Clark and Dr. Wnuk rely on Ex 2016 to argue that deoxyfluorination with DAST may
10 result in an “unfluorinated dehydration product” or a “rearrangement product.” Again, the
11 reliance on the article is surprising, because the introduction states, “Deoxo-Fluor [] and DAST []
12 are widely used in one-step reactions for the introduction of fluorine into organic compounds.”
13 Ex 2016, at 2561. And Dr. Wnuk agreed that this statement describes the state of the art for
14 fluorination in 2002. Ex 2139, at 139:13-21. Nevertheless, Dr. Wnuk points to two reactions,
15 Schemes 5 and 9, to allege that deoxyfluorination with DAST would have been unpredictable.
16 Ex 2001, ¶156. But for Scheme 5, the reaction that resulted in an “unfluorinated dehydration
17 product,” the reference itself teaches one of ordinary skill how to modify the conditions to
18 suppress the dehydration product and achieve successful deoxyfluorination with inversion of
19 configuration. Ex 2139, at 140:7 to 142:22. In the second reaction, Scheme 9, the reaction
20 produced the desired fluorination product in addition to the rearrangement product. Ex 2139, at.
21 143:3-11. As such, Ex 2016 does nothing to change whether one of ordinary skill in the art
22 would have been able to synthesize compounds within the scope of the Storer Claims without
23 due experimentation. Ex 1200, ¶116.
Clark and Dr. Wnuk rely on Ex 2017 for the proposition that DAST fluorination may not
2 be successful. Paper No. 162, p. 23, ll. 2-4; Ex 2001, ¶156. Ex 2017 disclosed two DAST
3 reactions: one that was successful and one that was not. Ex 2139, at 145:17-22. The DAST
4 reaction that was unsuccessful was not performed on a nucleoside. Id. at 146:2-4. And the
5 reaction that was successful proceeded with inversion, precisely as one of ordinary skill in the art
6 would have expected. Id. at 146:23 to 147:6. Accordingly, Ex 2017 does not change the fact
7 that one of ordinary skill in the art would have been able to use DAST to successfully fluorinate
8 hydroxyl groups on nucleosides with the expected inversion of configuration. Ex 1200, ¶¶119-
9 120.
10 The last reference that Clark and Wnuk rely on in support of their argument that
11 fluorination with DAST was unpredictable is Ex 2018. They contend that deoxyfluorination
12 with DAST may result in a “rearrangement product.” Paper No. 162, p. 23, ll. 2-4; Ex 2001,
13 ¶156. But the reaction that resulted in rearrangement also resulted in successful fluorination of a
14 nucleoside with 2′-OH(down) to form a nucleoside with 2′-F (up) in a 30% yield. Ex 2139, at
15 149:6-9. And Ex 2018 teaches that using DAST for deoxyfluorination of a nucleoside with a 2′-
16 OH (up) to form a nucleoside with a 2′-F (down) proceeded with inversion and gave the desired
17 product in an 82% yield without any rearrangement products reported. Ex 2018, at 559; Ex 2139,
18 at 149:10 to 150:11. Again, the reference relied on by Clark and Wnuk does not change that one
19 of ordinary skill in the art would have predicted that deoxyfluorination with DAST would have
20 proceeded with inversion of configuration. (Ex 1200, ¶125.)
