Paper No. ___
`Filed: April 16, 2017
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS
`LLC, ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA,
`INC., SUN PHARMACEUTICAL INDUSTIRES, LTD., SUN
`PHARMACEUTICAL INDUSTRIES, INC., AND SUN PHARMA GLOBAL
`FZE,
`Petitioners,
`
`v.
`
`NOVARTIS A.G.,
`Patent Owner.
`_____________________________
`
`IPR2017-008541
`Patent No. 9,187,405
`_____________________________
`
`PETITIONERS’ MOTION FOR OBSERVATIONS REGARDING THE
`CROSS-EXAMINATION OF DR. JEROLD CHUN
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`
`with this proceeding.
`
`
`Filed: April 16, 2017
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS
`LLC, ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA,
`INC., SUN PHARMACEUTICAL INDUSTIRES, LTD., SUN
`PHARMACEUTICAL INDUSTRIES, INC., AND SUN PHARMA GLOBAL
`FZE,
`Petitioners,
`
`v.
`
`NOVARTIS A.G.,
`Patent Owner.
`_____________________________
`
`IPR2017-008541
`Patent No. 9,187,405
`_____________________________
`
`PETITIONERS’ MOTION FOR OBSERVATIONS REGARDING THE
`CROSS-EXAMINATION OF DR. JEROLD CHUN
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`
`with this proceeding.
`
`
`
`
`
`Petitioners hereby submit observations on the deposition testimony of
`
`Novartis’s declarant Dr. Jerold Chun given on April 9, 2018 (EX1063).
`
`1.
`
`
`
`In EX1063 at 61:10-63:17, 67:18-25, 70:13-22, 134:18-137:12, 138:17-
`
`139:8, 141:5-145:6, 146:2-18, Dr. Chun testified that he has consulted for Novartis
`
`since 2003, that his 16-year relationship with Novartis is his longest, that Novartis
`
`paid him to participate in post-marketing and commercial activities for fingolimod,
`
`and that three of his post-docs were funded by a Novartis fellowship. This is
`
`relevant to Dr. Chun's credibility because it shows he has a deep and long-standing
`
`financial relationship with Novartis and its fingolimod product. EX2098 (Chun
`
`Decl), ¶¶1, 10-16; Paper 63 (PO Sur-Reply), 2, 6-7.
`
`2.
`
`
`
`In EX1063 at 77:23-84:22, 87:10-88:7, 90:5-91:10, 92:3-93:6, 94:4-16,
`
`150:14-151:16, 153:12-16, Dr. Chun testified that he believed Drs. Webb and Rao
`
`were the primary drafters and lead authors of the Webb paper, that he did not have
`
`firsthand knowledge about who did most of the writing, that he did not know
`
`which co-author wrote which portion of the Webb paper, that he did not remember
`
`which co-authors did which experiments, that co-author Hale was not part of his
`
`team. This is relevant to Dr. Chun's assertion that his declaration speaks for the
`
`"collective judgment" of all nine authors of the Webb paper. EX2098, ¶¶7-8;
`
`Paper 63, 6-7; see also EX2096 (3rd Steinman Decl), ¶40.
`
`3.
`
`
`
`In EX1063 at 148:19-24, Dr. Chun testified that Webb was the first
`
`
`
`-1-
`
`
`
`
`
`reference he co-authored that discussed an EAE experiment, and that his EAE
`
`experience "was limited" when he began at Merck in 2001. Id., 150:7-13, 13:8-10.
`
`This is relevant to Dr. Chun's assertions that his testimony regarding Webb should
`
`be relied upon over Dr. Benet's. EX2098, ¶¶7-8, 17, 36-44; Paper 63, 2, 6-7.
`
`4.
`
`
`
`In EX1063 at 96:8-19, 97:5-22, 159:21-160:13, Dr. Chun testified that the
`
`key and primary conclusion of the Webb paper was a "proof of concept" for using
`
`fingolimod therapeutically to treat a model of MS in Swiss Jim Lambert (SJL)
`
`mice with EAE. He testified that the abstract sets forth the key conclusions, basic
`
`conclusions, and overall conclusions of the Webb paper, and the abstract makes no
`
`mention of any 70% lymphopenia threshold for efficacy. Id., 153:22-155:23. This
`
`is relevant to Dr. Chun's assertions that an about 70% lymphopenia threshold for
`
`efficacy was a "basic" or "overall" conclusion of the Webb paper. EX2098, ¶34;
`
`Paper 63, 5-7; see also, Paper 27 (POR), 16-19; EX2003 (1st Lublin Decl), ¶33;
`
`EX2024 (2nd Jusko Decl), ¶¶70-75; EX2096, ¶26; Paper 56 (Pet. Reply), 11-12;
`
`EX2039 (Giesser Depo), 74:1-86:8; EX1047 (Benet Decl), ¶¶38-48.
