counsel: The Davis Firm, PC; Latham & Watkins LLP
Case Identification: 2:17-cv-00558, E.D. Tex., 07/28/2017
Venue Allegations: Venue is asserted on the basis that Defendant is a foreign corporation, which may be sued in any judicial district where it is subject to the court's personal jurisdiction.
Core Dispute: Plaintiff alleges that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff’s Nascobal® nasal spray constitutes an act of infringement of six patents related to cyanocobalamin (Vitamin B12) formulations and intranasal delivery methods.
Technical Context: The technology concerns aqueous, low-viscosity formulations for intranasal delivery of Vitamin B12, a treatment for certain deficiencies that traditionally required injections, thereby offering a more convenient self-administration option.
Key Procedural History: This is a Hatch-Waxman action initiated in response to Defendant's June 16, 2017 notice letter, which contained a Paragraph IV Certification asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by its proposed generic product. The complaint was filed within the 45-day statutory window.

Case Timeline

Date	Event
2003-03-04	Earliest Patent Priority Date ('636, '489, '349, '353, '714, '007 Patents)
2007-06-12	'636 Patent Issued
2008-07-29	'489 Patent Issued
2011-02-01	'349 Patent Issued
2011-08-23	'353 Patent Issued
2015-01-27	'714 Patent Issued
2016-08-16	'007 Patent Issued
2017-06-16	Defendant's ANDA Notice Letter Sent
2017-07-28	Complaint Filing Date

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

U.S. Patent No. 7,229,636 - “Cyanocobalamin Low Viscosity Aqueous Formulations for Intranasal Delivery,” issued June 12, 2007.

The Invention Explained

Problem Addressed: The patent describes that prior art methods for intranasal delivery of Vitamin B12 required either high concentrations (greater than 1%) of the vitamin or administration in a viscous gel to ensure sufficient absorption, as low-viscosity solutions were thought to be quickly cleared from the nasal mucosa without permitting useful absorption (’636 Patent, col. 3:4-14). Additionally, some prior formulations used mercury compounds as preservatives (’636 Patent, col. 3:26-30).
The Patented Solution: The invention is a stable, mercury-free, low-viscosity (<1000 cPs) aqueous solution of cyanocobalamin that achieves a therapeutically effective bioavailability (at least 7% relative to an intramuscular injection) when administered as a nasal spray (’636 Patent, Abstract; col. 3:48-56). The solution achieves this through a specific combination of a buffering agent, a humectant, and a preservative, which allows for effective absorption without the need for a high-viscosity gel (’636 Patent, col. 5:16-24).
Technical Importance: This approach provided a patient-friendly alternative to injections and unpleasant high-viscosity gels for maintenance therapy of Vitamin B12 deficiency (’636 Patent, col. 3:35-46).

Key Claims at a Glance

The complaint asserts independent claims 1 and 24 (Compl. ¶38).
Claim 1 (Composition):
- A stable pharmaceutical aqueous solution of cyanocobalamin and water.
- Comprising a preservative selected from a specific list (e.g., benzalkonium chloride).
- Comprising a buffer selected from a specific list (e.g., citric acid, sodium citrate).
- Comprising a humectant selected from a specific list (e.g., glycerin).
- The solution has a viscosity less than about 1000 cPs.
- The solution has a bioavailability of at least about 7% relative to an intramuscular injection.
- A proviso that the solution contains no mercury or mercury compounds.
Claim 24 (Method of Administration): A method of administering cyanocobalamin by infusing the nose with an aqueous solution having the properties described in claim 1.
The complaint also asserts dependent claims 30 and/or 31 (Compl. ¶38).

U.S. Patent No. 7,404,489 - “Cyanocobalamin Low Viscosity Aqueous Formulations for Intranasal Delivery,” issued July 29, 2008.