21 At p. 23, ll. 4-12, Clark argues that deoxyfluorination of tertiary alcohols could fail to
22 produce fluorinated products. In support of its argument, Clark cites paragraph 157 of Ex 2001
23 (the Wnuk report, relying solely on Ex 2035, Ex 2041, Ex 2042, Ex 2043, and Ex 2029), and Ex
2029 (internal Idenix email and report), Ex 2035 (internal Idenix email), Ex 2041 (internal
2 Idenix report), Ex 2042 (internal Idenix report), Ex 2043 (internal Idenix lab notebook), Ex 2045
(Sommadossi exhibit list from the 1st 3 Interference), and Ex 2007 (the Decision on Priority in the
1st 4 Interference). As internal Idenix documents or documents created in 2013 or later, not a
5 single one of these exhibits is a prior art publication that would have formed part of the
6 knowledge of one of ordinary skill in the art. As such, they would have not impacted whether
7 one of ordinary skill in the art would have predicted that deoxyfluorination of a tertiary alcohol
8 using DAST would successfully proceed. Indeed, the very first publication in 1975 on DAST as
9 a fluorinating reagent states that DAST reacts with tertiary alcohols giving “high yields of the
10 unrearranged fluorinated product.” Ex 2023, at 575. Furthermore, standard references like
11 Larock 1999 (Ex 1199) and Ex 1225 would have pointed one of ordinary skill in the art to the
12 use of DAST for deoxyfluorination. For example Ex 1225 teaches that “DAST … convert
13 primary, secondary, tertiary, allylic and benzylic alcohols into fluorides under mild conditions in
14 high yield with little by-product formation.” Ex. 1225, at 88 (emphasis added). As even Wnuk
15 agreed, one of ordinary skill in the art would have expected deoxyfluorination of a tertiary
16 alcohol to proceed with inversion of configuration. Ex 2139, at. 134:2-6. Furthermore, skilled
17 chemists are accustomed to adapting reaction conditions to overcome the problem of
18 unanticipated side products or failures to obtain the desired product. As such, one of ordinary
19 skill in the art, armed with his or her own training and experience, coupled with the wealth of
20 knowledge and examples of set forth in the prior art directed to fluorinated chemical compounds,
21 would have been able to synthesize 2′-F (down) compounds of Counts 2 and 3 by deoxy-
22 fluorination of nucleosides with a 2′-OH (up) tertiary alcohol using DAST. (Ex. 1200, ¶88.)
23 Clark also argues on p. 23, l. 13 to p. 24, l. 5 that the ’350 Application does not include
working examples of, or provide any guidance regarding, how to make compounds falling within
2 Counts 2 and 3. The response is that the specification does provide guidance for synthesizing
3 compounds of the Storer Claims without undue experimentation. As a legal matter, the
4 specification need not teach how to make a compound if the artisan would have known how to
5 do so at the time of filing. Martin, 454 F.2d at 752; Goeddel, Paper 109, at 40-42, 45; Rochester,
6 358 at 921. Furthermore, starting materials and working examples of how to make a compound,
7 are not required. In re Strahilevitz, 668 F.2d 1129, 1232 (C.C.P.A. 1982); Martin, 454 F.2d at
8 752. Nevertheless, the specification expressly describes starting materials, reagents and
9 reactions that would have been applicable to the preparation of compounds of Counts 2 and 3.
10 Ex 1200, ¶97; Ex 1002, at 122:21 to 125:15, at 135:10-20; Ex 1003, at 1948:1-15; 2706:1-15.
Both experts agree that the structure of the compounds of Counts 2 and 3 would inform
12 one of ordinary skill in the art that a fluorination reagent would be required for synthesis.
13 Ex 1200, ¶89; Ex 2139, at 101:8-15. And as discussed above, the fluorination reagent, DAST,
14 was known to one of ordinary skill in the art for substituting a fluorine for a hydroxyl group with
15 inversion. Therefore, recognizing that inversion will occur, one of ordinary skill in the art would
16 have known to start with a nucleoside having a similar structure to that defined by the claims, but
17 with a 2′-OH (up), in order to obtain the desired 2′-F(down) structure. (Ex 1200, ¶90.)
