PTAB

IPR2018-00330

Pfizer Inc v. Genentech Inc

Key Events

Petition

petition

Title: PROTEIN PURIFICATION
Brief Description: The ’142 patent is directed to compositions of the anti-HER2 antibody humMAb4D5-8 (trastuzumab). The claims require that the amount of "acidic variant(s)" in the composition is less than about 25%.

Prior Art Relied Upon: Andya (International Publication No. WO 1997/04801).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner argued that Andya disclosed all limitations of claims 1-3. Andya described aqueous pharmaceutical formulations of the humMAb4D5-8 antibody reconstituted from lyophilized material. Petitioner asserted that analysis of stability data in Andya’s Figure 5, which reported 82% native protein at time zero, necessarily meant the composition contained a maximum of 18% non-native variants. Because all acidic variants are non-native variants, the total amount of acidic variants must be less than the claimed 25%. Andya also disclosed that the antibody degrades via deamidation, forming an acidic variant, and that the composition includes a pharmaceutically acceptable carrier.
- Key Aspects: Petitioner asserted that to the extent the presence and amount of acidic variants were not explicit, they were inherently disclosed. Experiments conducted by Petitioner's expert (Dr. Buick) allegedly confirmed that producing the antibody according to prior art methods inevitably results in compositions meeting the claim limitations.

Prior Art Relied Upon: Andya (International Publication No. WO 1997/04801).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner argued that Andya taught a composition of humMAb4D5-8 with 18% acidic variants. A person of ordinary skill in the art (POSA) would have known that deamidation of asparagine was a major degradation pathway for antibodies, leading to acidic variants with potentially reduced activity. The specific site of deamidation disclosed in Andya (Asn30) was known to be in the antibody's antigen-binding region (CDR1), directly impacting its function.
- Motivation to Combine: A POSA would combine Andya's disclosure with the general knowledge that reducing known degradation products is desirable to improve product quality and efficacy. Since the acidic variants were known to occur in the antibody recognition region and exhibit reduced activity, a POSA would have been motivated to obtain a composition with a low level of such variants, such as the level disclosed by Andya.
- Expectation of Success: A POSA would have had a reasonable expectation of success in achieving a composition with less than 25% acidic variants. Cation exchange chromatography (CEX) was a well-known and standard method for separating proteins based on charge, and a POSA would have known how to use and optimize CEX to reduce the amount of charged acidic variants from the main antibody product.

Prior Art Relied Upon: Waterside (a 1996 conference slide presentation).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner contended that Waterside, a slide presentation on characterizing human monoclonal antibodies, disclosed an anti-HER2 antibody composition meeting all limitations of claim 1. Waterside presented cation exchange chromatograms of the antibody rhuMAb HER2, which the ’142 patent acknowledged is the same as humMAb4D5-8. Petitioner's analysis of the chromatograms, by calculating the relative area of the peaks corresponding to acidic variants, showed that the compositions contained between 9.5% and 16.4% acidic variants, well below the claimed threshold of "less than about 25%."

Prior Art Relied Upon: Waterside (a 1996 conference slide presentation).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner argued Waterside disclosed compositions of humMAb4D5-8 containing specific levels of acidic variants (9.5% to 16.4%), which were known to include a deamidated variant at position Asn30. Waterside also taught that this specific acidic variant exhibited only 82% of the specific activity of the parent antibody. The composition was for an antibody in phase III clinical trials, implying formulation in a pharmaceutically acceptable carrier.
- Motivation to Combine: A POSA would be motivated to reduce the amount of acidic variants in the humMAb4D5-8 composition based on Waterside's explicit disclosure that a key acidic variant had significantly reduced biological activity. The motivation was to ensure a more potent and consistent therapeutic product.
- Expectation of Success: A POSA would have had a reasonable expectation of success in preparing a composition with less than 25% acidic variants. Waterside itself used CEX, the standard tool for separating such variants. A POSA would have known that this well-established technique could be readily applied to reduce levels of known, activity-reducing impurities.

"composition": Petitioner proposed this term be construed broadly to mean a composition appropriate for any use, not limited to a specific amount, therapeutic use, process, or scale of manufacture. This construction prevents the Patent Owner from importing limitations not present in the claims.
"acidic variant": Petitioner argued this term should be construed according to its explicit definition in the ’142 patent specification: "a variant of a polypeptide of interest which is more acidic... than the polypeptide of interest," with a deamidated variant being a primary example.
"humMAb4D5-8": Petitioner asserted this term should be construed as synonymous with "rhuMAb HER2" and "huMAb4D5-8" as used in the prior art. This position was based on admissions in the ’142 patent specification and statements made by the inventor during prosecution of a related application, which estopped the Patent Owner from arguing otherwise.