The Invention Explained

Problem Addressed: While the '636 patent focuses on the chemical formulation, this related patent addresses the physical delivery mechanism. Effective intranasal drug delivery requires not just the right formulation but also a device that can generate a spray with specific physical characteristics to ensure proper deposition on the nasal mucosa (’489 Patent, col. 6:14-25).
The Patented Solution: The invention is a pharmaceutical kit comprising the aqueous cyanocobalamin solution in a container paired with a specific 'droplet-generating actuator.' This actuator is claimed to produce a spray with a defined 'spray pattern ellipticity ratio' of about 1.0 to 1.4 when measured at a 3.0 cm height, ensuring a consistent and effective spray pattern for drug delivery (’489 Patent, col. 5:35-46; col. 17:7-12). Figures 1A, 1B, and 2 illustrate the spray pump kit, the spray plume, and the resulting spray pattern (’489 Patent, Figs. 1A, 1B, 2).
Technical Importance: By claiming the drug formulation in combination with a delivery device having specific spray characteristics, the invention seeks to control the physical parameters of administration critical for achieving the desired bioavailability.

Key Claims at a Glance

The complaint asserts independent claim 1 (Compl. ¶66).
Claim 1 (Kit):
- A pharmaceutical kit for nasal drug delivery.
- Comprising an aqueous solution of cyanocobalamin and excipients in a container.
- Comprising a droplet-generating actuator attached to the container.
- The actuator produces a spray of the solution through a tip when engaged.
- The spray has a spray pattern ellipticity ratio of from about 1.0 to about 1.4 when measured at a height of 3.0 cm from the actuator tip.

Multi-Patent Capsule: U.S. Patent No. 7,879,349

Patent Identification: ’349 Patent, “Cyanocobalamin Low Viscosity Aqueous Formulations for Intranasal Delivery,” issued February 1, 2011.
Technology Synopsis: A continuation of the '489 patent, this patent claims a stable, mercury-free, low-viscosity aqueous formulation of cyanocobalamin with specific bioavailability characteristics, similar to the '636 patent. The claims are directed to the pharmaceutical composition itself and methods of administration.
Asserted Claims: Independent claims 1 (composition) and 9 (method of administration) (Compl. ¶89).
Accused Features: The Lupin ANDA Product is alleged to be a stable aqueous solution with the claimed components, viscosity, and bioavailability (Compl. ¶93).

Multi-Patent Capsule: U.S. Patent No. 8,003,353

Patent Identification: ’353 Patent, “Cyanocobalamin Low Viscosity Aqueous Formulations for Intranasal Delivery,” issued August 23, 2011.
Technology Synopsis: A divisional of the '489 patent, this patent focuses on the method of administering the cyanocobalamin solution. The claims recite administering the solution as a spray with a specific ellipticity ratio, similar to the kit claim of the '489 patent.
Asserted Claims: Independent claim 1 (method of administration) (Compl. ¶117).
Accused Features: The proposed label for the Lupin ANDA Product allegedly instructs users to administer the product as a spray, which is alleged to have the claimed ellipticity ratio (Compl. ¶118, ¶126).

Multi-Patent Capsule: U.S. Patent No. 8,940,714

Patent Identification: ’714 Patent, “Cyanocobalamin Low Viscosity Aqueous Formulations for Intranasal Delivery,” issued January 27, 2015.
Technology Synopsis: A continuation of the '353 patent, this patent claims a method of administering a pharmaceutically effective amount of cyanocobalamin to a 'subject in need thereof.' The claims again focus on the concentration, viscosity, and relative bioavailability of the solution.
Asserted Claims: Independent claims 1 and 10 (methods of administration) (Compl. ¶142).
Accused Features: The Lupin ANDA Product is alleged to be a solution with the claimed properties, and its proposed label allegedly instructs administration to a subject in need thereof (Compl. ¶147, ¶150-151).

Multi-Patent Capsule: U.S. Patent No. 9,415,007

Patent Identification: ’007 Patent, “Cyanocobalamin Low Viscosity Aqueous Formulations for Intranasal Delivery,” issued August 16, 2016.
Technology Synopsis: A continuation of the '714 patent, this patent narrows the method of use to administration to a 'subject having vitamin B12 deficiency associated with gastric surgery.' This patent also includes kit claims.
Asserted Claims: Independent claims 1 (method of administration) and 13 (kit) (Compl. ¶166).
Accused Features: The proposed label for the Lupin ANDA Product allegedly indicates administration for subjects with vitamin B12 deficiency associated with gastric surgery (Compl. ¶171). The product itself is alleged to be a kit with the claimed components (Compl. ¶175).

