UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARIVIACEUTICALS INC.,
`
`Petitioner,
`
`V.
`
`ASTRAZENECA AB,
`Patent Owner.
`
`Case: IPR2015—01340
`
`U.S. Patent No. RE44,186
`
`DECLARATION OF JEFFREY ROBL, PH.D.
`
`Page 1 of 6
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`Astraleneca Exhibit 2173
`
`Mylan V. Astraleneca -
`IPR2015-013-I0
`
`AstraZeneca Exhibit 2173
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 6
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARIVIACEUTICALS INC.,
`
`Petitioner,
`
`V.
`
`ASTRAZENECA AB,
`Patent Owner.
`
`Case: IPR2015—01340
`
`U.S. Patent No. RE44,186
`
`DECLARATION OF JEFFREY ROBL, PH.D.
`
`Page 1 of 6
`
`Astraleneca Exhibit 2173
`
`Mylan V. Astraleneca -
`IPR2015-013-I0
`
`AstraZeneca Exhibit 2173
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 6
`
`
`
`Case No. IPR20l5—01340
`
`Patent No. RE44,186
`
`I, Jeffrey Robl, declare as follows:
`
`I.
`
`Introduction
`
`1.
`
`All facts in this declaration are based on my personal knowledge
`
`unless otherwise stated.
`
`2.
`
`3.
`
`I am one of the co—inVentors of U.S. Patent No. RE44,186 (Ex. 1001).
`
`I completed and successfully defended my Ph.D.
`
`thesis in 1987,
`
`joined Squibb as a full time employee in 1987, and received a Ph.D. degree in
`
`1988. Since 1987, I have worked at Bristol—Myers Squibb Co. (“BMS”) and its
`
`predecessor.
`
`4.
`
`In 1998, I was an Associate Director in the Metabolic Diseases
`
`department within BMS.
`
`In late-1998, I proposed to one of the biology leaders in
`
`the Metabolic Diseases department the idea of synthesizing dipeptidyl peptidase
`
`(“DPP-IV”) inhibitors to treat diabetes, and presented the idea at the November 20,
`
`1998 Metabolic Diseases New Target Evaluation meeting. Around that time, I
`
`prepared a document
`
`that
`
`identifies potential starting points for a medicinal
`
`chemistry program. See EX. 2169.
`
`. 5.
`
`I initially proposed a Variety of unknown’ chemical structures with
`
`constrained rings as potential DPP-IV inhibitors. For instance, I proposed the
`
`constrained ring structures identified as “Aliphatic Bieyclics,” “Benzo-Fused
`
`Page 2 of 6
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`Page 2 of 6
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`Case No. IPR20l 5-01340
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`Patent No. RE44,186
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`Bicyclics,” “Non-Bicyclics,” and other constrained “Miscellaneous” compounds.
`
`Id.
`
`6.
`
`I also identified two compounds as “Literature Standards.”
`
`Id.
`
`I
`
`identified these compounds because they were the most prominently highlighted
`
`reversible DPP- IV inhibitors in the literature, and I wanted them to serve as
`
`benchmarks for our program. Probiodrug developed the compound on the left, and
`
`F erring developed the compound on the right. Both “Literature Standards”
`
`included a sulfur in its pyrrolidine ring.
`
`7.
`
`In January 1999, BMS’s DPP-IV research group began actively
`
`working on generating constrained compounds, and the first new compounds were
`
`synthesized in February 1999.
`
`8.
`
`The initial constrained ring structures that we tested were essentially
`
`inactive against DPP-IV. See, e. g., Ex. 2183 at 1. Our group experimented by
`
`generating analogs with different ring sizes, but we began to understand that the
`
`constrained analogs did not exhibit promising inhibition of DPP- IV, and our group
`
`gradually shifted our focus away from those analogs.
`
`9.
`
`We also began exploring one of my initial
`
`ideas of fusing a
`
`cyclopropyl group to the cyanopyrrolidine ring and first highlighted our work in
`
`the Chemistry Significant Events report around August 1999. See Ex. 2184 at 1-2;
`
`Page 3 of 6
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`2
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`Page 3 of 6
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`
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`Case No. IPR20l5-01340
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`Patent No. RE44,186
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`see also Ex. 2169 (“Non—Bicyclics” including a cyclopropyl group fused to a
`
`pyirolidine ring).
`
`The group knew that the pyrrolidine at the Pl position did not
`
`tolerate many modifications, but I thought that it may be worthwhile to introduce a
`
`cyclopropyl group there. To do so, We needed to identify scientific literature that
`
`provided a synthetic scheme for generating cyclopropyl pyrrolidines.
