`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`MYLAN PHARMACEUTICALS INC., ACTAVIS
`LABORATORIES FL, INC., AMNEAL PHARMACEUTICALS LLC,
`AMNEAL PHARMACEUTICALS OF NEW YORK, LLC, DR. REDDY’S
`LABORATORIES, INC., DR. REDDY’S LABORATORIES, LTD.,
`SUN PHARMACEUTICALS INDUSTRIES, LTD.,
`SUN PHARMACEUTICALS INDUSTRIES, INC.,
`TEVA PHARMACEUTICALS USA, INC., WEST-WARD
`PHARMACEUTICAL CORP., and HIKMA PHARMACEUTICALS, LLC,
`
`Petitioners
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`
`Patent Owner
`
`Case IPR2016-013321
`Patent 8,822,438 B2
`
`
`
`
`
`PETITIONERS’ RESPONSE TO PATENT OWNER’S
`MOTION FOR OBSERVATIONS ON CROSS-EXAMINATION
`
`
`
`1 Case IPR2017-00853 has been joined with this proceeding.
`
`
`
`
`
`Petitioners hereby respond to Patent Owner’s Motion for Observations on
`
`Cross Examination (“OCE”). Paper No. 70.
`
`Response to OCE 3-6: Patent Owner’s Observations 3-6 misstate the record
`
`when they assert that Dr. Garnick “testified” as described. These Observations are
`
`not the “testimony” of Dr. Garnick. Instead, Patent Owner has cited transcript
`
`passages where its attorney read into the record either a portion or a paraphrase of
`
`a portion of a document and asked Dr. Garnick to confirm the substance or
`
`language of the passage. Patent Owner then reported Dr. Garnick’s simple act of
`
`confirming the attorney’s statement as Dr. Garnick’s “testimony” on the issue. For
`
`example, the entirety of the cited question and answer in Observation 5 is:
`
`Q. So on page 1097, in the right-hand column, third full paragraph it
`
`states, “Overall, ketoconazole plus hydrocortisone would have to be
`
`judged ineffective as secondary hormone therapy for most patients
`
`with advanced prostatic cancer,” correct?
`
`A. Yes.
`
`Ex. 2185 at 104:13-19. In view of Patent Owner’s improper use of the observation
`
`procedure, which is designed to highlight allegedly relevant “testimony,”
`
`Observations 3-6 should be stricken from the record.
`
`Response 1: Dr. Garnick’s testimony is nothing more than an acknowledgement of
`
`the core purpose of scientific and medical research: the development of additional
`
`1
`
`
`
`
`
`therapies to treat conditions. To the extent Patent Owner is implying that the next
`
`developments were directed only at “chemotherapy,” rather than other treatment
`
`modalities, Dr. Garnick’s complete testimony establishes that implication as false.
`
`Dr. Garnick testified that enzalutamide (now marketed as Xtandi®, which is not a
`
`chemotherapy agent), was already in the prior art before the priority date of U.S.
`
`Patent No. 8,822,438 (“’438 patent”). Ex. 2185 at 46:20-47:15, 53:15-54:4. This
`
`testimony also refutes Patent Owner’s assertion that abiraterone was the next-
`
`discovered drug shown to provide a survival benefit; in fact, enzalutamide was
`
`known first and has been shown to provide a survival benefit.
`
`Response 2: Patent Owner’s cite is irrelevant. The approval of abiraterone acetate
`
`with prednisone (under New Drug Application No. 202379)—the only approval of
`
`any abiraterone acetate product—occurred on April 28, 2011, long after the ’438
`
`patent’s claimed priority date of 2006, and therefore (even if a “milestone”) it
`
`bears no significance to the ’438 patent’s obviousness. In addition, abiraterone
`
`acetate, a compound known in the prior art, provides the patient benefit to which
`
`Dr. Garnick refers. Ex. 1002 ¶¶ 78-93; Ex. 1104 ¶¶ 89-111. Further, as Dr.
