IPAB’s Pegasys Decision: Was the Obviousness Analysis Truncated?

Although the IPAB’s decision (dated November 2, 2012) revoking IN198952 on the Hepatitis C drug Pegasys has been widely reported, I am not sure if the decision’s take on obviousness has been analysed sufficiently. This post is a preliminary look on the analysis in the decision.

The patent IN198952 (1032/MAS/1997) claimed “A Physiologically Active Branched PEG-IFN alpha conjugate”, which is used to treat Hepatitis C. The claims in the patent have been reproduced in Para 22 of the IPAB’s order as follows:

We Claim

1. A physiologically active branched PEG IFNα conjugate having the formula  ( the same formula extracted earlier in page), 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 polyethylene glycol units in said conjugate is from 26,000daltons to about 66,000 daltons.

2. A conjugate of claim 1 wherein the molecular weight of the polyethylene glycol units is from about 35,000 units to about 45,000 units.

3. A conjugate of claim 2 wherein the molecular weight of the polyethylene units is about 40,000 daltons.

4. A conjugate of claim 1 wherein R and R’ are methyl.

5. A conjugate of claim 1 wherein X is NH.

6. A conjugate of claim 1 wherein the IFNα is IFNα2a.

7. A conjugate of claim 1 wherein the average sum of n and n’ is 850 to 1000.

8. A conjugate of claim 1 wherein R and R’ are methyl, X is NH, IFN α is IFN α2a and one or both of n and n’ is 420.

9. A conjugate of claim 1 wherein R and R’ are methyl ; IFN α is IFN α 2a; and one or both of n and n’ is 520.

10. A conjugate of claim 1 which had greater antiproliferative activity than IFNα and less antiviral activity than IFNα.

11. A method for producing a PEG-IFN α conjugate having an increased anti-proliferative activity and decreased antiviral activity as compared to IFNα, which method consists of covalently linking a reagent of Formula II to IFNα to produce said PEG –IFN α conjugate.

12. Pharmaceutical compositions comprising a PEG-IFNα as claimed in anyone of claims 1-10 and a therapeutically inert carrier.

13. A physiologically active branched PEG-IFN conjugate substantially as herein described with reference to the accompanying drawings.

The validity of the invention was assailed primarily on grounds of lack of inventive step and Section 3(d) (Please read Para 33 onwards).

What is the Invention About?

The invention claimed in the patent relates to a class of proteins called “Interferons” which play a pivotal role in the immune mechanism of the body involving eradication of pathogens or tumors.

Claim 1 of the patent is pretty specific and is directed to a specific product which is a branched PEG - Interferon-α conjugated,  where PEG moiety of 26kDA – 66kDA is covalently linked to the Interferon molecule at a specific site. Stated otherwise, the invention related to a Pegylated interferon. Pegylation refers to the attachment of a Polyethylene Glycol (PEG) chain to a molecule.

For me, the strength of the patent lies in the specificity of the claim. Specific substituents at specified sites on the Interferon molecule have been mentioned in the claim. This, to a certain extent, is indicative of the bonafides of the patentee and the fact that the attempt is to not claim something which is unduly broad without sufficient substantiation.

Analysis of the IPAB’s obviousness Reasoning

The IPAB seems to have largely relied upon the Monfardini document to arrive at a conclusion of obviousness. I am not sure if this reliance was justified because the Monfardini document generally spoke of the effect of pegylation on activity of proteins.

The question that needs to addressed from an obviousness point of view is, does the Monfardini document which is dated 1995, combined with the then state of art on effect of pegylation on proteins, contain enough positive assertions to render the specific pegylated interferon claimed in the patent, obvious?

I ran a search on prior art related to pegylation of proteins and I came across the following documents:

-  http://www.ncbi.nlm.nih.gov/pubmed/17101522 : This is a 2001 article, i.e. after the date of filing of the Indian patent, suggesting that pegalylation site did not affect the activity of growth factor protein. In this case, the protein activity was affected solely by the size of PEGylation and was directly proportional to the PEG size attached.