`
`Such
`
`literature did not exist.
`
`Instead, we found an article by Hanessian et al., Probing
`
`the Importance ofSpacial ana’ Conformational Domains in Captopril Analogs for
`
`Angiotensin Converting Enzyme Activity, 8 BIOORGANIC & MED. CHEM. LETTERS
`
`2123 (1998) (Ex. 2028), which disclosed a scheme for cyclopropanating proline
`
`groups. We used this scheme to synthesize our first cyclopropyl compound, BMS—
`
`356379.
`
`I
`
`10.
`
`BMS-35 63 79 had a nitrile at the 2—position and a cyclopropyl group
`
`at
`
`the 4,5-position.
`
`EX. 2184 at 1-2. With a K of 28 nM, BMS—356379
`
`represented the first breakthrough by the group. Based on this breakthrough, We
`
`conducted extensive
`
`structure-activity-relationship (“SAR”)
`
`studies on the
`
`cyclopropyl series. That SAR indicated that, depending on the location and
`
`stereochemistry of the cyclopropyl group, there was a dramatic and unpredictable
`
`effect on potency. Ex. 2l85. For instance, some compounds with the cyclopropyl
`
`group at the 2,3—pos‘ition did not exhibit significant inhibitor activity, while some,
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`Page 4 of 6
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`Page 4 of 6
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`Case No. IPR2015—01340
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`Patent No. RE44,186
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`but not all, of the compounds with the cyclopropyl group at the 3,4—position did.
`
`See, e.g., Ex. 2186 at 2 (compare to BMS—378736 to BMS—3 83680).
`
`11. We also discovered an unexpected increase in potency from the
`
`combination of a cis-4,5-cyclopropyl—pyrrolidine in the P1 position and a tert-butyl
`
`group in the P2 position. Ex. 2182. Positive data from the tert-butyl compound
`
`led us to propose and test a series of beta-branched derivatives,
`
`including
`
`adamantyl. Ex. 2187; Ex. 2182. We found that not all beta-branched groups gave
`
`potent DPP-IV inhibitors. Ex. 2175 at 2.
`
`12.
`
`In the cyclopropyl series, we observed interesting properties related to
`
`‘one of our cis-4,5—cyclopropyl compounds with a cyclopentyl group in the P2
`
`position. That compound, BMS-431285, exhibited exceptionally good in viva
`
`inhibitor activity, (see Ex. 2188 at 1), but had an unusual disconnect between its
`
`pharmacokinetic (“PK”) and pharmacodynamic (“PD”) profile, showing low
`
`bioavailablity and a short half-life, yet a prolonged PD effect (id. at 3). When the
`
`group searched for the administered compound in plasma,
`
`it found that
`
`the
`
`compound was not present for a very long time and was not present at a high
`
`concentration. The team hypothesized that the PD effect was due to an active
`
`metabolite formed in viva.
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`Page 5 of 6
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`4
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`Page 5 of 6
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`Case No. IPR20l 5-01340
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`Patent No. RE44,l86
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`13. At around the same time, we synthesized BMS—469767, which
`
`contains a cis-4,5—cyclopropyl—pyrrolidine and an adamantyl group at
`
`the P2
`
`position. Pharmacokinetic and metabolism studies revealed a profile similar to that
`
`exhibited previously with vinyl—containing analogues
`
`such as BMS—43l285
`
`discussed above. See EX. 2189 at 4, Table 2. Additional data suggested that BMS-
`
`469767’s activity was mediated through a rapidly produced metabolite. We then
`
`obtained liquid chromatography/mass spectrometry data suggesting that the likely
`
`metabolism candidate was the product of hydroxylation.
`
`Id. at'5. We then
`
`synthesized putative metabolites.
`
`As a result,
`
`in October 2000, we first
`
`synthesized BMS—477l 18, which is now known as saxagliptin. EX. 2190 at 2.
`
`14.
`
`I declare that all statements made herein of my knowledge are true,
`
`and that all statements made on information and belief are believed to be true, and
`
`that these statements were made with the knowledge that willful false statements
`
`and the like so made are punishable by fine or imprisonment, or both, under
`
`Section 1001 of Title 18 of the United States Code.
`
`Datedf A¢u3u§l ZMQGNP
`
`By:
`
`Jeffrey Robl
`
`Page 6 of 6
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`5
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`Page 6 of 6
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