One Skilled In The Art As Of June 28, 2002 Would Have
Known How-To-Make A Compound Within Counts 2 And 3 :
Without Undue Experimentation
2 On p. 21, l. 23 to p. 25, l. 2, p. 30, ll. 1-6, and p. 39, l. 14 to p. 40, l. 4, Clark argues that
3 the ’350 and ’907 Applications lack enablement for anticipating Counts 2 and 3 because one of
4 ordinary skill in the art could not have synthesized a nucleoside of Counts 2 and 3 without undue
5 experimentation. Storer’s response is that the skilled artisan, as of June 28, 2002, would have
6 been able to make a compound of Counts 2 and 3 without undue experimentation. Ex 1200,
7 ¶¶74-99. Clark’s how-to-make enablement argument comes down to the theory that one of
8 ordinary skill would not know how to synthesize nucleosides with a 2'-methyl (up)-2'-F (down)
9 configuration and therefore could not have synthesized a compound of Counts 2 and 3 (see p. 21,
10 ll. 23-24, p. 22, l. 17 to p. 23, l. 4). As set forth below, Clark is wrong in its theory.
One of Ordinary Skill in the Art Could Synthesize 2'-
12 Methyl (up)-2'-F (down) Nucleosides Without Undue
13 Experimentation
Clark argues that one of ordinary skill in the art, given the ’350 and ’907 Applications,
15 could not have devised a successful route to synthesize a 2'-methyl (up)-2'-F (down) nucleoside
16 without undue experimentation because fluorination chemistry was allegedly unpredictable (p.
17 22, l. 17 to p. 23, l. 4). Clark’s argument that fluorination chemistry was unpredictable is belied
18 by the publications in the art and Dr. Wnuk’s testimony at deposition. Ex 1200, ¶¶100-131.
19 On p, 22, ll. 17-20, Clark asserts that “there was no precedent in the literature for
20 installing a 2’-fluoro-2’-methyl substitution pattern on a nucleoside’s sugar ring.” But 2'-methyl-
21 2'-OH nucleosides were well known by June 2002. Ex 1132, ¶5; Ex 1144 and Ex 2019, at 949;
22 Ex 1115, at 40 to 45. And the structural differences between the known nucleosides and the
23 nucleosides of Counts 2 and 3 would have been well within the skill of the person of skill in the
24 art to accommodate when synthesizing such compounds. Ex 1200, ¶¶91, 95.
25 Furthermore, by 2002 substitution of a hydroxyl (OH) group with fluorine was a well
25
1 known organic transformation, sometimes referred to as deoxyfluorination. Ex 1200, ¶79; Ex
2 2139, at 127:4-7. Indeed, this type of transformation was so well known by 2002 that it was
3 found in reference texts. Ex 1200, ¶80; Ex 1199, at 689-90 (Chapter 8, “Halogenation of
4 Alcohols”). Ex 1199 lists several fluorination reagents and the publications describing the
5 deoxyfluorination reaction conditions using those reagents. Ex 1199, at 689-690. The reagent
6 Et2NSF3, also known as DAST, was commonly used to fluorinate a variety of chemical
7 compounds with success. Id.; Ex 1200, ¶81. Accordingly, one of ordinary skill in the art would
8 have appreciated that DAST could have been used to transform the OH group of known
9 nucleosides into the fluorinated nucleosides of the Counts. Ex 1200, ¶85.
By 2002, DAST was known as the “the most convenient and powerful reagent for
11 deoxyfluorination” reactions. Ex 2014, at 259; Ex 1200, ¶82; Ex 1223, at 2357; Ex 2139, at
12 126:17 to 127:3. Despite this, Clark, relying on Dr. Wnuk’s opinion, speculates on p. 22, l. 22 to
13 p. 23, l. 4 that fluorination with DAST “could fail” by “resulting in unfluorinated elimination
14 and/or rearrangement products, or products with the wrong stereochemistry.” But an inspection
15 of the references Dr. Wnuk cites makes clear that one of ordinary skill would have used DAST to
16 successfully fluorinate a 2'-OH group on a nucleoside. Indeed, Dr. Wnuk fails to provide a
17 single reference to show that a 2'-F (down) nucleoside could not have been made or that one
18 skilled in the art would have been deterred from doing so. Ex 1200, ¶128.
The first reference relied on by Clark and its expert Dr. Wnuk is Ex 2104. Paper 162, at
20 23, ll. 2-4; Ex 2001, ¶156. This article opens by stating that “diethylaminosulfur trifluoride
21 (DAST) appears to be the most convenient and powerful reagent for deoxyfluorination.” Ex
22 2014, at 259. While Dr. Wnuk asserts that Ex 2014 teaches that a reaction with DAST may
23 result in “non-fluorination side reactions” (Ex 2001, ¶ 156), he nevertheless admitted during
ross examination that the reactions he cited in Ex 2014 still resulted in a 30% yield of the
2 desired fluorinated products. Ex 2139, at 129:14-21; Ex 2014, at 259, fn* (30% of three
3 fluoroinositol analogues). Both parties’ experts agree that one of ordinary skill in the art could
4 have isolated and separated compounds with a less than 1% yield for reactions conducted on a
5 gram scale. Ex 1197, at 7902 to 7908; Ex 1200, ¶103; Ex 2139, at. 99:19-100:8. And Dr. Wnuk
6 agreed that Ex 2014 does not deter one of ordinary skill in the art from using DAST for
7 deoxyflourination. Ex 2139, at 131:6-10.