`
`Garnick testified, enzalutamide (now marketed as Xtandi®, another effective non-
`
`chemotherapy treatment for mCRPC), was also in the prior art and met any clinical
`
`need that abiraterone acetate would have satisfied. Ex. 2185 at 46:20-47:15,
`
`53:15-54:4.
`
`2
`
`
`
`
`
`Response 3: Patent Owner’s cite confirms that Dr. Garnick was correct when he
`
`stated, in his reply declaration, that “Attard 2009 enrolled patients who were
`
`previously on ketoconazole.” Ex. 1104 ¶ 99. In the same sentence, Dr. Garnick
`
`noted that Ryan 2011, another alleged anchor of Dr. Rettig’s opinion on
`
`unexpected results, did not enroll patients who were previously on ketoconazole.
`
`Id. As Dr. Garnick noted, this is just one of “several of the weaknesses of Dr.
`
`Rettig’s cross-study comparisons from the viewpoint of a medical practitioner.”
`
`Id. at ¶ 97 n.4. As Dr. Garnick and Dr. McKeague noted in their reply
`
`declarations, the sum total of these several weaknesses (of which Patent Owner
`
`cited only one) renders invalid Dr. Rettig’s conclusion on unexpected results
`
`because it makes clear that Dr. Rettig did not perform a credible comparison of
`
`available clinical data. Ex. 1104 ¶¶ 98-101; Ex. 1091 ¶¶ 44-52.
`
`Response 4: The alleged “testimony” is simply a request that Dr. Garnick confirm
`
`what is written in Attard 2009 and does not involve Dr. Garnick giving
`
`particularized testimony based on his expertise. In addition, the quoted portion of
`
`Attard 2009 has no nexus to the claims because it relates to the use of
`
`dexamethasone after abiraterone acetate, not the claimed abiraterone acetate-
`
`prednisone co-therapy. Ex. 1104 ¶¶ 105, 120; Ex. 1091 ¶¶ 30, 48, 57-59.
`
`Response 5: Janssen’s citation is not Dr. Garnick’s testimony—Dr. Garnick
`
`simply confirms what is written in Trump. Janssen takes a single quotation out of
`
`3
`
`
`
`
`
`context, ignoring the widespread practice in the prior art of prescribing
`
`ketoconazole and a glucocorticoid to advanced prostate cancer patients. Ex. 1104
`
`¶¶ 19-21. As Dr. Garnick testified, Gerber discloses the effective combination of
`
`ketoconazole and prednisone to treat castration-resistant prostate cancer, regardless
`
`of whether ketoconazole and hydrocortisone was used in the same way with the
`
`same effectiveness. Ex. 2185 at 135:4-136:3; Ex. 1104 ¶¶ 12, 24, 32-38.
`
`Response 6: Again, Dr. Garnick merely confirms what is written in Sonino and
`
`does not give affirmative testimony. Sonino also was not cited in Dr. Garnick’s
`
`reply declaration, so any testimony regarding Sonino is outside the scope of his
`
`declaration, an objection that was preserved in the record. Ex. 2185 at 109:1.
`
`Further, regardless of its specific side effect profile, ketoconazole was known to
`
`inhibit adrenal steroid synthesis and require concomitant glucocorticoid therapy.
`
`Ex. 1097 ¶¶ 38-42, 52-55, 62-66; Ex. 1104 ¶¶ 5, 11-13, 16-23, 25-27. Finally, as
`
`Dr. Garnick and Dr. Bantle explain, the prior art disclosed that abiraterone was
`
`expected to cause mineralocorticoid excess, necessitating the use of concomitant
`
`glucocorticoid replacement therapy. Ex. 1097 ¶¶ 25-26, 43, 56-59; Ex. 1104
`
`¶¶ 71-79; Ex. 2185 at 166:18-167:21.
`
`Response 7: Patent Owner’s cite is irrelevant. The Board’s claim construction
`
`does not require that prednisone be used to “treat” prostate cancer, in the limited
`
`sense of providing an antitumor or anticancer effect (as Patent Owners have
`
`4
`
`
`
`
`
`repeatedly asserted, despite the Board’s ruling in Amerigen (IPR2016-00286)).