18 In his expert report, Dr. Wnuk identified a compound that he named (2′R)-2′-deoxy-2′-
19 fluoro-2′-C-methyluridine as a nucleoside that one of ordinary skill would have recognized as
20 within the scope of Counts 2 and 3 (Ex 2001, ¶¶323-324) (“Claimed Compound”). Dr. Wnuk
21 agreed that one of ordinary skill in the art would have recognized compound 17 in the Matsuda
22 article, (“Matsuda Compound 17”), as a precursor to a compound within the scope of the Storer
23 Claims depicted at ¶ 323 of his report (“Claimed Compound”). Ex 2139, at 107:18-108:6,
As can be seen above, Matsuda Compound 17 differs from the Claimed Compound in
5 that the configuration at the 2′ location is inverted with a 2′-OH instead of a 2′-F. Ex 1200, ¶92;
6 Ex 2139, at 107:18 to 108:6. Both parties’ experts agree that the synthesis of the Claimed
Compound would have been essentially a one step8 7 reaction of Matsuda Compound 17 with
8 DAST. Ex 1200, ¶94; Ex 2139, at 156:2-12.) In other words, DAST deoxyfluorinates the 2′-
9 OH(up)-2′-Methyl(down) group with inversion resulting a 2′-Methyl(up)-2′-F(down) group. The
10 synthesis of Matsuda Compound 17 is disclosed in Matsuda 1999. Ex 1200, ¶93; Ex 1144 & Ex
11 2019, at 946-952. The synthesis of Matsuda Compound 17 is the same as the first few steps of
12 Scheme 4 in the ’350 Application. Ex 1132, ¶67; Ex 1003, at 124. In particular, the second
13 compound (2′-keto) of Scheme 4 (Ex 1003, at 125), below, is the starting material of Matsuda
where R1
and R2 14 form a TIPDS protecting group and Base is uridine. Ex 1132,¶65-69; Ex 1144
15 & Ex 2019, at 946-952.
The reaction may require adding, removing and/or changing protecting groups, all of
which were routine in the art. Ex 1200, ¶95; Ex 2139, at 111:25 to 112:4.
Furthermore, the ’305 Application discloses that the R6 1 -M reagent can be an organolithium
2 reagent, which would include the methyl lithium reagent used to synthesize Matsuda Compound
3 17. Ex 1132,¶ 65-69; Ex 1003, at 118; Ex 1144 & Ex 2019, at 946-952. As such, the ’350
4 Application does provide one of ordinary skill in the art with starting materials and guidance for
5 making the compounds within Counts 2 and 3 without undue experimentation. Ex 1200, ¶97.
6 And contrary to Clark’s implication at p. 16, ll. 1-2, fluorinated starting materials (as opposed to
7 fluorinating reagents such as DAST) wound not have been required for synthesis of compounds
8 within the scope of the Storer Claims as evident by Matsuda Compound 17. Ex 1200 , ¶96
10 result in an “unfluorinated dehydration product” or a “rearrangement product.” Again, the
11 reliance on the article is surprising, because the introduction states, “Deoxo-Fluor [] and DAST []
12 are widely used in one-step reactions for the introduction of fluorine into organic compounds.”
13 Ex 2016, at 2561. And Dr. Wnuk agreed that this statement describes the state of the art for
14 fluorination in 2002. Ex 2139, at 139:13-21. Nevertheless, Dr. Wnuk points to two reactions,
15 Schemes 5 and 9, to allege that deoxyfluorination with DAST would have been unpredictable.
16 Ex 2001, ¶156. But for Scheme 5, the reaction that resulted in an “unfluorinated dehydration
17 product,” the reference itself teaches one of ordinary skill how to modify the conditions to
18 suppress the dehydration product and achieve successful deoxyfluorination with inversion of
19 configuration. Ex 2139, at 140:7 to 142:22. In the second reaction, Scheme 9, the reaction
20 produced the desired fluorination product in addition to the rearrangement product. Ex 2139, at.
21 143:3-11. As such, Ex 2016 does nothing to change whether one of ordinary skill in the art
22 would have been able to synthesize compounds within the scope of the Storer Claims without
23 due experimentation. Ex 1200, ¶116.
Clark and Dr. Wnuk rely on Ex 2017 for the proposition that DAST fluorination may not
2 be successful. Paper No. 162, p. 23, ll. 2-4; Ex 2001, ¶156. Ex 2017 disclosed two DAST
3 reactions: one that was successful and one that was not. Ex 2139, at 145:17-22. The DAST
4 reaction that was unsuccessful was not performed on a nucleoside. Id. at 146:2-4. And the
5 reaction that was successful proceeded with inversion, precisely as one of ordinary skill in the art
6 would have expected. Id. at 146:23 to 147:6. Accordingly, Ex 2017 does not change the fact
7 that one of ordinary skill in the art would have been able to use DAST to successfully fluorinate
8 hydroxyl groups on nucleosides with the expected inversion of configuration. Ex 1200, ¶¶119-
9 120.
