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.”
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.