 Excerpts from the article – “The improvement of stability in the rat skin wound tissue was dependent on the increase of the PEG size attached.”

 -    http://www.jbc.org/content/280/8/6327 : This is a 2004 article suggesting inverse relationship between Size of PEGylation and therapeutic activity of protein.

 Excerpts from the article – “The progressive relationship between decreased activity and increased PEG size suggests that pegylation may interfere with interaction and binding of IFN-α to the IFNAR1-IFNAR2 heterodimeric receptor.”

What these two articles specifically seem to suggest is that the amount of pegylation is a critical parameter since the size/amount of pegylation results in varying degrees of response. More importantly, the relation between the increase in activity and pegylation size is not linear/proportional/direct.

Also, these articles were published 4 and 7 years (respectively) after the filing of the Indian patent in 1997. If there was no clarity in the state of art on the nature of the relationship between the amount of pegylation and activity of proteins in 2004, I am not sure it could be said that the 1995 Monfardini document used by the IPAB, combined with the state of art in the year 1995, could render the Indian patent obvious.

Similarly, the following articles show that the significance of pegylation site was still being understood in 2002 and 2004:

 - https://www.thieme-connect.com/ejournals/abstract/10.1055/s-2003-41635: This is a 2002 article which suggests that while Pegylation of proteins was becoming increasingly common within the pharmaceutical industry as a way of altering the activity of the parent molecule, different proteins showed different pharmacokinetic response when it comes to the different PEG moieties attached to the native protein, the site of attachment and the type of bond involved.

The difference in activity is witnessed even within the Interferon group of proteins, i.e. Interferon 2-α and Interferon 2-β may show vastly different activities in response to the above mentioned PEGylation.

Excerpts from the Article : “the different PEG moieties attached to the native protein, the site of attachment and the type of bond involved lead to vast differences with respect to the pharmacokinetics (including absorption, biodistribution, metabolism and elimination) and pharmacodynamics of these two compounds.

-  http://www.jbc.org/content/280/8/6327: This is a 2004 article clearly indicating that site of Pegylation plays an immensely important role in the activity of protein. Positional isomers of IFN-α2b showed vastly different activities, where maximum activity was seen when Pegylated at Histidine site and minimum in case of PEGylation at Cystine site. Pegylation at Lysine sites showed intermediate activity.

Excerpts from the Article - “We prepared purified, homogeneous, positional pegylation isomers of IFN-α2b that were monopegylated using 5–30-kDa linear PEG molecules attached at 7 primary reactive amino acid residues: Cys¹, His³⁴, Lys³¹, Lys⁸³, Lys¹²¹, Lys¹³¹, and Lys¹³⁴. The isomers were evaluated for STAT translocation and antiviral and antiproliferative activity.The site of pegylation strongly influenced activity relative to an IFN-α2b control. The highest residual activity was observed with the His³⁴ positional isomers, and the lowest was observed with the Cys¹positional isomers. The Lys positional isomers demonstrated intermediate activity, with a general order of Lys¹³⁴ > Lys⁸³ ∼ Lys¹³¹ ∼ Lys¹²¹ > Lys³¹. “

Clearly, in as late as 2004, independent research and experimentation was required for different proteins on the effect of pegylation site and size on different proteins since the effects were neither uniform nor predictable. Out of the 11 possible sites available for pegylation in the interferon molecule, attachment at different sites could have led to varying results.

The Monfardini document did not contain enough material to teach or suggest or motivate the site or size of pegylation for a conjugated interferon. Also, merely because the Monfardini document does not exclude interferon from its scope, it shouldn’t be concluded that interferons form part of the disclosure in the document.

Simply put, there wasn’t enough material to either apply an obviousness or “obvious to try” standard considering that the state of art even in 2004 was not settled on the effects of pegylation. Consequently, it would be incorrect to place reliance on the Monfardini publication which was published 1995, to arrive at a finding of obviousness in relation to a claim as specific as the one in the '952 patent.

One sincerely hopes to see a much more nuanced analysis of the prior art in IPAB’s decisions in the future, because the Pegasys decision leaves much to be desired on the scientific front.