`
`5.
`
`
`
`Dr. Chun agreed that Webb Figure 5A demonstrates rapid improvement in
`
`clinical score during administration of each of the tested doses of FTY720.
`
`EX1063, 160:23-161:9. When asked whether he agreed the lower clinical scores
`
`demonstrates an alleviation of the relapse and a deeper depression in clinical score
`
`than what was observed in the control group, Dr. Chun agreed that there appeared
`
`-2-
`
`
`
`
`
`to be "reductions in the clinical score" in the fingolimod doses. Id., 162:7-25. This
`
`is relevant to Novartis's assertion that the 0.03 mg/kg dose lacked any efficacy and
`
`that Dr. Giesser's recognition of an efficacy trend in Figure 5 indicated she lacked
`
`expertise. EX2098, ¶¶28-29; Paper 63, 1, 5-8; see also EX2039, 70:18-86:8; Paper
`
`27, 16-17; EX2022 (1st Steinman Decl), ¶¶130-36; EX2024, ¶¶76-77.
`
`6.
`
`
`
`In EX1063 at 155:24-156:14, 159:8-20, Dr. Chun testified that one of
`
`Webb's key conclusions is that when phosphorylated fingolimod interacts with the
`
`S1P receptors on lymphocytes and thereby causes lymphocyte sequestration, that
`
`this is not the only mechanism by which fingolimod is providing therapeutic
`
`treatment against EAE. This is relevant to Novartis's arguments that proof of
`
`persistently achieving at least 70% lymphopenia without variation was required to
`
`see any efficacy against RRMS. EX2098, ¶¶5-8, 36, 43-44; Paper 63, 5-7; see also
`
`Paper 27, 34-38; EX2096, ¶¶48-52; Paper 56, 11-12; EX1047, ¶¶38-65.
`
`7.
`
`
`
`In EX1063 at 101:14-20, 103:13-107:18, 125:17-25, Dr. Chun testified that
`
`he does not have the data underlying the Webb paper, does not have access to it,
`
`has not had access to it since he left Merck, has not reviewed it for ~16-years, has
`
`never asked Merck for access to it, left any Webb-related materials describing the
`
`data at Merck when he left Merck, did not review any summaries or descriptions of
`
`it in preparing his declaration, and left Merck sometime around June 2003. This is
`
`relevant to Dr. Chun's reliance on the underlying data in contravention of 37 C.F.R.
`
`-3-
`
`
`
`
`
`§ 42.65. EX2098, ¶¶1-8, 16-17, 21-44; Paper 63, 2, 6-7.
`
`8.
`
`
`
`In EX1063 at 126:2-127:8, 181:7-13, Dr. Chun testified that he did not
`
`personally submit Webb for publication, did not know who did, and did not know
`
`when any of the co-authors gave final approval for publication. Id., 181:14-182:15.
`
`Dr. Chun testified that he did not know how many peer reviewers provided
`
`comments on the Webb paper and did not know what revisions were made before
`
`publication. Id., 271:23-272:13. This is relevant to Dr. Chun's assertion the "about"
`
`70% sentence reflected the collective judgment of all nine authors of Webb.
`
`EX2098, ¶¶1-8, 16-17, 21-44; Paper 63, 5-7.
`
`9.
`
`
`
`In EX1063 at 182:16-183:15, Dr. Chun testified that, prior to the submission
`
`of the Webb manuscript for publication, he never discussed with any of co-authors
`
`Hale, Tham, Lin, Lariosa-Willingham, Yu, or Mandala any correlation between
`
`lymphopenia and cumulative clinical score. This is relevant to Dr. Chun's assertion
`
`the "about" 70% sentence reflected the collective judgment of all nine authors of
`
`Webb. EX2098, ¶¶1-8, 16-17, 21-44; Paper 63, 5-7.