`
`Indeed, under the correct understanding of the term “treat,” approved by the Board,
`
`Gerber teaches the use of prednisone to treat prostate cancer because Gerber
`
`teaches administration of prednisone with a steroid synthesis inhibitor to address
`
`side effects. Ex. 2185 at 128:18-22 (“[Q.] So based on your review of Gerber, you
`
`concluded that the patients in Gerber were receiving prednisone as glucocorticoid
`
`replacement therapy in order to address side effects, correct? [A.] Yes.”); Ex. 1104
`
`¶ 33.
`
`Response 8: Janssen omits Dr. Garnick’s complete testimony, which observes that
`
`many physicians administer glucocorticoids other than prednisone with abiraterone
`
`acetate, or prednisone in amounts different than Zytiga®’s label. Ex. 2185 at
`
`149:1-12 (“Some of my colleagues administer abiraterone acetate with
`
`hydrocortisone. Some may use five milligrams, and two and a half milligrams of
`
`prednisone. So it’s - you know, it’s administration with a glucocorticoid. Not
`
`necessarily requiring prednisone.”). Dr. Garnick’s complete testimony contradicts
`
`Dr. Rettig’s broad proclamation that “[d]octors prescribe ZYTIGA® therapy for
`
`mCRPC patients because of the observed enhanced survival benefit of the
`
`combination of abiraterone acetate and prednisone in mCRPC patients.” Ex. 2038
`
`¶ 219.
`
`Response 9: Janssen incorrectly implies that abiraterone acetate patients with low
`
`5
`
`
`
`
`
`adrenal reserve do not need replacement glucocorticoid therapy. Rather, any
`
`significant physiological stress to a patient with low adrenal reserve can be fatal.
`
`Ex. 1097 ¶ 54. Moreover, the O’Donnell Synacthen data showing low adrenal
`
`reserve further
`
`indicated the presence of either adrenal
`
`insufficiency or
`
`mineralocorticoid excess, both requiring glucocorticoid supplementation. Id.
`
`¶¶ 50-62. Skilled artisans at the priority date, as Attard 2005 notes, would
`
`therefore have been concerned about adrenal insufficiency, low adrenal reserve,
`
`and mineralocorticoid excess, all three of which would have counseled toward
`
`administration of a glucocorticoid like prednisone. Ex. 1023 at 5 (“Patients will be
`
`closely monitored for the development of glucocorticoid insufficiency or
`
`hypertension.”); Ex. 1097 ¶¶ 43-66.
`
`Response 10: Janssen improperly draws broad conclusions from a very narrow
`
`question. Dr. Bantle agreed only that abiraterone acetate did not cause
`
`mineralocorticoid excess during the 12-day O’Donnell study period. As Dr. Bantle
`
`explained in his declaration, mineralocorticoid excess takes substantial time to
`
`develop, so the O’Donnell patients’ lack of mineralocorticoid excess was not
`
`definitive. Ex. 1097 ¶¶ 72, 74. And even though the O’Donnell patients had not
`
`developed mineralocorticoid excess by the study’s conclusion, “the clinical results
`
`in O’Donnell would have further concerned a person of ordinary skill in the art
`
`(“POSA”)
`
`that patients administered abiraterone acetate may develop
`
`6
`
`
`
`
`
`mineralocorticoid excess.” Id. ¶¶ 59-60.
`
`Response 11: The cited testimony is irrelevant. Petitioners do not dispute which
`
`enzymes are inhibited by ketoconazole and abiraterone acetate. Both drugs were
`
`known to inhibit production of cortisol, in part because of CYP17 inhibition
`
`(abiraterone acetate is a 10-times greater inhibitor of CYP17 than ketoconazole).
`
`Ex. 1097 ¶¶ 44-49, 90. That knowledge, with O’Donnell’s disclosures, would
`
`have motivated skilled artisans to administer abiraterone acetate with prednisone:
`
`Q Is it your opinion, based on the data as it exists in the O’Donnell
`
`reference, that a person of ordinary skill in the art would necessarily
`
`administer prednisone
`
`the next
`
`time she or he administered
`
`abiraterone acetate to a patient?
