The
PTAB (Patent Trial & Appeal Board) granted Apotex’s petition for an inter
partes review (IPR2016-01542) of Amgen’s U.S. Patent 8,952,138, which covers a
method of refolding proteins. Amgen has
asserted the same patent in a civil case against Apotex, accusing Apotex’s
Neulasta biosimilar of infringing the ‘138 Patent.
Claim 1 of
the ‘138 Patent claims a method for refolding a protein:
1. A method of refolding a protein expressed in a
non-mammalian expression system and present in a volume at a concentration of
2.0 g/L or greater comprising: (a) contacting the protein with a refold buffer
comprising a redox component comprising a final thiol-pair ratio having a range
of 0.001 to 100 and a redox buffer strength of 2 mM or greater and one or more
of: (i) a denaturant; (ii) an aggregation suppressor; and (iii) a protein
stabilizer; to form a refold mixture; (b) incubating the refold mixture; and
(c) isolating the protein from the refold mixture.
Apotex's
obviousness position relies mostly on two references, Schlegl (US 2007/0238860) and
Hevehan (Biotechnology and Bioengineering, 1996, 54(3):221-230). Apotex asserted that Schlegl discloses contacting bovine α-lactalbumin with a refold buffer comprising a redox
component as part of the dilution refold method of Schlegl to form a refold
mixture. Apotex further asserted that a
person of ordinary skill in the art would understand that the addition of
cystine and cysteine in Schlegl serves as the redox system or redox component
for bovine α- lactalbumin. According to Apotex, this redox component has a thiolpair ratio of 2 and a redox buffer strength of
6 mM. Regarding the second reference, Apotex asserted that
Hevehan describes contacting a hen egg white lysozyme with a refold buffer comprising
a redox component to form a refold mixture.
According to Apotex, the redox component had a thiol-pair ratio of
between 0.3 and 9 and a redox buffer strength of 5 mM to 19 mM, the optimum
being between 10-16 mM.
In
granting the IPR petition, the PTAB disagreed with Amgen that claim 1 requires a separate solution of “redox component” having a discrete volume and the “one
or more of” components (i), (ii), and (iii) having a discrete volume. Rather,
the PTAB stated that the broadest reasonable reading of the redox “component”
is as a component portion of the refold buffer overall.
Accordingly, the PTAB found that Apotex had demonstrated a reasonable
likelihood of prevailing on its assertion that the challenged claims are obvious. (Claims 1-11 and 13-24 under 35 U.S.C. §
103(a) as unpatentable over Schlegl and Hevehan and Claim 12 under 35 U.S.C. §
103(a) as unpatentable over Schlegl, Hevehan, and Hakim (mAbs, 1:3, 281-287)).
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