`
`10.
`
`
`
`In EX1063 at 169:14-172:25, 173:14-175:8, 176:19-178:12, 179:23-181:6,
`
`Dr. Chun testified that Webb Figure 6C correlated nadir lymphopenia at day 25 to
`
`cumulative clinical score at day 25 and could not identify any graph or table in
`
`Webb correlating lymphopenia to clinical efficacy not at the lymphopenia nadir.
`
`This is relevant to Novartis's and Dr. Chun's arguments that correlation of
`
`-4-
`
`
`
`
`
`lymphopenia with clinical efficacy should not be taken at the lymphocyte nadir.
`
`EX2098, ¶¶7, 24-33, 37-43; Paper 63, 5-7; Paper 27, 16-19.
`
`11.
`
`
`
`In EX1063 at 185:2-186:23, Dr. Chun testified that it was an error to say
`
`"any efficacy" in the last paragraph of page 118 of Webb and that this section of
`
`the paper should be read simply to say that they expected other researchers would
`
`have the easiest time reproducing Webb's data if they achieved about 70%
`
`lymphopenia. Dr. Chun testified that a proper way to correct the error on page 118
`
`of the Webb paper would be to phrase it as saying, "In dose response experiments,
`
`we found that a threshold of about 70 percent depletion of peripheral lymphocytes
`
`was required to see the most consistent or predominant efficacy, " and that this
`
`"would be better than" saying "any efficacy." Id., 187:19-188:6. This is all relevant
`
`to the arguments of Novartis and its experts that "at least" 70% lymphopenia was
`
`required to see any efficacy. EX2098, ¶¶5-8, 38; Paper 63, 5-7; see also, e.g.,
`
`Paper 27, 1-2, 34-35; EX2024, ¶¶8-10, 70, 75, 92; EX2096, ¶¶26-28; Paper 56,
`
`11-12; EX2039, 74:1-86:8; EX1047, ¶¶38-65.
`
`12.
`
`
`
`In EX1063, 188:7-189:25, Dr. Chun agreed that a scientist reading the Webb
`
`paper would understand that the "about 70%" comment was merely referring to
`
`"the results that were observed in that paper" for this "particular model, the SJL
`
`EAE mouse," and would not interpret it as actually saying that 70% lymphopenia
`
`was required to see "any" efficacy. This is relevant to Novartis's arguments that "at
`
`-5-
`
`
`
`
`
`least" 70% lymphopenia was required to see any efficacy. EX2098, ¶¶5-8, 38;
`
`Paper 63, 5-7; see also, e.g., Paper 27, 1-2, 34-35; EX2024, ¶¶8, 82, 154; EX2096,
`
`¶¶27, 30, 73; Paper 56, 11-12; EX2039, 74:1-86:8; EX1047, ¶¶38-65.
`
`13.
`
`
`
`In EX1063 at 190:2-191:5, 191:15-24, Dr. Chun testified that the statement
`
`in Webb about 70% lymphopenia pertains only to SJL mice and does not establish
`
`that a threshold of about 70% depletion of peripheral lymphocytes was required to
`
`see efficacy in Wistar or Lewis rats. This is relevant to Novartis’s arguments that
`
`"at least" 70% lymphopenia was required to see any efficacy. EX2098, ¶¶5-8, 38;
`
`Paper 63, 5-7; see also, e.g., Paper 27, 1-2, 34-35; EX2024, ¶¶8, 164; EX2096,
`
`¶¶3, 38; Paper 56, 11-12; EX2039, 74:1-86:8; EX1047, ¶¶38-65.
`
`14.
`
`
`
`In EX1063 at 272:14-273:6, Dr. Chun testified that he was not aware of any
`
`subsequent prior art reference that discusses a 70% threshold of lymphopenia for
`
`efficacy, or that cites the Webb paper for this proposition. This is relevant to Dr.
`
`Chun's declaration testimony that he was not aware of the 70% statement in Webb
`
`being retracted or criticized in any peer reviewed paper. EX2098, ¶35; Paper 63, 6;
`
`see also Paper 56, 11-12; EX2039, 74:1-86:8; EX1047, ¶¶38-65.
`
`15.
