Invalidation of Roche’s Pegasys Patent. Was insufficient disclosure to blame?

The Intellectual Property Appellate Board set aside, grant of Indian Patent No: 198953 to F. Hoffmann-La Roche AG in an appeal after the Controller upheld, validity of the patent in a post-grant opposition. The grant was set aside on grounds that invention claimed is obvious in view of the prior arts cited and also, it does meet requirements of section 3(d) of the Patent Act.

The patent relates to one of Roche’s important biological drugs ‘Pegasys’ which is a pegylated form of Interferon alpha used for treatment of Hepatitis C. The 1997 application was published in 2006 after which post-grant oppositions were filed by M/s. Wockhardt and Sankalp. Controller (T.V. Madhusudhan) had upheld validity of the patent during post grant opposition.

The invention claimed in the patent relates to a class of proteins called ‘Interferons’ which are produced by the body against pathogens such as bacteria and viruses and play a pivotal role in body’s immune mechanism. It is pharmaceutically active and used in the treatment of Hepatitis-C. Unmodified Interferon alpha has several disadvantages such as rapid absorption and removal from the body, degradation by proteolytic enzymes due to which it has a low serum half-life of 4 to 6 hours. Further, all foreign proteins when injected into the body, elicit some immune response though the degree of such response may vary considerably. In order to overcome the disadvantages, proteins is conjugated to a polymer called polyethylene glycol (PEG). This improves stability, solubility and reduces immunogenicity of the conjugated protein when administered into the body.

Pegylation is the process of attachment of one or more PEG chains to another molecule.The site and amount of

pegylation are key factors in determining the activity of a conjugated protein. The amount and site of pegylation can elicit different pharmacokinetic responses, even in the same protein molecules. Interferon possess multiple sites for pegylation and attachment at each of this different sites could have given pegylated interferon, albeit with different pharmacokinetic properties.

Claim 1 of the invention claims a branched PEG (polyethylene glycol) Interferon alpha conjugate having the formula

Formula I

wherein R and R’ are independently lower alkyl, X is NH or O; n and n’ are integers having a sum of from 600 to 1500; and the average molecular weight of the PEG unit is between 26,000 daltons to 66,000 daltons.

The protein conjugate described in the present invention has two linear PEG molecules attached to a single site on Interferon alpha. The advantage of this configuration provides a PEG conjugate with double the PEG mass without having multiple sites of pegylation. The resultant branched PEG interferon conjugate according to the invention, shows enhanced therapeutic activity in comparison to native Interferon as well as liner PEG interferon conjugate (which were already known at the time invention was made).

While deciding on the obviousness issue, Justice Prabha Sridevan observed the following

From the patent specification: (a) Interferons were known to be pharmaceutically active against Hepatitis C; (b) It was known that PEG conjugated proteins have certain clinically useful properties which are better physical and thermal stability, protection against enzymatic degradation, increased solubility, longer in-vivo half-life, and decreased clearance and enhanced potency. PEG conjugated proteins were also known to have reduced immunogenicity and antigenicity. (c) Pegylated interferons had a higher anti-proliferative activity was also known prior to the invention. Based on the above, she concluded the following in relation to the conjugates claimed in the invention, “These are admittedly common general knowledge on the date of invention and therefore improved activity could not have been a surprise it was expected”.

She further observes that the Prior arts disclosed use of higher molecular weights PEG molecules to increase circulation time, activity and to reduced immunogenicity of the administered protein conjugates; Prior arts, particular Mofardini, which was also referenced in the patent’s specification, disclosed branched PEG conjugates of enzymes, having similar structure of the branched PEG molecule disclosed in the Patent, which showed marked improvements over liner PEG conjugates of such enzymes. Thus, a person skilled in the art could have used conventional methods to arrive at the conjugates of the present invention using information available in the prior arts. The results were predictable and there was no surprising effect. She particularly commented that “Even if one grants a degree of unpredictability in the behavior of interferon (vis-à-vis the enzyme), there was a greater reason to expect success since interferon had positively responded to liner PEG conjugates”. In view of the above, novelty was acknowledge however the invention claimed in the Patent was held to be obvious and grant of the Patent was set aside

It may be argued that teachings of Mofardini only relate to pegylated enzymes and not interferons which are completely different in structure, activity and function, hence teachings of Mofardini, cannot be said to have rendered pegylated interferons of the present invention obvious. Though Roche’s patent talks in detail about the size and structure of the PEG molecule used to create PEG conjugated interferon, it contains little information with regard to the site of attachment for the PEG molecule except that it mentions that they may be attached to a primary amino groups on lysine or  the Hydroxyl group on serine or N-terminus of Interferon alpha. Was some crucial piece of information left out from the specification which could have enabled Roche to better describe its inventive contribution in the field of pegylated interferons? May be or may be not, but for now what is to be seen is whether Roche will prefer any further proceedings against the IPAB judgement or accepts the doomed faith of Indian Patent No: 198953.

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