Radius Health Inc v. Orbicular Pharmaceutical Tech Pvt Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Radius Health Inc (Massachusetts) and Ipsen Pharma Sas (France)
  • Defendant: Orbicular Pharmaceutical Technologies Pvt Ltd (India)
  • Plaintiff’s Counsel: Choate Hall & Stewart LLP
• Case Identification: 1:22-cv-11546, D. Mass., 11/02/2023
• Venue Allegations: Venue is alleged to be proper because the Defendant is a foreign corporation with no state of residence in the United States.
• Core Dispute: Plaintiffs allege that Defendant's submission of an Abbreviated New Drug Application (ANDA) to market a generic version of the osteoporosis drug Tymlos® (abaloparatide) constitutes an act of infringement of five U.S. patents covering the drug's formulation, methods of use, and methods of testing.
• Technical Context: The technology at issue is abaloparatide, a synthetic analog of a human parathyroid hormone-related peptide used as an anabolic (bone-building) agent for the treatment of osteoporosis in postmenopausal women.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant's filing of a Paragraph IV certification with the FDA, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by its proposed generic product. U.S. Patent No. RE49,444 is a reissue of U.S. Patent No. 7,803,770, which was surrendered upon the reissue patent's grant. This filing is a Second Amended Complaint.

Case Timeline

Date	Event
2006-10-03	Priority Date for ’444, ’333, and ’382 Patents
2012-04-03	U.S. Patent No. 8,148,333 Issues
2014-06-10	U.S. Patent No. 8,748,382 Issues
2017-04-28	Priority Date for ’208 and ’041 Patents
2017-04-28	FDA approves New Drug Application for Tymlos®
2021-05-04	U.S. Patent No. 10,996,208 Issues
2022-08-08	Defendant’s Notice of Paragraph IV Certification dated
2022-08-09	Plaintiffs receive Defendant’s Notice Letter
2023-03-07	U.S. Reissue Patent No. RE49,444 Issues
2023-10-10	U.S. Patent No. 11,782,041 Issues
2023-11-02	Second Amended Complaint Filed

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

U.S. Reissue Patent No. RE49,444 - "Method of Treating Osteoporosis Comprising Administration of PTHRP Analog"

• Patent Identification: RE49,444, issued March 7, 2023.

The Invention Explained

• Problem Addressed: The complaint notes that at the time of its approval, Tymlos® (abaloparatide) was the first new anabolic (bone-building) agent for osteoporosis in nearly fifteen years, suggesting a need for alternatives to existing antiresorptive therapies (Compl. ¶5).
• The Patented Solution: The patent claims a method for treating osteoporosis by administering a specific daily dosage—80 micrograms—of the synthetic peptide analog abaloparatide via subcutaneous injection to a human patient (Compl. ¶65). This specific dosing regimen is presented as a method of treatment.
• Technical Importance: The invention provides a specific method of use for a novel anabolic agent, distinct from prior therapies that primarily worked by preventing bone resorption (Compl. ¶5).

Key Claims at a Glance

• The complaint asserts at least Claim 1 (Compl. ¶64).
• Claim 1, an independent claim, includes the following essential elements:
  • A method of treating osteoporosis
  • comprising daily subcutaneous administration
  • of a composition comprising 80 µg of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2
  • to a human in need thereof.
• The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 8,148,333 - "Stable Composition Comprising a PTHRP Analogue"

• Patent Identification: 8,148,333, issued April 3, 2012.

The Invention Explained

• Problem Addressed: The patent's background describes the need for pharmaceutical formulations of peptide-based drugs that are acceptable in terms of storage stability and ease of preparation (’333 Patent, col. 1:16-25). Peptide drugs can be prone to degradation in liquid formulations.
• The Patented Solution: The invention is a storage-stable liquid composition of abaloparatide. Stability is achieved by including an effective amount of a pH buffer that maintains the composition's pH within a specific range of about 4.5 to 5.6, which is disclosed as improving the stability of the peptide analog in solution (’333 Patent, col. 2:53-56; Compl. ¶27).
• Technical Importance: This technology enables the provision of abaloparatide in a ready-to-use, multi-dose injection pen, avoiding the need for reconstitution by the patient and facilitating convenient administration (’333 Patent, col. 2:5-8).

Key Claims at a Glance

• The complaint asserts at least Claim 1 (Compl. ¶86).
• Claim 1, an independent claim, includes the following essential elements:
  • A storage-stable composition suitable for administration to a subject
  • comprising: a) a PTHrP analogue having the sequence [Glu22,25, Leu23,28,31, Aib29, Lys26,30] hPTHrP(1-34)NH2 (SEQ ID NO.2); and
  • b) an effective amount of a pH buffer to maintain the pH in a range of about 4.5 to about 5.6.
• The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 8,748,382 - "Method of Drug Delivery for Bone Anabolic Protein"

• Patent Identification: 8,748,382, issued June 10, 2014.
• Technology Synopsis: This patent claims methods of stimulating bone growth in a subject by administering the storage-stable compositions comprising abaloparatide and a pH buffer as described in the ’333 Patent (Compl. ¶28, ¶108). It covers the therapeutic application of the stable formulation.
• Asserted Claims: The complaint asserts at least independent Claim 1 (Compl. ¶107).
• Accused Features: The Defendant's ANDA product, by being a bioequivalent and storage-stable abaloparatide formulation, and its proposed label instructing administration for bone growth stimulation, are alleged to infringe (Compl. ¶109).