`
`
`
`In EX1063 at 274:18-275:2, Dr. Chun testified that Webb's discussion of
`
`"about" 70% lymphopenia "underscores the subjectivity or inherent variability in
`
`the assay" and that "a 60 percent versus 70 percent in this assay will be very, very
`
`difficult to separate experimentally." Dr. Chun agreed that about 70% was just a
`
`-6-
`
`
`
`
`
`"best guess as to what someone else in the community could do and see the same
`
`thing," that it did not rule out seeing the same efficacy with 59% or 50%
`
`lymphopenia, and that Webb's data "did not speak to what other kinds of
`
`percentages that might be encountered" and was "further made uncertain by the
`
`limited assessments of lymphopenia that were done on the mice." Id., 275:2-
`
`276:21. This is relevant to Novartis’s argument that "at least" 70% lymphopenia
`
`was required to see any efficacy. EX2098, ¶¶5-8, 38; Paper 63, 5-7; see also, e.g.,
`
`Paper 27, 1-2, 34-35; EX2024, ¶¶8, 164; EX2096, ¶3; Paper 56, 11-12; EX2039,
`
`74:1-86:8; EX1047, ¶¶38-65.
`
`16.
`
`
`
`In EX1063 at 278:3-279:4, 284:11-285:19, 316:16-317:12, 318:12-20, Dr.
`
`Chun testified that Exhibit 1055 is the Tedesco-Silva paper published in 2005 in
`
`Transplantation that is cited as citation 4 in the Keller paper (EX1054) he co-
`
`authored, and that the study was funded by Novartis. Dr. Chun agreed that Exhibit
`
`1055 describes its Figure 2 as showing that reductions from baseline lymphocyte
`
`counts were sustained in patients receiving FTY720 throughout the treatment
`
`period. EX1063, 285:20-286:25, 294:6-14. Dr. Chun agreed that the change in
`
`lymphocyte counts for the FTY720 groups in Figure 2 appeared sustained "beneath
`
`the control level" after week 4 through the end of treatment at the end of week 12.
`
`Id., 312:3-25. This is relevant to Dr. Chun's assertions that sustained suppression of
`
`lymphocytes would be needed for efficacy in humans against MS. EX2098, ¶44;
`
`-7-
`
`
`
`
`
`see also id., ¶¶8, 29, 36-40; EX2096, ¶¶42-49; Paper 63, 6-7; Paper 56, 5.
`
`17.
`
`
`
`In EX1063 at 294:22-295:25, 317:13-318:11, Dr. Chun testified that he
`
`would want to review additional data to understand the conclusions from Tedesco-
`
`Silva (Exhibit 1055) and that Exhibit 1056 (Skerjanec) was published in 2005 in
`
`the Journal of Clinical Pharmacology. Dr. Chun agreed that Figure 5 of Exhibit
`
`1056 provides graphs showing absolute lymphocyte counts for various doses of
`
`fingolimod compared to a control group. EX1063, 296:2-297:3, 299:8-20. Dr.
`
`Chun agreed that the absolute lymphocyte count between the end of week 1 and
`
`the end of week 12 was about 1600 for the control and was sustained below 1000
`
`mm3 for the four fingolimod treatment groups in Figure 5 "if one takes the graph at
`
`face value." EX1063, 308:11-311:3. Dr. Chun did not disagree that the fingolimod
`
`treatment groups cluster in a way that makes it difficult to resolve them from one
`
`another with a great deal of precision. EX1063, 311:18-312:3. This is relevant to
`
`Dr. Chun's assertion in his declaration that sustained suppression of lymphocytes
`
`would be needed for efficacy in humans against multiple sclerosis. EX2098, ¶44;
`
`see also id., ¶¶8, 29, 36-40; Paper 63, 6-7; Paper 56, 5.
`
`18.
`
`
`
`In EX1063 at 198:11-199:10, Dr. Chun testified that Section 3.1 of Webb
`
`provides results for EAE in untreated (with fingolimod) SJL mice. Dr. Chun
`
`testified that the 10-30% mortality referenced at the end of Section 3.1 on page 112
`
`of Webb refers to EAE SJL mice that had not been treated with fingolimod.
`
`-8-
`
`
`
`
`
`EX1063, 201:7-19. This is relevant to Novartis's argument that deaths of 10-30%
`
`of FTY-treated mice in Figure 5 demonstrates wide variability in granular data
`
`underlying Figure 5 such that the undisclosed granular data proved at least 70%
`
`lymphopenia was required to see any efficacy. EX2098, ¶30; Paper 63, 6-7; see
`
`also, e.g., EX2096, ¶¶31-32.
