Interference No. 104,522 PaperIO8
Nichols v. Tabakoff Page 40
12 - p. 76J. 15). Notebook Ex 2018 contains an entry "2/16 NIVIR shows [4-amino-7
chloro-2-quinoline carboxylic acid structure] so does MS."
85. It appears that Dr. Nichols conceived of his third synthetic scheme "[oln or before
about February 15, 1994" (NR, p. 29, 124), before he knew for sure that schemes one
and two did not work. To wit,
[o]n or about February 15, 1994, ... [Dr. Nichols] decided that phosgene
1COC121may be reactive enough to attach its acyl carbon to the 4-amino
group of the 4-amino-2-carboxylic-quinoline compound, after which, ...
[he] would attempt to attach a secondary amine [N] to the carboryl group
[CO] because it was a stronger Lewis base and (2) there was not a risk of
it forming a dimer with another quinoline structure. ... [NR, p. 29, 124.]
86. Dr. Nichols already had diethylamine in his laboratory. He substituted
triphosgene for phosgene when he found out that triphosgene was commercially
available whereas phosgene was not. Dr. Nichols ordered triphosgene from Aldrich
Chemical Company. [NR, p. 13, 5 38; p. 29, Tj 24-25.]
87. We note for the record that Dr. Ruth testified that "phosgene (an acyl halide) and
triphosgene are equivalent" for this acylation reaction, citing "Aldrich Catalog Handbook
of Fine Chemicals 1994-1995, p. 1427 (Tabakoff Exhibit 1010)" (Ex 1007, p. 5, ý 15).
We also note that March discloses "[w]hen phosgene is the acyl halide, both aliphatic
and aromatic primary annines give chloroformamides CICONHR that lose HCI to give
isocyanates RNCO" (Ex 1009, p. 418). Thus, it appears that triphosgene would have
been expected to acylate either an aliphatic or aromatic primary amine.
88. According to Dr. Nichols and his notebook Ex 2020, 4-amino-7-chloro-2
quinoline carboxylate was made on March 23, 1994. That 4-amino compound was
reacted with triphosgene, followed by diethylamine on March 27, 1994. However,
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