U.S. Patent No. 10,996,208 - "Abaloparatide Formulations and Methods of Testing, Storing, Modifying, and Using Same"

• Patent Identification: 10,996,208, issued May 4, 2021.
• Technology Synopsis: This patent addresses the identification and control of a specific abaloparatide-related impurity, beta-Asp10. It claims formulated drug products characterized by a low level of this impurity (≤5% w/w of total peptide content), as well as methods for establishing the suitability of a product for administration by detecting and quantifying this impurity (’208 Patent, Abstract; Compl. ¶29).
• Asserted Claims: The complaint asserts at least independent Claim 14 (Compl. ¶129).
• Accused Features: The ANDA product is alleged to be a formulated abaloparatide drug product that will necessarily meet the claimed low impurity profile to be bioequivalent to Tymlos®, and its suitability will have been established by testing for such impurities (Compl. ¶131).

U.S. Patent No. 11,782,041 - "Abaloparatide Formulations and Methods of Testing, Storing, Modifying, and Using Same"

• Patent Identification: 11,782,041, issued October 10, 2023.
• Technology Synopsis: Continuing the technology of the ’208 patent, this patent claims novel formulated abaloparatide drug products having an even lower level of the beta-Asp10 impurity (e.g., ≤3%). It also claims methods of treating a subject by administering this highly purified drug product (Compl. ¶30, ¶152).
• Asserted Claims: The complaint asserts at least Claim 4, which depends on Claim 1 (Compl. ¶151-152).
• Accused Features: The ANDA product is alleged to meet the stricter impurity profile of ≤3% beta-Asp10, and its proposed label will instruct administration of a daily 80 µg dose, thereby infringing the claimed method of treatment (Compl. ¶154).

III. The Accused Instrumentality

• Product Identification: The accused instrumentality is Defendant Orbicular's proposed generic abaloparatide injection product, which is the subject of Abbreviated New Drug Application (ANDA) No. 217245 filed with the U.S. Food and Drug Administration (Compl. ¶1).
• Functionality and Market Context: The complaint alleges, based on Defendant's Notice Letter, that the ANDA Product is an "injection solution for subcutaneous use" containing abaloparatide as its active ingredient (Compl. ¶65). The product is formulated at a concentration of 3120 mcg/1.56 mL (2000 mcg/mL) and is intended to deliver a daily dose of 80 µg (Compl. ¶13, ¶65). The complaint further alleges that the ANDA Product's label will recommend the same indication, usage, dosage, and administration as the branded Tymlos® product for treating postmenopausal women with osteoporosis (Compl. ¶43, ¶45, ¶46). The filing of the ANDA signifies Defendant's intent to market a generic version of Tymlos® before the expiration of the patents-in-suit (Compl. ¶15).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

RE49,444 Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
[a] method of treating osteoporosis	The label for the ANDA Product will allegedly recommend the same "Indication and Usage as Tymlos®," which is for the treatment of osteoporosis in postmenopausal women at high risk for fracture.	¶43, ¶46	RE49,444, Title
comprising daily subcutaneous administration	The ANDA Product is described as an "injection solution for subcutaneous use," and the proposed label will allegedly recommend the same daily dosage and administration as Tymlos®.	¶31, ¶45, ¶65	RE49,444, col. 10:1-3
of a composition comprising 80 µg of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2	Defendant's Notice Letter allegedly states that the active ingredient is abaloparatide and that the indicated dosage will be 80 µg per day.	¶65	RE49,444, col. 16:35-43
to a human in need thereof.	The product is intended for administration to postmenopausal women with osteoporosis at high risk for fracture.	¶46	RE49,444, col. 8:54-56

• Identified Points of Contention:
  • Scope Questions: The primary infringement theory is inducement based on the proposed product label. A potential point of contention is whether the final, FDA-approved label for the ANDA product will contain language that mandates or merely suggests the claimed "daily" administration, and whether any alternative instructions could allow a user to avoid practicing every element of the claim.
  • Technical Questions: Infringement of this method claim is not contingent on the specific formulation details of the ANDA product, but rather on the instructions for its use. The key evidence will be the language of the proposed and final product labeling.