10 The last reference that Clark and Wnuk rely on in support of their argument that
11 fluorination with DAST was unpredictable is Ex 2018. They contend that deoxyfluorination
12 with DAST may result in a “rearrangement product.” Paper No. 162, p. 23, ll. 2-4; Ex 2001,
13 ¶156. But the reaction that resulted in rearrangement also resulted in successful fluorination of a
14 nucleoside with 2′-OH(down) to form a nucleoside with 2′-F (up) in a 30% yield. Ex 2139, at
15 149:6-9. And Ex 2018 teaches that using DAST for deoxyfluorination of a nucleoside with a 2′-
16 OH (up) to form a nucleoside with a 2′-F (down) proceeded with inversion and gave the desired
17 product in an 82% yield without any rearrangement products reported. Ex 2018, at 559; Ex 2139,
18 at 149:10 to 150:11. Again, the reference relied on by Clark and Wnuk does not change that one
19 of ordinary skill in the art would have predicted that deoxyfluorination with DAST would have
20 proceeded with inversion of configuration. (Ex 1200, ¶125.)
21 At p. 23, ll. 4-12, Clark argues that deoxyfluorination of tertiary alcohols could fail to
22 produce fluorinated products. In support of its argument, Clark cites paragraph 157 of Ex 2001
23 (the Wnuk report, relying solely on Ex 2035, Ex 2041, Ex 2042, Ex 2043, and Ex 2029), and Ex
2029 (internal Idenix email and report), Ex 2035 (internal Idenix email), Ex 2041 (internal
2 Idenix report), Ex 2042 (internal Idenix report), Ex 2043 (internal Idenix lab notebook), Ex 2045
(Sommadossi exhibit list from the 1st 3 Interference), and Ex 2007 (the Decision on Priority in the
1st 4 Interference). As internal Idenix documents or documents created in 2013 or later, not a
5 single one of these exhibits is a prior art publication that would have formed part of the
6 knowledge of one of ordinary skill in the art. As such, they would have not impacted whether
7 one of ordinary skill in the art would have predicted that deoxyfluorination of a tertiary alcohol
8 using DAST would successfully proceed. Indeed, the very first publication in 1975 on DAST as
9 a fluorinating reagent states that DAST reacts with tertiary alcohols giving “high yields of the
10 unrearranged fluorinated product.” Ex 2023, at 575. Furthermore, standard references like
11 Larock 1999 (Ex 1199) and Ex 1225 would have pointed one of ordinary skill in the art to the
12 use of DAST for deoxyfluorination. For example Ex 1225 teaches that “DAST … convert
13 primary, secondary, tertiary, allylic and benzylic alcohols into fluorides under mild conditions in
14 high yield with little by-product formation.” Ex. 1225, at 88 (emphasis added). As even Wnuk
15 agreed, one of ordinary skill in the art would have expected deoxyfluorination of a tertiary
16 alcohol to proceed with inversion of configuration. Ex 2139, at. 134:2-6. Furthermore, skilled
17 chemists are accustomed to adapting reaction conditions to overcome the problem of
18 unanticipated side products or failures to obtain the desired product. As such, one of ordinary
19 skill in the art, armed with his or her own training and experience, coupled with the wealth of
20 knowledge and examples of set forth in the prior art directed to fluorinated chemical compounds,
21 would have been able to synthesize 2′-F (down) compounds of Counts 2 and 3 by deoxy-
22 fluorination of nucleosides with a 2′-OH (up) tertiary alcohol using DAST. (Ex. 1200, ¶88.)
23 Clark also argues on p. 23, l. 13 to p. 24, l. 5 that the ’350 Application does not include
working examples of, or provide any guidance regarding, how to make compounds falling within
2 Counts 2 and 3. The response is that the specification does provide guidance for synthesizing
3 compounds of the Storer Claims without undue experimentation. As a legal matter, the
4 specification need not teach how to make a compound if the artisan would have known how to
5 do so at the time of filing. Martin, 454 F.2d at 752; Goeddel, Paper 109, at 40-42, 45; Rochester,
6 358 at 921. Furthermore, starting materials and working examples of how to make a compound,
7 are not required. In re Strahilevitz, 668 F.2d 1129, 1232 (C.C.P.A. 1982); Martin, 454 F.2d at
8 752. Nevertheless, the specification expressly describes starting materials, reagents and
9 reactions that would have been applicable to the preparation of compounds of Counts 2 and 3.