`
`19.
`
`
`
`In EX1063 at 203:13-25, Dr. Chun testified that he did not recall the number
`
`of animals used in each experiment, but only assumed it was greater than four to
`
`obtain a statistical result. Dr. Chun testified that he did not know of any place in
`
`the Webb paper where it says that the N value for Figure 5A is 12 and that he is
`
`"not a statistician, so I do not know what was used for construction of these
`
`graphs." Id., 204:12-21. Dr. Chun agreed that he does not have personal knowledge
`
`about the number of mice that were included in each data point at each day for
`
`each dose in Webb Figure 5. Id., 209:5-19. Dr. Chun agreed that no EAE
`
`experiment where N equals 4 could possibly return an average clinical score of
`
`0.75 while including one or more mouse receiving a clinical score of a 4 or a 5. Id.,
`
`250:6-252:14. This is relevant to Novartis's argument that deaths of 10-30% of
`
`FTY-treated mice were masked by the average and S.E.M. values graphed in
`
`Figure 5. EX2098, ¶¶6-7, 18, 24-33; EX2022, ¶¶130-32; EX2096, ¶¶33-35; Paper
`
`63, 6-7; see also EX1047, ¶¶41-47; Paper 56, 11-14.
`
`20.
`
`
`
`In EX1063 at 259:2-262:7, Dr. Chun did not know what measure of
`
`-9-
`
`
`
`
`
`statistical significance was applied to Webb Figure 5, but agreed upon review that
`
`the difference in cumulative clinical score between the 0.3 mg/kg dose and the 0.03
`
`mg/kg dose was about 1 (14 vs. 15), and that the 0.3 mg/kg dose was "slightly
`
`above 95 percent confidence" and the 0.03 mg/kg dose was "slightly below" 95%
`
`confidence. This is relevant to Novartis's arguments that Webb Figure 5 rules out
`
`efficacy for the 0.03 mg/kg dose and that Dr. Giesser's interpretation of Webb
`
`Figure 5 reveals an alleged lack of expertise. EX2098, ¶¶28-29; Paper 63, 1;
`
`EX2039, 70:18-86:8; Paper 27, 16-17; EX2022, ¶¶130-36; EX2024, ¶¶76-77.
`
`21.
`
`
`
`In EX1063 at 264:24-265:13, 266:14-23, Dr. Chun agreed that the highest
`
`dose in Webb Figure 5 suppressed lymphocytes for only about two days after
`
`dosing ceased. He could not "resolve the number of days" after cessation of
`
`treatment with fingolimod before clinical scores went as high as or above those for
`
`the control group, but said "it appears" to be approximately two days. Id., 164:15-
`
`165:3. This is relevant to Novartis's arguments that proof of persistently achieving
`
`at least 70% lymphopenia without variation was required to see any efficacy.
`
`EX2098, ¶¶5-8, 38; Paper 63, 5-7; see also, e.g., Paper 27, 34-35; EX2024, ¶164;
`
`EX2096, ¶3; Paper 56, 11-12; EX1047, ¶¶38-65.
`
`
`
`Date: April 16, 2016
`
`
`
`Respectfully submitted,
`
`/ Steven W. Parmelee /
`Steven W. Parmelee
`Reg. No. 31,990
`
`
`
`
`
`
`
`-10-
`
`
`
`
`
`CERTIFICATE OF SERVICE
`
`This is to certify that I caused to be served a true and correct copy of the
`
`foregoing Motion for Observations, on this 16th day of April, 2018, on the Patent
`
`Owner at the correspondence address of the Patent Owner as follows:
`
`Jane M. Love, Ph.D.
`Robert W. Trenchard
`GIBSON, DUNN & CRUTCHER LLP
`200 Park Avenue, 47th Floor
`New York, NY 10166
`Email: jlove@gibsondunn.com
`Email: rtrenchard@gibsondunn.com
`
`
`
`Dated: April 16, 2018
`
`
`
`
`
`
`
`
`Respectfully submitted,
`
`/ Steven W. Parmelee /
` Steven W. Parmelee, Lead Counsel
` Reg. No. 31,990
`
`
`
`
`
`-11-
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
