`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`MYLAN, INC.,
`Petitioner,
`
`v.
`
`AVENTIS PHARMA, S.A.,
`Patent Owner.
`
`
`_____________________________
`
`Case No. IPR2016-00712
`Patent No. 8,927,592
`
`_____________________________
`
`
`
`REPLY DECLARATION OF DR. RAHUL SETH
`
`
`
`
`
`
`
`MYLAN - EXHIBIT 1043
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`QUALIFICATIONS ..................................................................................... 1
`
`II.
`
`LEGAL STANDARDS ................................................................................ 2
`
`III. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................ 3
`
`IV. STATE OF THE ART ................................................................................... 4
`
`V.
`
`RESPONSE TO ARGUMENTS FROM AVENTIS AND DR.
`SARTOR REGARDING THE CLAIMS OF THE ’592 PATENT ................ 4
`
`VI. RESPONSE TO ARGUMENTS FROM AVENTIS AND DR.
`SARTOR REGARDING THE PROPOSED SUBSTITUTE CLAIMS ....... 20
`
`VII. THE PROPOSED SUBSTITUTE CLAIMS WOULD HAVE BEEN
`OBVIOUS TO A PERSON OF ORDINARY SKILL ................................. 24
`
`VIII. THE TEACHINGS OF MITA .................................................................... 40
`
`IX. THE ALLEGED “TEACHING AWAY” .................................................... 41
`
`X.
`
`CONCLUDING STATEMENTS ................................................................ 42
`
`XI. APPENDIX – LIST OF EXHIBITS ............................................................ 44
`
`
`-i-
`
`
`
`
`
`I.
`
`I, Rahul Seth, declare as follows:
`
`QUALIFICATIONS
`
`1.
`
`I am the same Dr. Rahul Seth who previously submitted a declaration
`
`(EX1002) filed with the petition in this IPR on March 15, 2016 (“Original
`
`Declaration”). My Original Declaration and my CV (EX1003) detail my
`
`background, education, credentials, experience, and compensation. I also discussed
`
`in my Original Declaration some characteristics of a person of ordinary skill in the
`
`art. Unless noted otherwise in this declaration, the information and opinions
`
`contained in my Original Declaration remain the same.
`
`2.
`
`I have been asked by counsel for Mylan Pharmaceuticals Inc. to
`
`evaluate and provide my opinions regarding the testimony of Dr. Alton Sartor
`
`contained in his First Declaration (EX2001, filed on June 24, 2016) and in his
`
`Second Declaration (EX2176, filed on December 13, 2016). In addition to
`
`reviewing Dr. Sartor’s First and Second Declarations, I also reviewed and
`
`considered the materials cited in his declarations, as well as the materials cited and
`
`discussed in this declaration. My opinions are based upon my review of these
`
`materials, as well as my knowledge, education, and training.
`
`3.
`
`Upon such consideration, it remains my considered opinion that
`
`claims 1-5 and 7-30 of the ’592 patent would have been obvious to a person of
`
`ordinary skill in the art in view of the prior art as it would be understood by a
`
`person of ordinary skill in the art at the time of the claimed invention. Further, it is
`
`1
`
`
`
`
`
`also my opinion that the amendments to the claims proposed by the Patent Owner
`
`and Dr. Sartor would not alter this analysis, and that the proposed amended claims
`
`31-34 similarly would have been obvious to a person of ordinary skill at the time
`
`of the claimed invention.
`
`II. LEGAL STANDARDS
`
`4. My Original Declaration provides my understanding of the legal
`
`standards that are applicable in this case. Furthermore, I have been informed that
`
`the Board may consider factors referred to as secondary considerations or objective
`
`indicia of non-obviousness that are presented by the Patent Owner to rebut a
`
`showing a obviousness. I am informed that the Patent Owner bears the burden of
`
`providing such evidence, but that the ultimate burden of persuasion on the issue of
`
`obviousness falls on the petitioner. I am also informed that for secondary indicia to
`
`be probative of non-obviousness, there must be a sufficient connection or “nexus”
`
`between the asserted secondary consideration and the novel aspects of the
`
`challenged claim.