`
`A Yes, based on three things: First, the experience with ketoconazole
`
`which is a drug of the same class known to produce adrenal
`
`insufficiency; second, based on the very abnormal Synacthen test
`
`results documenting these patients had adrenal dysfunction; and third,
`
`by the concluding sentence in the abstract, which is probably the most
`
`important part of the whole manuscript where O’Donnell says,
`
`“Adrenal cortical suppression may necessitate” --
`
`Q Sorry, Doctor, can you tell me where you are?
`
`A I’m reading the last sentence of the abstract on the first page --
`
`Q The abstract, okay.
`
`A -- which I think is the most important part of the manuscript and the
`
`part most likely to be read by anyone who picks up on this article. He
`
`7
`
`
`
`
`
`says or she, I’m not sure which, “Adrenocortical suppression may
`
`necessitate
`
`concomitant
`
`administration
`
`of
`
`replacement
`
`glucocorticoid.” Knowing those three things, I would say were I to
`
`prescribe abiraterone and not administer concomitant glucocorticoid,
`
`and if that patient should develop adrenal insufficiency and have a bad
`
`outcome, I would be guilty of malpractice.
`
`Ex. 2188 at 104:6-105:10.
`
`Response 12: The cited testimony does not undermine Dr. Bantle’s opinions.
`
`Janssen asserts that, despite O’Donnell’s consistently abnormal Synacthen test
`
`results, a POSA would have known that abiraterone acetate does not cause adrenal
`
`insufficiency, low adrenal reserve, or mineralocorticoid excess because the
`
`O’Donnell patients did not yet have clinical symptoms after 12 days of treatment.
`
`Paper 35 at 20-24. Dr. Bantle explained that these three conditions are all slow-
`
`developing, and initial symptoms may be subclinical and non-specific, so a POSA
`
`would not have ruled out these complications based solely on the lack of reported
`
`symptoms after 12 days of abiraterone acetate treatment. Ex. 1097 ¶¶ 72-74. That
`
`ketoconazole reduces cortisol levels “in a matter of days” (as opposed to weeks)
`
`does not mean that ketoconazole causes clinically-apparent adrenal insufficiency in
`
`12 days. Id. And importantly, this fact about ketoconazole would not cause skilled
`
`artisans to ignore the abnormal Synacthen tests or O’Donnell’s repeated teachings
`
`that “[a]drenocortical suppression may necessitate concomitant administration of
`
`8
`
`
`
`
`
`replacement glucocorticoid.” Id. ¶¶ 43-66; Ex. 1003 at 1 (abstract); see also Ex.
`
`2188 at 104:6-105:10.
`
`Response 13: The testimony Janssen cites is irrelevant. As Dr. Garnick and Dr.
`
`Bantle discussed in their declarations, and reaffirmed in their depositions, a POSA
`
`would have considered abiraterone acetate, ketoconazole, and aminoglutethimide
`
`to treat prostate cancer via the same drug class mechanism: inhibition of adrenal
`
`steroid synthesis. Ex. 1104 ¶¶ 18-31; Ex. 1097 ¶¶ 44-49; Ex. 2185 at 151:4-20;
`
`Ex. 2188 at 61:15-63:5. Skilled artisans understood that adrenal steroid synthesis
`
`inhibitors had undesirable collateral impacts on production of other steroids
`
`besides testosterone, and thus required replacement glucocorticoid therapy. Ex.
`
`1104 ¶¶ 18-31; Ex. 1097 ¶¶ 44-49. Contrary to the implication of Janssen’s motion
`
`for observation, Petitioners do not dispute abiraterone acetate, ketoconazole, and
`
`aminoglutethimide’s precise effects on adrenal steroid synthesis. Rather, Dr.
`
`Bantle explains that even if a POSA reviewed the exact enzymes abiraterone
`
`acetate, ketoconazole, and aminoglutethimide were known to inhibit, that prior art
`
`would have only further motivated skilled artisans to administer abiraterone acetate
`
`with a glucocorticoid. Ex. 1097 ¶¶ 50-66.
