PTAB

IPR2025-00233

Formycon AG v. Regeneron Pharmaceuticals, Inc.

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1. Case Identification

2. Patent Overview

  • Title: VEGF Antagonist Formulations Suitable for Intravitreal Administration
  • Brief Description: The ’865 patent relates to stable ophthalmic formulations of a vascular endothelial growth factor (VEGF) antagonist, specifically the fusion protein aflibercept. The claims are directed to liquid formulations comprising aflibercept, an organic co-solvent, a buffer, and a stabilizing agent, with specific stability characteristics after storage.

3. Grounds for Unpatentability

Ground 1: Vial Claims - Claims 1-12, 14-17, 19-20, 22-25, 51-53, and 55 are obvious over Fraser in view of Wulff, the 2006 Presentations, the ’319 Publication, and the FDA Container Closure Guidance.

  • Prior Art Relied Upon: Fraser (J. Clin. Endocrinol. Metab., Nov. 2004), Wulff (Endocrinology, Jul. 2002), 2006 Presentations (Regeneron investor presentations, Feb./Mar. 2006), International Publication No. WO 00/75319 (’319 Publication), and FDA Container Closure Guidance (May 1999).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that a person of ordinary skill in the art (POSITA), motivated by the 2006 Presentations disclosing successful intravitreal use of aflibercept for wet AMD, would have modified the only known aflibercept formulation at the time—an intravenous formulation disclosed in Fraser and Wulff. This known formulation contained all the key excipient types: aflibercept (a VEGF antagonist), polysorbate 20 (an organic co-solvent), phosphate buffer, and sucrose (a stabilizing agent). The ’319 Publication was cited to confirm the known amino acid sequence of aflibercept.
    • Motivation to Combine: The 2006 Presentations described aflibercept as a potential "best-in-class" treatment for wet AMD administered via intravitreal injection. This would have strongly motivated a POSITA to develop a formulation suitable for this purpose. The logical starting point was the intravenous formulation from Fraser/Wulff. The necessary modifications were argued to be obvious: (1) selecting the 4 mg dose disclosed as safe and effective in the 2006 Presentations; (2) reducing the injection volume from 2 mL (in Fraser/Wulff) to the known safe intravitreal volume of 0.1 mL, resulting in the claimed 40 mg/mL concentration; and (3) reducing the sucrose from 20% to an iso-osmotic level (<10%) to prevent eye damage. Storing the resulting formulation in a vial was an obvious choice per the FDA Guidance.
    • Expectation of Success: A POSITA would have a high expectation of success because the 2006 Presentations already established that a 4 mg intravitreal dose of aflibercept was safe and effective. The required modifications involved using well-known excipients at concentrations common for intravitreal drugs to achieve iso-osmolarity, a standard and routine practice in formulation development.
    • Key Aspects: Petitioner contended that the claimed stability limitations (e.g., ≥98% native conformation after 2 months at 5°C) are an inherent property of the obvious-to-try formulation. Alternatively, achieving this stability was obvious, as it required only routine optimization, and the stability levels were consistent with those reported for similar antibody formulations in the prior art.

Ground 2: Pre-Filled Syringe (PFS) Claims - Claims 26-36, 39-42, 44-45, 47-50, and 54 are obvious over Fraser in view of Wulff, the 2006 Presentations, the ’319 Publication, and Nayar.

  • Prior Art Relied Upon: Fraser, Wulff, 2006 Presentations, ’319 Publication, and Nayar (Pharm. Biotechnol., 2002).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground is identical to Ground 1, except it challenges claims reciting storage in a pre-filled syringe (PFS) instead of a vial. The arguments for the formulation's composition, concentration, and stability are the same.
    • Motivation to Combine: The motivation to create the intravitreal formulation is identical to Ground 1. The motivation to use a PFS comes from prior art like Nayar, which taught that a PFS was a convenient and "most preferred" dosage form for therapeutic protein products because it eliminates the step of withdrawing the drug from a vial.
    • Expectation of Success: The expectation of success was high for the same reasons as Ground 1. Choosing between a vial and a PFS was presented as a simple, obvious choice between two well-known, conventional container systems for injectable drugs, with the PFS offering known advantages in convenience.

4. Key Claim Construction Positions

  • "about 6.2-6.3" (Claim 9): Petitioner argued this term must be broader than the literal range of 6.2-6.3. A POSITA would have understood that pH meters at the time had a measurement error of +/- 0.1 to 0.2 pH units. Therefore, the pH of 6.0 disclosed in Fraser for the starting formulation would be understood to fall within the scope of "about 6.2," rendering the claim obvious. Petitioner further noted that the ’865 patent's own examples show that formulations with a stated pH of 6.25 or 6.3 had measured pH values that fluctuated over time into a range of 6.1-6.4, supporting a broader construction of "about."

5. Key Technical Contentions (Beyond Claim Construction)

  • Inherent or Obvious Stability: A central contention was that the claimed stability and turbidity values are not patentable because they are either an inherent property of an obvious formulation or were obvious to achieve. Petitioner argued that the "Modified Fraser/Wulff" formulation is a species within the genus of stable formulations disclosed in the ’865 patent's own examples and in another Regeneron patent (Dix). Because these references teach that similar formulations are stable, the claimed stability was not unexpected. A POSITA would have been motivated to maximize stability (e.g., >98% native conformation) as a routine goal and would have achieved it through standard optimization techniques.

6. Arguments Regarding Discretionary Denial

  • §325(d) (Same Art/Arguments): Petitioner argued discretionary denial under §325(d) is unwarranted because the prior art and arguments were not previously considered by the USPTO. During prosecution, the Examiner only issued obviousness-type double patenting rejections and did not substantively evaluate any obviousness combinations like those presented in the petition, even though some references were cited in an Information Disclosure Statement.
  • §314(a) (Parallel Litigation/Serial Petitions): Petitioner argued against discretionary denial under the General Plastic and Fintiv factors. It noted that while another IPR was filed by Samsung Bioepis, Petitioner is not the same party or a real party in interest, and thus serial petition concerns do not apply. To address Fintiv, Petitioner stipulated that, if the IPR is instituted, it will not pursue in the parallel district court proceeding the same grounds raised in the petition or any grounds that could have reasonably been raised.

7. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-12, 14-17, 19-20, 22-36, 39-42, 44-45, and 47-55 of the ’865 patent as unpatentable.