`
`5.
`
`I also understand that evidence of “secondary considerations” may be
`
`weighed against evidence of the scope and content of, and the level of skill in, the
`
`art to rebut a conclusion of obviousness where appropriate.
`
`6.
`
`I understand that such secondary considerations, where in evidence,
`
`may include: (i) the commercial success of a product due to the merits of the
`
`claimed invention; (ii) the satisfaction by the invention of a long-felt, but
`
`-2-
`
`
`
`
`
`previously unsatisfied need; (iii) the failure of others to find the solution provided
`
`by the claimed invention; (iv) deliberate copying of the invention by others; (v)
`
`unexpected results achieved by the invention; (vi) praise of the invention by others
`
`skilled in the art.
`
`7.
`
`I further understand when evaluating unexpected results in relation to
`
`the obviousness analysis, the asserted unexpected results should be evaluated based
`
`on the expectations of the person of ordinary skill in the art at the time of the
`
`invention. I also understand that that an unexpected results analysis should
`
`compare the results of the claimed invention to that of the closest prior art. I also
`
`understand that unexpected results showing a difference in kind may be more
`
`probative than evidence sowing simply a difference of degree as compared to the
`
`results of the closest prior art.
`
`III. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`8.
`
`I explained in my Original Declaration that a person of ordinary skill
`
`in the art would be an oncologist, would hold a medical degree (e.g., a D.O. or an
`
`M.D.), and would have experience treating patients with prostate cancer by
`
`administering chemotherapeutic drugs.
`
`9.
`
`Dr. Sartor testified during his deposition that the person of ordinary
`
`skill in the art of the ’592 patent is a practicing oncologist. Ex. 1041, 140:2-7; see
`
`also EX2001, ¶24. Dr. Sartor also states that the skilled artisan would have
`
`experience evaluating new therapies for prostate cancer and would have access to
`
`-3-
`
`
`
`
`
`information regarding the mechanisms of drug resistance and pharmacokinetics.
`
`EX2001, ¶24. Dr. Sartor states that any differences between our descriptions of the
`
`person of ordinary skill are immaterial. Id., ¶ ¶26-27. I agree that Dr. Sartor’s
`
`description of the person of ordinary skill would not alter the opinions rendered in
`
`my Original Declaration or in this declaration.
`
`IV. STATE OF THE ART
`
`10.
`
`In his description of the state of the art, Dr. Sartor sates that “mCRPC
`
`is an incurable condition; therefore the goals of therapy are to improve quality of
`
`life through symptom control and to prolong the life of patients.” Id., ¶ 30. I agree
`
`with Dr. Sartor that each of these outcomes can be an important goal of therapy.
`
`Indeed, in many cases, improvement of quality of life through symptom control
`
`(including pain alleviation via reduction in cancer cells) is a primary aim of
`
`mCRPC treatment. A person of ordinary skill would understand today and would
`
`have understood in 2008 that one of the purposes of administering a taxane (such
`
`as docetaxel or cabazitaxel) to a patient with mCRPC that has progressed during or
`
`after docetaxel is to prolong the survival of that patient.
`
`V. RESPONSE TO ARGUMENTS FROM AVENTIS AND DR. SARTOR
`REGARDING THE CLAIMS OF THE ’592 PATENT
`
`11.
`
`I understand that Dr. Sartor asserts that I have not sufficiently shown
`
`why a person of ordinary skill in the art would have used prednisone in
`
`combination with cabazitaxel. EX1076, ¶176. To begin with, both Winquist and
`
`the TROPIC Listing disclose administration of cabazitaxel with prednisone for
`
`-4-
`
`
`
`
`
`treatment of mCRPC. EX1008, 1; EX1009, 3948. Furthermore, as I explained in
`
`paragraphs 61, 62, and 126 of my Original Declaration, prednisone at 10 mg/day
`
`was already the recommended dose for docetaxel, as listed on the Taxotere Label.
