Celltrion Inc v. Regeneron Pharmaceuticals Inc

1. Case Identification

• Case #: IPR2025-00456
• Patent #: 11,084,865
• Filed: January 15, 2025
• Petitioner(s): Celltrion, Inc.
• Patent Owner(s): Regeneron Pharmaceuticals, Inc.
• Challenged Claims: 1-50

2. Patent Overview

• Title: Stable Formulations of VEGF Antagonists
• Brief Description: The ’865 patent is directed to stable ophthalmic formulations of a glycosylated VEGF (Vascular Endothelial Growth Factor) antagonist, specifically aflibercept. The claims require the formulation to maintain high levels of the protein in its "native conformation" after prolonged storage.

3. Grounds for Unpatentability

Ground 1: Anticipation over US432 - Claims 1-17, 19-42, and 44-50 are anticipated by US432

• Prior Art Relied Upon: US432 (Application # 2007/0293432).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that US432, an earlier-published application in the ’865 patent's priority chain with an identical specification, discloses every element of the challenged claims. Independent claims 1 and 26 require a formulation with a glycosylated VEGF antagonist, specific excipients (buffer, co-solvent, stabilizing agent), and a stability limitation (at least 98% in native conformation after two months at 5°C). Petitioner contended that Examples 3 and 4 of US432 disclose formulations with all the claimed excipients that inherently meet the stability limitation, showing 99.2% and 99.1% native conformation at two months. Petitioner further argued that although US432 does not explicitly state the protein is glycosylated in the examples, it discloses that the protein may be glycosylated and is produced in CHO cells, which a POSITA would have known results in glycosylation. Dependent claims are allegedly anticipated as these examples disclose the specific concentrations, pH ranges, and components recited therein.
  • Key Aspects: The central thesis of this ground is that the ’865 patent is not entitled to its claimed priority date, making US432 (with its identical disclosure) anticipatory prior art.

Ground 2: Obviousness over US432 and WO685 - Claims 18 and 43 are obvious over US432 in view of WO685

• Prior Art Relied Upon: US432 (Application # 2007/0293432) and WO685 (International Publication No. WO 2017/129685).

• Core Argument for this Ground:

  • Prior Art Mapping: This ground addresses claims 18 and 43, which add the negative limitation that the formulation "does not contain phosphate." Petitioner asserted that US432 teaches using a buffer, such as a phosphate buffer, at a preferred pH of 6.2-6.3 but does not require it. WO685 discloses stable aflibercept formulations that are highly similar to those in US432 but use a non-phosphate histidine buffer at a pH of 6.2.
  • Motivation to Combine: A POSITA looking to formulate the stable aflibercept compositions of US432 would have been motivated to substitute the phosphate buffer with the histidine buffer taught in WO685. The motivation stemmed from WO685's teaching that a histidine-buffered formulation achieved equal or better stability compared to phosphate-buffered formulations, providing a known, successful alternative for achieving the desired stability and pH.
  • Expectation of Success: A POSITA would have had a reasonable expectation of success in making this substitution. The high similarity between the formulation components and parameters in US432 and WO685 (protein, concentration, excipients, pH) would lead one to expect that substituting a known, suitable buffer from WO685 would yield a stable formulation as described in US432.

• Additional Grounds: Petitioner also asserted that all claims (1-50) are obvious over US432 alone. This was presented as an alternative to Ground 1, arguing that even if glycosylation was not inherent in US432's examples, it would have been obvious for a POSITA to use a glycosylated VEGF antagonist as explicitly taught by US432's specification.

4. Key Claim Construction Positions

• "at least 98% [or 99%]...is present in native conformation following storage": Petitioner proposed this phrase should be construed as the percentage relative to the amount of native conformation at time zero, not as an absolute percentage of the total protein used. This construction is based on the specification's goal of "increased stability" and Petitioner's assertion that measuring against the initial protein amount is technically inconsistent with how size-exclusion chromatography (SEC) works, as some protein may be aggregated from the start.
• "glycosylated": Petitioner adopted the construction stipulated in related litigation, meaning "containing at least one amino acid residue with an attached carbohydrate." This broad construction is central to Petitioner's argument that the general glycosylation limitation lacks written description support beyond a single specific example.

5. Key Technical Contentions (Beyond Claim Construction)

• Lack of Written Description Support Denies Priority Date: The petition's central technical-legal argument was that the ’865 patent is not entitled to an effective filing date earlier than October 12, 2018. Petitioner argued the common specification, as filed in 2006, lacks written description support for the key stability and general glycosylation limitations added during prosecution. The specification allegedly provides only isolated data points in examples without disclosing the claimed ranges (e.g., "at least 98%") or showing the inventor possessed the broad genus of generally glycosylated proteins. This lack of support breaks the priority chain, making the earlier-published US432 application, with its identical specification, valid §102/§103 prior art.

6. Arguments Regarding Discretionary Denial

• §325(d) (Same Art/Arguments): Petitioner argued against denial, asserting that the art and arguments are materially different from those considered during prosecution. Prosecution of the ’865 patent family primarily involved obviousness-type double patenting rejections, and the examiner never considered US432 as prior art in a §102 or §103 context. The core issue of whether the claims are entitled to an early priority date was never examined.
• §314(a) (Fintiv Factors): Petitioner contended that discretionary denial based on parallel litigation is unwarranted. It noted that the co-pending district court case against Petitioner is in its earliest stages with no trial date set, and that the grounds raised in the IPR are materially different from those litigated in a separate, completed trial against a different party (Mylan). Petitioner stipulated it would not pursue the same grounds in district court if the IPR is instituted.

7. Relief Requested

• Petitioner requested institution of an inter partes review and cancellation of claims 1-50 of the ’865 patent as unpatentable.