8,148,333 Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
[a] storage-stable composition suitable for administration to a subject	The complaint alleges that by filing an ANDA and representing its product as bioequivalent to Tymlos®, Defendant has necessarily represented that its product is a storage-stable composition suitable for administration.	¶88	’333 Patent, col. 4:41-47
comprising: a) a PTHrP analogue having the sequence [Glu22,25, Leu23,28,31, Aib29, Lys26,30] hPTHrP(1-34)NH2 (SEQ ID NO.2);	Defendant's Notice Letter allegedly identifies the active ingredient as abaloparatide and provides its specific amino acid sequence, which matches the claimed sequence.	¶87	’333 Patent, col. 2:4-8
and b) an effective amount of a pH buffer to maintain the pH in a range of about 4.5 to about 5.6.	The complaint alleges on information and belief that because the ANDA Product must be the "same as Tymlos®," it will contain an effective amount of a pH buffer to maintain the pH within the claimed range to ensure stability.	¶88	’333 Patent, col. 2:53-56

• Identified Points of Contention:
  • Scope Questions: The definition of "storage-stable" may be a central issue. The parties could dispute the degree of stability required to meet this limitation and the time and temperature conditions under which that stability must be demonstrated.
  • Technical Questions: A key factual question will be whether the Defendant's formulation actually contains "an effective amount of a pH buffer" and whether that buffer actually maintains the pH "in a range of about 4.5 to about 5.6." The complaint's allegation is based on the premise of bioequivalence, which the Defendant may argue does not require an identical formulation.

V. Key Claim Terms for Construction

• The Term: "storage-stable composition" (from Claim 1 of the ’333 Patent)

• Context and Importance: The definition of this term is critical because infringement of the '333 patent hinges on whether the accused generic product meets this requirement. A narrow definition tied to specific stability data could provide a path for non-infringement, while a broader definition could encompass any formulation that is sufficiently stable for commercial use. Practitioners may focus on this term because the patent provides a specific, potentially limiting definition in the specification.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification's general statements about the invention providing stable compositions for parenteral administration could support a broader, functional definition of stability suitable for the product's intended shelf life and use (’333 Patent, col. 1:16-25, col. 4:32-37).
  • Evidence for a Narrower Interpretation: The specification provides a specific definition: a composition is "storage-stable if the amount, purity of the PTHrP remains above about 95% of the original amount under one of the following conditions: (1) storage for over 2 years at 5° C.; or (2) storage for over 30 days at 25° C" (’333 Patent, col. 4:41-47). A defendant may argue this language limits the claim scope to compositions meeting these exact criteria.

• The Term: "wherein the suitability of the formulated abaloparatide drug product for administration to a subject has been established by a method comprising: detecting and quantifying the presence of ≤5% w/w beta-Asp10" (from Claim 14 of the ’208 Patent)

• Context and Importance: This limitation requires not just a product with a certain purity but also that its "suitability" was "established by" a specific testing method. The dispute may turn on whether the Defendant's standard quality control procedures for batch release constitute "establishing suitability" as required by the claim.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: Plaintiffs may argue that any analytical testing performed by the Defendant to confirm that its product meets FDA purity requirements and contains ≤5% beta-Asp10 inherently "establishes" its "suitability" for administration, thus satisfying the claim element (’208 Patent, col. 2:40-45).
  • Evidence for a Narrower Interpretation: Defendant may argue that this claim language requires a specific, formal act of establishing suitability for a particular purpose (e.g., a clinical trial or regulatory submission) that is distinct from routine, post-manufacturing quality control testing. The term "established" could be construed to require more than simple measurement.

VI. Other Allegations

• Indirect Infringement: The complaint alleges both induced and contributory infringement for all asserted patents. The primary basis for inducement is the allegation that the Defendant's proposed product labeling will instruct physicians and patients to administer the ANDA Product in a manner that directly infringes the asserted method claims (Compl. ¶66, ¶109, ¶154).
• Willful Infringement: The complaint does not use the word "willful," but it alleges that Defendant had knowledge of the patents-in-suit at least since the time it filed its ANDA with a Paragraph IV certification (Compl. ¶71, ¶92, ¶114, ¶136, ¶159). It further alleges that Defendant acted "without a reasonable basis for believing that it would not be liable for infringing" and that its non-infringement positions are "devoid of any objective good-faith basis" (Compl. ¶73, ¶93, ¶115, ¶137, ¶160). These allegations, coupled with a request for attorneys' fees under 35 U.S.C. § 285 based on the case being "exceptional," lay the factual predicate for a later claim of willfulness.

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

• A core issue will be one of compositional identity: What are the precise formulation characteristics—specifically the buffer system, pH range, and impurity profile (e.g., beta-Asp10 levels)—of the Defendant's proposed generic product? A key evidentiary question is whether these characteristics fall within the specific ranges claimed by the composition and formulation patents ('333, '208, '041), or if the Defendant has designed a formulation that is bioequivalent yet compositionally distinct.
• A central legal question will be one of induced infringement: Will the final, FDA-approved label for the Defendant’s ANDA product contain instructions that will inevitably lead a substantial number of users (physicians and patients) to perform every step of the claimed methods of treatment and administration ('444, '382, '041)?
• The case may also turn on a question of claim construction: Can the term "storage-stable" ('333 patent) be limited to the specific quantitative definition provided in the specification, and does the phrase "establishing the suitability" ('208 patent) require a specific act beyond routine quality control testing? The court's interpretation of these terms could significantly impact the scope of the claims and the infringement analysis.