Interference No. 104,522 Paper108
Nichols v. Tabakoff Page 38
78. Furthermore, although Dr. Nichols testified that he did not remember Leeson (Ex
2016) being among the synthesis papers sent to him by Dr. Snell (NR, p. 72,1. 23 - p.
73,1. 12), Dr. Nichols testified that he used Leeson as the starting point for his synthetic
scheme (NR, p. 27, ý% 28-29; p. 27, ýT 13-14).
79. In particular, Dr. Nichols testified that he had seen a similar compound described
in a paper by Leeson entitled "4-Amido-2-carboxytetrahydroquinolines. Structure
Activity Relationships for Antagonism at the Glycine Site of the NMDA Receptor." (Ex
2016). Leeson disclosed seven different synthetic schemes (Ld., pp. 1954-1956). For
example, Leeson prepared "[u]reas ... from reactions of 66 [2-carboxy-5,7-dichloro-4
amidotetrahydroquinoline] with the appropriate isocyanates" (id., p. 1955, c. 1).
80. According to Dr. Nichols,
The compounds synthesized by Leeson substitute a urea compound onto
saturated [i.e., aliphatic] rings, whereas the synthesis method of the
present invention substitutes a urea compound onto an unsaturated [i.e.,
aromatic] ring. Based on our long experience of working in the lab with
kynurenates, I can attest that kynurenates behave both chemically and
biologically different from the tetrahydroquinoline counterparts utilized
Leeson. The 4-amino group in the kynurenate compound exists as a
tautomer with the ring nitrogen, making it unreactive with the isocyanates
used by Leeson. This is why, as stated in my prior declaration, the
reaction used by Leeson to synthesize 4-urea substituted
tetrahydroquinoline derivatives was not effective in synthesizing the
compounds of this interference. Exh. 2012, T 30. [NR, p. 20, % 12.]
In other words, Dr. Nichols appears to think an isocyanate might not react with a
4-amino-2-carboxyquinoline.
81. Nonetheless, on (a) January 20 and (b) February 3, 1994, Dr. Nichols attempted
his first synthetic scheme, i.e., reacting isocyanate with the 4-amino group of two
aromatic ring compounds, i.e., (i) 4-amino-5,7-dichloro-2-carboxyquinoline methyl ester
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