`
`See EX1024, 1 (“HRPC: 75 mg/m2 with 5 mg prednisone twice a day
`
`continuously.”) Tannock, one of the references I cite to in the grounds, further
`
`establishes the usage of prednisone at this dose for mCRPC. See EX1002, ¶¶108-
`
`111 (discussing EX1013). Furthermore, Winquist, the TROPIC Listing, and
`
`Tannock each also describe comparator arms including mitoxantrone plus
`
`prednisone, further demonstrating that administration of prednisone was standard
`
`when treating mCRPC, including (for Winquist and the TROPIC Listing) in the
`
`post-docetaxel setting. See EX1008, 1; EX1009, 3948; EX1013, 1502.
`
`12. The existence of alternative docetaxel therapies using estramustine
`
`(EX2176, ¶176, citing EX2077, 18) would not lead a person of ordinary skill to
`
`conclude that prednisone must not be used, in light of the many references I have
`
`cited to that suggest its use. Nor would the alternative mitoxantrone therapies using
`
`hydrocortisone that Dr. Sartor refers to (EX2176, ¶176) have dissuaded a person of
`
`ordinary skill.
`
`13. Dr. Sartor also suggests that a doctor would avoid using prednisone
`
`after docetaxel therapy, because of possible side effects or the possibility of its
`
`benefits being transient. EX2176, ¶¶179-182. However, the Novantrone label
`
`relied on by Dr. Sartor teaches the use of prednisone in mCRPC patients (EX2111,
`
`9), and Dr. Sartor identifies mitoxantrone therapy as the “community standard” for
`
`-5-
`
`
`
`
`
`mCRPC post-docetaxel prior to 2009. EX2176, ¶39. The Novantrone label bears
`
`an issue date of August, 2008, and is listed for download from the FDA database at
`
`http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process
`
`&ApplNo=019297 as SUPPL-30. A person of ordinary skill would have
`
`understood that continued prednisone treatment after docetaxel treatment was a
`
`reasonable option, as it was a standard treatment choice in the post-docetaxel
`
`setting in 2008.
`
`14. Dr. Sartor also suggests that the availability of doses other than 10
`
`mg/day of prednisone would be considered. EX2176, ¶183. While a person of
`
`ordinary skill would consider such alternative doses as available options, this
`
`would not lead a such a person to avoid the dose of 10 mg/day that was the most
`
`common dose for mCRPC treatment, both with docetaxel and with mitoxantrone.
`
`Accordingly, a person of ordinary skill would not be dissuaded from administering
`
`prednisone in combination with cabazitaxel for mCRPC, as explicitly taught by
`
`Winquist and the TROPIC Listing, including at the 10 mg/day dose taught by
`
`Tannock.
`
`15.
`
`In my original declaration, I described the objective response rates
`
`reported in Pivot, Beardsley, and other references in terms of the RECIST criteria.
`
`See, e.g. EX1002, ¶27. The RECIST criteria are rules for measuring tumor size and
`
`changes, e.g. in response to chemotherapy. The rules for determining partial
`
`response in terms of change in diameter, or equivalently in terms of area or
`
`volume, are generally learned by oncologists as part of their introductory radiology
`
`-6-
`
`
`
`
`
`courses. I cited to the ’592 patent as correctly reciting these well-known criteria.
`
`EX1002, ¶27, citing EX1001 at 11:1-9. The RECIST criteria, including the
`
`mathematical relationships of diameter, area, and volume inherent to these criteria
`
`(i.e., 30% reduction in diameter, 50% reduction in area, 65% reduction in volume
`
`for a uniformly shrinking lesion), are described in detail by Padhani et al. See
`
`EX1051, 983-84.
`
`16. Dr. Sartor refers to multiple clinical trials involving drugs that did not
`
`receive FDA approval to support his assertion that there would have been no
`
`reasonable expectation of success in practicing the method disclosed by Winquist
`
`and the TROPIC Listing. EX2176, ¶¶59-67, 95-100, 102, 104-09, 149-52.
`
`However, none of the studies Dr. Sartor refers to supports this argument.