10 Ex 1200, ¶97; Ex 1002, at 122:21 to 125:15, at 135:10-20; Ex 1003, at 1948:1-15; 2706:1-15.
Both experts agree that the structure of the compounds of Counts 2 and 3 would inform
12 one of ordinary skill in the art that a fluorination reagent would be required for synthesis.
13 Ex 1200, ¶89; Ex 2139, at 101:8-15. And as discussed above, the fluorination reagent, DAST,
14 was known to one of ordinary skill in the art for substituting a fluorine for a hydroxyl group with
15 inversion. Therefore, recognizing that inversion will occur, one of ordinary skill in the art would
16 have known to start with a nucleoside having a similar structure to that defined by the claims, but
17 with a 2′-OH (up), in order to obtain the desired 2′-F(down) structure. (Ex 1200, ¶90.)
18 In his expert report, Dr. Wnuk identified a compound that he named (2′R)-2′-deoxy-2′-
19 fluoro-2′-C-methyluridine as a nucleoside that one of ordinary skill would have recognized as
20 within the scope of Counts 2 and 3 (Ex 2001, ¶¶323-324) (“Claimed Compound”). Dr. Wnuk
21 agreed that one of ordinary skill in the art would have recognized compound 17 in the Matsuda
22 article, (“Matsuda Compound 17”), as a precursor to a compound within the scope of the Storer
23 Claims depicted at ¶ 323 of his report (“Claimed Compound”). Ex 2139, at 107:18-108:6,
As can be seen above, Matsuda Compound 17 differs from the Claimed Compound in
5 that the configuration at the 2′ location is inverted with a 2′-OH instead of a 2′-F. Ex 1200, ¶92;
6 Ex 2139, at 107:18 to 108:6. Both parties’ experts agree that the synthesis of the Claimed
Compound would have been essentially a one step8 7 reaction of Matsuda Compound 17 with
8 DAST. Ex 1200, ¶94; Ex 2139, at 156:2-12.) In other words, DAST deoxyfluorinates the 2′-
9 OH(up)-2′-Methyl(down) group with inversion resulting a 2′-Methyl(up)-2′-F(down) group. The
10 synthesis of Matsuda Compound 17 is disclosed in Matsuda 1999. Ex 1200, ¶93; Ex 1144 & Ex
11 2019, at 946-952. The synthesis of Matsuda Compound 17 is the same as the first few steps of
12 Scheme 4 in the ’350 Application. Ex 1132, ¶67; Ex 1003, at 124. In particular, the second
13 compound (2′-keto) of Scheme 4 (Ex 1003, at 125), below, is the starting material of Matsuda
where R1
and R2 14 form a TIPDS protecting group and Base is uridine. Ex 1132,¶65-69; Ex 1144
15 & Ex 2019, at 946-952.
The reaction may require adding, removing and/or changing protecting groups, all of
which were routine in the art. Ex 1200, ¶95; Ex 2139, at 111:25 to 112:4.
Furthermore, the ’305 Application discloses that the R6 1 -M reagent can be an organolithium
2 reagent, which would include the methyl lithium reagent used to synthesize Matsuda Compound
3 17. Ex 1132,¶ 65-69; Ex 1003, at 118; Ex 1144 & Ex 2019, at 946-952. As such, the ’350
4 Application does provide one of ordinary skill in the art with starting materials and guidance for
5 making the compounds within Counts 2 and 3 without undue experimentation. Ex 1200, ¶97.
6 And contrary to Clark’s implication at p. 16, ll. 1-2, fluorinated starting materials (as opposed to
7 fluorinating reagents such as DAST) wound not have been required for synthesis of compounds
8 within the scope of the Storer Claims as evident by Matsuda Compound 17. Ex 1200 , ¶96