III. The Accused Instrumentality

Product Identification

Defendant's proposed generic cyanocobalamin nasal spray, identified as the "Lupin ANDA Product" (Compl. ¶6).

Functionality and Market Context

The complaint alleges the Lupin ANDA Product is a generic copy of Plaintiff's Nascobal® brand nasal spray and contains the same active ingredient in the same concentration (Compl. ¶6, ¶40).
Functionally, it is alleged to be a "stable pharmaceutical aqueous solution" comprising cyanocobalamin, water, a preservative (such as benzalkonium chloride), a buffer (such as citric acid and sodium citrate), and a humectant (such as glycerin) (Compl. ¶42).
The product is designed for intranasal administration via a spray actuator, and the complaint alleges the resulting formulation has a viscosity below 1000 cPs and a bioavailability of at least 7% relative to an intramuscular injection (Compl. ¶42). The spray produced is alleged to have an ellipticity ratio between 1.0 and 1.4 (Compl. ¶71).
No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

'636 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A stable pharmaceutical aqueous solution of cyanocobalamin comprised of cyanocobalamin and water...	The Lupin ANDA Product is alleged to be a stable pharmaceutical aqueous solution comprising cyanocobalamin and water.	¶42	col. 3:50-56
...a preservative selected from the group consisting of benzyl alcohol, parabens thimerosal, chlorobutanol, benzethonium chloride, and benzalkonium chloride, and combinations thereof...	The accused product is alleged to contain a preservative from the recited group, specifically benzalkonium chloride.	¶42	col. 5:36-40
...a buffer selected from the group consisting of citric acid, sodium citrate...and combinations thereof...	The accused product is alleged to contain a buffer from the recited group, specifically citric acid and sodium citrate.	¶42	col. 5:20-22
...and a humectant selected from the group consisting of sorbitol, propylene glycol, and glycerin, and combinations thereof...	The accused product is alleged to contain a humectant from the recited group, specifically glycerin.	¶42	col. 5:30-35
...wherein said solution of cyanocobalamin is suitable for intranasal administration, and has a viscosity less than about 1000 cPs...	The accused product is alleged to be suitable for intranasal administration and to have a viscosity of less than about 1000 cPs.	¶42	col. 3:51-52
...and wherein said solution of cyanocobalamin has a bioavailability of cyanocobalamin when administered intranasally of at least about 7% relative to an intramuscular injection of cyanocobalamin...	The accused product is alleged to have a bioavailability of at least about 7% relative to an intramuscular injection.	¶42	col. 3:52-56
...with the proviso that the solution contains no mercury or mercury compounds.	The accused product is alleged to contain no mercury or mercury compounds.	¶42	col. 3:41-43

'489 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A pharmaceutical kit for nasal drug delivery comprising: an aqueous solution of cyanocobalamin and excipients in a container...	The Lupin ANDA Product is alleged to be a kit for nasal drug delivery comprising an aqueous solution of cyanocobalamin in a container.	¶71	col. 7:10-14
...and a droplet-generating actuator attached to said container and fluidly connected to the cyanocobalamin solution in the container...	The accused product is alleged to include a droplet-generating actuator attached to the container.	¶71	col. 7:14-17
...wherein said actuator produces a spray of the cyanocobalamin solution through a tip of the actuator when said actuator is engaged...	The accused product's actuator is alleged to produce a spray through a tip when engaged.	¶71	col. 7:18-21
...wherein said spray of cyanocobalamin solution has a spray pattern ellipticity ratio of from about 1.0 to about 1.4 when measured at a height of 3.0 cm from the actuator tip.	The accused product's spray is alleged to have a spray pattern ellipticity ratio within the claimed range when measured at the specified height.	¶71	col. 7:22-26

Identified Points of Contention

Factual/Evidentiary Questions: The core of the dispute may turn on factual evidence, not claim construction. Key questions include: Can Plaintiff prove that Defendant's proposed product, once manufactured, will actually meet the quantitative limitations of the claims? For example, what evidence supports the allegation that the Lupin ANDA Product will have a "bioavailability... of at least about 7%" ('636 Patent) or a "spray pattern ellipticity ratio of from about 1.0 to about 1.4" ('489 Patent)? In an ANDA case, this is often based on the assumption that the generic must be bioequivalent to the branded drug, which was designed to meet these specifications.
Scope Questions: For the method-of-use patents ('714, '007), a central question will be whether Defendant's proposed label will induce infringement. This analysis will focus on whether the label's language encourages, recommends, or promotes the specific patented methods of administration to the claimed patient populations (e.g., those with deficiency "associated with gastric surgery").