Clark and Dr. Wnuk then point to Ex 2015 for the proposition that fluorination with
9 DAST may proceed with double inversion resulting in a “product with unexpected
10 stereochemistry.” Paper No. 162, p. 23, ll. 2-4; Ex. 2001, ¶156. But even the title of the paper
11 indicates that double inversion was not the norm: “Unanticipated Retention of Configuration in
12 the DAST fluorination of Deoxy-4'-thiopyrimidine Nudeosides with ‘Up’ Hydroxyl Groups” Ex
13 2015, at 7569 (emphasis added). Further, the paper explains that the unexpected double
14 inversion was a result of the sulfur in the thiofuranose ring. Ex 2139, at 136:8-12. The
15 compounds of Counts 2 and 3 do not have a thiofuranose ring (i.e., a furanose with sulfur), and
16 are therefore structurally different than the compound that resulted in the unexpected retention of
17 configuration. Ex 1200, ¶109; Ex 2139, at 136:15-23.
Instead, one of ordinary skill in the art would have expected deoxyfluorination with
19 DAST to proceed with inversion in which the final stereochemical orientation of the fluorine
20 atom is opposite of the initial stereochemical orientation of the OH group (e.g., OH (up) would
21 result in F (down)). Ex 2139, at 133:17-134:7. As Dr. Wnuk testified, one of ordinary skill in
22 the art would have expected fluorination of OH groups using DAST to proceed with inversion.
23 Ex 2139, at 133:17-134:7. One of ordinary skill in the art would have therefore predicted that
deoxyfluorination of a nucleoside with a 2'-OH (up) group using DAST would proceed with
2 inversion to form a nucleoside with a 2'-F (down) group, like those of Counts 2 and 3, and thus
3 employ an appropriate synthetic route that takes inversion into account. Ex 1200, ¶86.
4 Moreover, the double inversion phenomenon was well known as of the priority date, as
5 evidenced by Ex 2015 itself. One of ordinary skill in the art would have been aware of the
6 possibility, and could have quickly corrected for it accordingly if necessary. Thus, Ex 2015 does
7 nothing to change whether one of ordinary skill in the art would have been able to synthesize
8 compounds within Counts 2 and 3 without undue experimentation. Ex 1200, ¶111.
Known How-To-Make A Compound Within Counts 2 And 3 :
Without Undue Experimentation
2 On p. 21, l. 23 to p. 25, l. 2, p. 30, ll. 1-6, and p. 39, l. 14 to p. 40, l. 4, Clark argues that
3 the ’350 and ’907 Applications lack enablement for anticipating Counts 2 and 3 because one of
4 ordinary skill in the art could not have synthesized a nucleoside of Counts 2 and 3 without undue
5 experimentation. Storer’s response is that the skilled artisan, as of June 28, 2002, would have
6 been able to make a compound of Counts 2 and 3 without undue experimentation. Ex 1200,
7 ¶¶74-99. Clark’s how-to-make enablement argument comes down to the theory that one of
8 ordinary skill would not know how to synthesize nucleosides with a 2'-methyl (up)-2'-F (down)
9 configuration and therefore could not have synthesized a compound of Counts 2 and 3 (see p. 21,
10 ll. 23-24, p. 22, l. 17 to p. 23, l. 4). As set forth below, Clark is wrong in its theory.
One of Ordinary Skill in the Art Could Synthesize 2'-
12 Methyl (up)-2'-F (down) Nucleosides Without Undue
13 Experimentation
Clark argues that one of ordinary skill in the art, given the ’350 and ’907 Applications,
15 could not have devised a successful route to synthesize a 2'-methyl (up)-2'-F (down) nucleoside
16 without undue experimentation because fluorination chemistry was allegedly unpredictable (p.
17 22, l. 17 to p. 23, l. 4). Clark’s argument that fluorination chemistry was unpredictable is belied
18 by the publications in the art and Dr. Wnuk’s testimony at deposition. Ex 1200, ¶¶100-131.
19 On p, 22, ll. 17-20, Clark asserts that “there was no precedent in the literature for
20 installing a 2’-fluoro-2’-methyl substitution pattern on a nucleoside’s sugar ring.” But 2'-methyl-
21 2'-OH nucleosides were well known by June 2002. Ex 1132, ¶5; Ex 1144 and Ex 2019, at 949;
22 Ex 1115, at 40 to 45. And the structural differences between the known nucleosides and the
23 nucleosides of Counts 2 and 3 would have been well within the skill of the person of skill in the
24 art to accommodate when synthesizing such compounds. Ex 1200, ¶¶91, 95.