`
`Response 14: Janssen omits that Dr. Bantle’s testimony on the risk of bias in data
`
`reviews is most relevant to Dr. Rettig’s unexpected results opinions—Dr. Rettig
`
`retrospectively cherry-picked data across multiple studies to reach conclusions in
`
`9
`
`
`
`
`
`litigation which were never drawn in the literature. See Ex. 1091 (McKeague
`
`Decl.). Additionally, Janssen’s questions were divorced from any context. When
`
`asked directly whether a POSA administered glucocorticoids with ketoconazole,
`
`Dr. Bantle testified that “I would again repeat I think the standard of care at that
`
`point in time—and I think even at the present time—would be to administer
`
`prednisone with [ketoconazole]. For instance, if you look at the Gerber citation
`
`that predated O’Donnell, prednisone was given with ketoconazole. It was part of
`
`what they considered to be the standard and appropriate treatment.” Ex. 2188 at
`
`106:18-107:9; see also id. at 109:19-114:20. Janssen asserts that Dr. Bantle’s
`
`testimony undermines Dr. Garnick’s opinions. But it did not: Dr. Garnick
`
`explained at length that “Gerber provides an extraordinary amount of useful
`
`clinical information . . . .” Ex. 2185 at 135:4-136:7.
`
`Response 15: Janssen quotes Dr. Bantle out of context to imply that corticosterone
`
`could compensate for reduced cortisol levels induced by abiraterone acetate. In the
`
`same line of questioning, Dr. Bantle explained “that normally production of
`
`corticosterone is trivial, so it doesn’t contribute in any meaningful way,” Ex. 2188
`
`at 26:5-7, that “it would take a very large amount of corticosterone, and I think no
`
`one could tell you how much would be necessary and if the adrenal glands could
`
`produce that much,” id. at 28:7-10, and that corticosterone “has less glucocorticoid
`
`activity than cortisol,” id. at 28:17-18. See id. at 25:21-26:16, 27:24-28:18.
`
`10
`
`
`
`
`
`Moreover, Dr. Bantle notes in his declaration that “[i]f overproduction of
`
`corticosterone compensates for the reduction in cortisol, the patient would likely
`
`suffer from mineralocorticoid excess.” Ex. 1097 ¶ 88 (citing Ex. 1023 (Attard
`
`2005) at 3 (“To produce enough corticosterone to compensate for the absence of
`
`cortisol, more intermediate steroids might be generated. . . . This ACTH-driven
`
`overproduction of mineralocorticoids often leads to hypertension.”)). Janssen
`
`never questioned Dr. Bantle on this ultimate opinion.
`
`Response 16: The testimony Janssen cites is legally irrelevant. Patent Owner must
`
`demonstrate commercial success, not Petitioner. See, e.g., Novartis AG v. Torrent
`
`Pharms. Ltd., 853 F.3d 1316, 1330-31 (Fed. Cir. 2017). Mr. Hofmann analyzed all
`
`the evidence offered by Dr. Vellturo and Janssen, and concluded it was insufficient
`
`to establish commercial success. Ex. 1134 ¶¶ 18-44; Ex. 2187 at 14:8-13.
`
`Response 17: As Mr. Hofmann explained, there is no dispute that efficacy and
`
`other previously-known features drive Zytiga® prescriptions. Ex. 2187 at 65:7-
`
`67:5. But abiraterone acetate’s efficacy was known in the prior art, so it has no
`
`nexus to the claims. Ex. 1134 ¶¶ 21-24; Ethicon Endo-Surgery, Inc. v. Covidien
`
`LP, 812 F.3d 1023, 1034 (Fed. Cir. 2016). Dr. Vellturo did not apportion the
`
`demand for Zytiga® that is due to abiraterone acetate’s anti-tumor benefits. Ex.
`
`1134 ¶ 23. And Janssen’s assertion that prednisone adds to abiraterone acetate’s
`
`anti-tumor effect remains wholly unproven. See Ex. 1091 ¶¶ 29-61; Ex. 1104
`
`11
`
`
`
`
`
`¶¶ 95-106.