V. Key Claim Terms for Construction

"bioavailability... of at least about 7% relative to an intramuscular injection of cyanocobalamin" (’636 Patent, Claim 1)

Context and Importance: This term is a critical quantitative limitation defining the efficacy of the formulation. The infringement analysis for the composition claims hinges on whether the accused product meets this specific performance threshold. Practitioners may focus on this term to dispute whether the accused product actually achieves this level of performance or to argue that the method of measuring it is ambiguous.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The use of "about" suggests the 7% value is not a rigid floor and may encompass values slightly below 7.0%. The specification repeatedly emphasizes achieving a bioavailability of "at least about 7%" without defining a specific upper bound, suggesting the key inventive concept is simply crossing this minimum effective threshold (’636 Patent, col. 3:54, col. 4:18).
- Evidence for a Narrower Interpretation: The detailed examples provide specific pharmacokinetic data where bioavailability was measured and calculated, including results of 6.1% (spray) and 6.2% (gel) relative to a 100 mcg IM injection when dose-normalized, which translates to a higher percentage for the claimed 500 mcg dose (’636 Patent, col. 11:1-3). A defendant might argue that the term should be interpreted strictly in light of the specific experimental conditions and calculation methods described in these examples.

"spray pattern ellipticity ratio" (’489 Patent, Claim 1)

Context and Importance: This term defines a key physical characteristic of the spray produced by the delivery device. Infringement of the kit and related method claims depends on whether the accused device produces a spray meeting this geometric parameter. The dispute could focus on the methodology for measuring this ratio and whether the accused product's spray falls within the claimed range.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim uses "about 1.0 to about 1.4," which provides some flexibility at the boundaries. The patent broadly defines the ratio as "the ratio of the major axis to the minor axis" without mandating a single, specific measurement technique, potentially allowing for various industry-standard methods (’489 Patent, col. 6:52-53).
- Evidence for a Narrower Interpretation: Example 4 of the patent provides a highly specific description of the test method used to derive the ellipticity ratio, including the specific equipment ("SprayView NSP system"), measurement distance (30 mm), and resulting data (an ellipticity ratio of 1.14) (’489 Patent, col. 16:20-65). A party might argue that the term should be construed as being limited to results obtained using this specific, disclosed methodology.

VI. Other Allegations

Indirect Infringement: The complaint alleges induced infringement for the method claims. The basis for inducement is Defendant’s proposed product labeling, which allegedly will encourage and instruct end-users to administer the product in a manner that directly infringes the patented methods (Compl. ¶43, ¶94, ¶118, ¶147-148, ¶171-172).
Willful Infringement: While the complaint does not use the word "willful," it repeatedly alleges that Defendant had knowledge of the patents-in-suit "at least the time it submitted the Paragraph IV Certifications to FDA" (Compl. ¶60, ¶83, ¶111, ¶136, ¶160, ¶184). It also seeks a declaration that the case is "exceptional" and an award of attorney fees under 35 U.S.C. § 285, which is the statutory mechanism for addressing litigation misconduct or exceptionally meritless infringement (Compl. ¶53, ¶76, Prayer for Relief ¶Y).

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

A central question will be one of evidentiary proof: Given that this is an ANDA case concerning a product not yet on the market, the infringement analysis will rely on bioequivalence data and product specifications. A key issue will be whether the evidence derived from Defendant's ANDA filing is sufficient to establish, by a preponderance of the evidence, that the proposed generic product will meet the specific quantitative limitations of the asserted claims, such as the minimum 7% relative bioavailability and the precise 1.0-1.4 spray ellipticity ratio.
A second core issue is one of induced infringement scope: For the later-issued patents that claim specific methods of use (e.g., treating deficiency associated with gastric surgery), the case will likely turn on the language of Defendant's proposed product label. The key question for the court will be whether the label's indications and instructions actively encourage or recommend the patented methods, thereby creating liability for induced infringement.