25 Furthermore, by 2002 substitution of a hydroxyl (OH) group with fluorine was a well
25
1 known organic transformation, sometimes referred to as deoxyfluorination. Ex 1200, ¶79; Ex
2 2139, at 127:4-7. Indeed, this type of transformation was so well known by 2002 that it was
3 found in reference texts. Ex 1200, ¶80; Ex 1199, at 689-90 (Chapter 8, “Halogenation of
4 Alcohols”). Ex 1199 lists several fluorination reagents and the publications describing the
5 deoxyfluorination reaction conditions using those reagents. Ex 1199, at 689-690. The reagent
6 Et2NSF3, also known as DAST, was commonly used to fluorinate a variety of chemical
7 compounds with success. Id.; Ex 1200, ¶81. Accordingly, one of ordinary skill in the art would
8 have appreciated that DAST could have been used to transform the OH group of known
9 nucleosides into the fluorinated nucleosides of the Counts. Ex 1200, ¶85.
By 2002, DAST was known as the “the most convenient and powerful reagent for
11 deoxyfluorination” reactions. Ex 2014, at 259; Ex 1200, ¶82; Ex 1223, at 2357; Ex 2139, at
12 126:17 to 127:3. Despite this, Clark, relying on Dr. Wnuk’s opinion, speculates on p. 22, l. 22 to
13 p. 23, l. 4 that fluorination with DAST “could fail” by “resulting in unfluorinated elimination
14 and/or rearrangement products, or products with the wrong stereochemistry.” But an inspection
15 of the references Dr. Wnuk cites makes clear that one of ordinary skill would have used DAST to
16 successfully fluorinate a 2'-OH group on a nucleoside. Indeed, Dr. Wnuk fails to provide a
17 single reference to show that a 2'-F (down) nucleoside could not have been made or that one
18 skilled in the art would have been deterred from doing so. Ex 1200, ¶128.
The first reference relied on by Clark and its expert Dr. Wnuk is Ex 2104. Paper 162, at
20 23, ll. 2-4; Ex 2001, ¶156. This article opens by stating that “diethylaminosulfur trifluoride
21 (DAST) appears to be the most convenient and powerful reagent for deoxyfluorination.” Ex
22 2014, at 259. While Dr. Wnuk asserts that Ex 2014 teaches that a reaction with DAST may
23 result in “non-fluorination side reactions” (Ex 2001, ¶ 156), he nevertheless admitted during
ross examination that the reactions he cited in Ex 2014 still resulted in a 30% yield of the
2 desired fluorinated products. Ex 2139, at 129:14-21; Ex 2014, at 259, fn* (30% of three
3 fluoroinositol analogues). Both parties’ experts agree that one of ordinary skill in the art could
4 have isolated and separated compounds with a less than 1% yield for reactions conducted on a
5 gram scale. Ex 1197, at 7902 to 7908; Ex 1200, ¶103; Ex 2139, at. 99:19-100:8. And Dr. Wnuk
6 agreed that Ex 2014 does not deter one of ordinary skill in the art from using DAST for
7 deoxyflourination. Ex 2139, at 131:6-10.
Clark and Dr. Wnuk then point to Ex 2015 for the proposition that fluorination with
9 DAST may proceed with double inversion resulting in a “product with unexpected
10 stereochemistry.” Paper No. 162, p. 23, ll. 2-4; Ex. 2001, ¶156. But even the title of the paper
11 indicates that double inversion was not the norm: “Unanticipated Retention of Configuration in
12 the DAST fluorination of Deoxy-4'-thiopyrimidine Nudeosides with ‘Up’ Hydroxyl Groups” Ex
13 2015, at 7569 (emphasis added). Further, the paper explains that the unexpected double
14 inversion was a result of the sulfur in the thiofuranose ring. Ex 2139, at 136:8-12. The
15 compounds of Counts 2 and 3 do not have a thiofuranose ring (i.e., a furanose with sulfur), and
16 are therefore structurally different than the compound that resulted in the unexpected retention of
17 configuration. Ex 1200, ¶109; Ex 2139, at 136:15-23.
Instead, one of ordinary skill in the art would have expected deoxyfluorination with
19 DAST to proceed with inversion in which the final stereochemical orientation of the fluorine
20 atom is opposite of the initial stereochemical orientation of the OH group (e.g., OH (up) would
21 result in F (down)). Ex 2139, at 133:17-134:7. As Dr. Wnuk testified, one of ordinary skill in
22 the art would have expected fluorination of OH groups using DAST to proceed with inversion.
23 Ex 2139, at 133:17-134:7. One of ordinary skill in the art would have therefore predicted that
deoxyfluorination of a nucleoside with a 2'-OH (up) group using DAST would proceed with
2 inversion to form a nucleoside with a 2'-F (down) group, like those of Counts 2 and 3, and thus
3 employ an appropriate synthetic route that takes inversion into account. Ex 1200, ¶86.
4 Moreover, the double inversion phenomenon was well known as of the priority date, as
5 evidenced by Ex 2015 itself. One of ordinary skill in the art would have been aware of the
6 possibility, and could have quickly corrected for it accordingly if necessary. Thus, Ex 2015 does
7 nothing to change whether one of ordinary skill in the art would have been able to synthesize
8 compounds within Counts 2 and 3 without undue experimentation. Ex 1200, ¶111.