`
`Response 18: Janssen’s citation is extremely misleading. Both Mr. Hofmann and
`
`Dr. Vellturo’s testimony is unequivocal that, as of 2004 and through the priority
`
`date, the ’213 patent blocked others from pursuing the claimed invention. Ex.
`
`2187 at 19:1-22, 22:16-23:3, 24:12-25:9, 26:8-27:14, 30:14-31:22; Ex. 1136 at
`
`19:16-22, 27:4-28:17; Ex. 1134 ¶¶ 8-17. Given that key prior art like O’Donnell
`
`(Ex. 1003) and Attard 2005 (Ex. 1023) was not published until after the blocking
`
`patent issued, a motivation to pursue the claimed invention was not fully realized
`
`in the “2002 time frame” to which Janssen refers.
`
`Response 19: Dr. McKeague is highly qualified to provide biostatistical opinions,
`
`and his opinions concern biostatistics. Ex. 1091 ¶¶ 2-6; Ex. 2186 at 15:9-21 (“My
`
`role in this is to analyze the nature of Dr. Rettig’s declaration in this case . . .
`
`concerning biostatistical issues.”). Dr. Rettig’s opinions regarding the alleged anti-
`
`cancer effect of prednisone administered with abiraterone acetate are based on
`
`fallacious and unreliable uses of data, so Dr. McKeague’s opinions are relevant
`
`and appropriate. Ex. 1091 ¶¶ 16, 29-61.
`
`Response 20(a)-(c): Janssen omits the very next question and answer following its
`
`observation 20(a):
`
`Q. So overlapping confidence intervals do not necessarily mean that
`
`there is no statistically significant difference; correct?
`
`THE WITNESS: Well, the implication is actually the other way
`
`12
`
`
`
`
`
`around. The implication is there’s not enough evidence of a
`
`significant difference. That’s the conclusion. And if you read my
`
`report, indeed, what I’m saying is Dr. Rettig does not provide enough
`
`evidence to conclude a statistically significant, and that’s, indeed,
`
`what we see in these confidence intervals. The overlapping confidence
`
`interval is a sign there’s not enough evidence to conclude a difference.
`
`Ex. 2186 at 51:9-22 (objection omitted). In addition, Dr. McKeague could not
`
`access the data underlying the studies on which Dr. Rettig relied. Only Janssen
`
`possessed the underlying data, which either Janssen withheld from Dr. Rettig, or
`
`Dr. Rettig withheld from Petitioners and the Board. And when Janssen asked Dr.
`
`McKeague whether he could “have calculated whether or not there is a statistically
`
`significant difference between the two groups . . . given the data that [he] cite[d] in
`
`[his] declaration,” Dr. McKeague replied that “[i]t’s not clear.” Id. at 89:2-11. As
`
`Dr. McKeague explained, demonstrating that the median TTPP values are
`
`statistically significantly different was “Dr. Rettig’s homework, which he did not
`
`do.” Id. at 90:14-91:4. “Dr. Rettig only looked at the point estimates, which, of
`
`course, is not a rigorous way of assessing the evidence for his claim of unexpected
`
`results. But we can assess the evidence in support of unexpected results by seeing
`
`whether the confidence intervals overlap, and indeed, they do to a significant
`
`degree.” Id. at 53:14-20.
`
`Response 21(a): As explained in Response 20, the fact that the confidence
`
`13
`
`
`
`
`
`intervals overlap, regardless of the amount of overlap, demonstrates that “there’s
`
`not enough evidence of a significant difference” between Dr. Rettig’s proffered
`
`median TTPP estimates. Ex. 2186 at 51:9-22. Dr. McKeague also testified that
`
`the confidence intervals overlap “to a significant degree.” Id. at 53:14-20. With
`
`respect to the “error” referred to in Janssen’s question, Dr. McKeague in his
`
`deposition acknowledged and corrected a single typographical error in two of his
`
`figures. Id. at 163:3-165:6; Ex. 1146. Dr. McKeague also noted that these
`
`corrections do not affect his opinion. Ex. 2186 at 165:2-6.
`
`Response 21(b): Janssen blatantly omits Dr. McKeague’s full answer. Dr.
`
`McKeague goes on to testify:
`
`All I say is there is a glaring inconsistency. I notice that the
`
`information on the CLINICALTRIALS.GOV website certainly came
`
`long after the publication itself. So that we can conjecture. We can
`
`speculate various explanations. Maybe there was some problem with
`
`the data analysis. Maybe the data changed, and they’re getting the
`
`correct value in the CLINICALTRIALS.GOV value, which is, of
`
`course, substantially larger than the value in the paper. The median
`
`TTPP.
`
`Ex. 2186 at 95:1-15; see also 95:17-98:11. The clinicaltrials.gov data—which
`
`refute Dr. Rettig’s unexpected results opinion—are important because the trial
`
`results Janssen reported to the FDA conflict with those Dr. Rettig presents. Ex.
`
`1091 ¶ 36. Only Janssen can know why the trial results it gave to Dr. Rettig differ
`
`14
`
`
`
`
`
`from those it reported to the FDA, and which is more reliable.
`
`Response 22: Janssen omits Dr. McKeague’s testimony that the difference in
`
`baseline PSA level between the studies Dr. Rettig compares is “a meaningful
`
`difference” and “especially problematic because it’s related to the outcome, the
`
`end point of the studies, which is—well, the primary end point—both the primary
`
`and the secondary end points are related to PSA levels, and here we see the
`
`subjects, the patients in the actual studies had very substantially different baseline
`
`PSA. Therefore, how can we make comparisons between those two studies about
`
`an end point that is PSA related when the two patient populations are very
`
`different[?]” Ex. 2186 at 120:13-121:2. As a biostatistician, Dr. McKeague
`
`explains that a biostatistician is alarmed when there is a substantial difference in
`
`the primary variable’s baseline values, and that any reliable analysis would
`
`demonstrate that the difference is not statistically significant. Ex. 1091 ¶ 50. Dr.
`
`Garnick, an oncologist, provides the opinion that the difference in baseline PSA
`
`levels is scientifically significant. Ex. 1104 ¶ 98. Dr. McKeague also notes that
`
`“one of the publications cited by Dr. Rettig indicates that different baseline PSA
`
`levels are significant.” Ex. 1091 ¶ 51 (emphasis in original).
`
`
`
`
`
`15
`
`
`
`Dated: May 10, 2017
`
`
`
`
`
`
`
`/Brandon M. White/
`Brandon M. White
`Reg. No. 52,354
`Perkins Coie LLP
`700 13th St., NW, Suite 600
`Washington, D.C. 20005
`Telephone: (202) 654-6206
`E-mail: bmwhite@perkinscoie.com
`
`Attorney for Mylan Pharmaceuticals Inc.
`
`16
`
`
`
`CERTIFICATE OF SERVICE
`
`The undersigned hereby certifies that the foregoing Petitioners’ Response to
`
`Patent Owner’s Motion for Observations on Cross-Examination was served
`
`electronically via email as follows:
`
`Patent Owners:
`
`Dianne B. Elderkin
`Barbara L. Mullin
`Ruben H. Munoz
`Akin Gump Strauss Hauer & Feld LLP
`JANS-ZYTIGA@akingump.com
`
`Todd L. Krause
`David T. Pritikin
`Bindu Donovan
`Paul J. Zegger
`Sidley Austin LLP
`ZytigaIPRTeam@sidley.com
`
`
`
`
`Petitioners:
`
`Samuel S. Park
`Jovial Wong
`Ryan B. Hauer
`Winston & Strawn LLP
`spark@winston.com
`jwong@winston.com
`rhauer@winston.com
`
`
`
`
`
`
`Dated: May 10, 2017
`
`
`
`/Brandon M. White/
`Brandon M. White
`
`Attorney for Mylan Pharmaceuticals Inc.
`
`
`
`1
`
`