`
`17. Dr. Sartor refers to three clinical trials in larotaxel that did not result
`
`in FDA approval. Two of these studies—in pancreatic and bladder cancer—were
`
`published after 2009, and would therefore not have informed a person of ordinary
`
`skill. EX2176, ¶¶63, 65. The third, from 2006, was a Phase III study in breast
`
`cancer, and demonstrated an overall survival benefit that was statistically
`
`indistinguishable from capecitabine—an FDA-approved treatment that had been
`
`shown to provide a survival benefit. EX2176, ¶64. Dr. Sartor improperly equates a
`
`lack of superiority to a lack of efficacy, whereas in fact the trial indicated no
`
`significant difference in overall survival. Moreover, larotaxel had a significantly
`
`worse side effect profile than cabazitaxel in Phase II trials than cabazitaxel.
`
`Compare EX2015, 1255, 1259 (9% febrile neutropenia, 8% neutropenic infection,
`
`-7-
`
`
`
`
`
`“acceptable safety profile”) with EX1010, 1547, 1550-51 (“a low febrile
`
`neutropenia rate (3%),” 4% neutropenic infection, “safety profile … was very
`
`favorable”). Notably, the median overall survival for cabazitaxel, as reported in
`
`Pivot, was 12.3 months (EX1010, 1548), compared to 9.8 months for taxane-
`
`resistant patients on larotaxel. EX2015, 1256. Given the inferior safety shown by
`
`larotaxel’s Phase II study, and its inferior overall survival, a person of ordinary
`
`skill in the art would not have concluded that larotaxel’s failure to show superiority
`
`to an FDA-approved breast cancer treatment meant that cabazitaxel treatment
`
`would lack a reasonable expectation of success.
`
`18. Dr. Sartor refers to a failed Phase II study in milataxel (EX2176, ¶66);
`
`however, the failure of milataxel at Phase II would not imply a failure in
`
`cabazitaxel, which was known to be undergoing Phase III trials. For similar
`
`reasons, the failure of Epothilone D in Phase II trials (EX2176, ¶67) would not
`
`undermine the expectation of success in cabazitaxel, which had reached Phase III,
`
`and would therefore be considered a cut above drugs that had failed to reach this
`
`final stage of testing.
`
`19. Dr. Sartor refers to a list of other drugs that did not receive an FDA
`
`approval to support his argument that a person of ordinary skill in the art would not
`
`have had a reasonable expectation of success in using cabazitaxel in the manner
`
`disclosed in the prior art, but none of these supports his thesis. For example,
`
`Suramin (EX2176, ¶95) was denied FDA approval even though it showed
`
`“statistically significant pain relief and PSA advantages;” this does not indicate a
`
`-8-
`
`
`
`
`
`likelihood of failure, but rather that a drug can fail to obtain FDA despite being
`
`useful. Astrasentan (EX2176, ¶96) was shown to reduce prostate specific antigen
`
`(PSA) levels significantly enough to be termed a “clinical response,” and had
`
`nonsignificant improvements in time to progression of cancer and PSA, and had
`
`significantly lower bone pain. EX2010, 1960, 1962, 1964; EX2190, 2176.
`
`Atrasentan again demonstrates that a lack of FDA approval is not the same as a
`
`lack of efficacy or utility.
`
`20. Dr. Sartor also identifies satraplatin (EX2176, ¶97) as a “failed
`
`candidate” despite it showing a real clinical benefit. Beardsley cites an article
`
`entitled “Satraplatin (S) demonstrates significant clinical benefits for the treatment
`
`of patients with HRPC: results of a randomized phase III trial [abstract #5019]. J
`
`Clin. Oncology 2007; 25(18S).” In this phase III trial, satraplatin treatment was
`
`found to result in a statistically significant increase in progression free survival.
`
`EX1022, 162-63. Dr. Sartor’s declaration appears to identify this as a failure,
`
`despite the statistically significant benefit, based solely on the fact that FDA
`
`approval was not granted. However, in my opinion, in light of satraplatin’s ability
`
`to benefit at least some patients, as demonstrated by the Phase III trial results,
`
`satraplatin should not be deemed a failure. I understand that Dr. Sartor agreed that
`
`there was a clinical benefit, notwithstanding the refusal of the FDA to grant
`
`approval for satraplatin. EX1041, 260:12-261:20.
`
`21. DN-101 is another drug that Dr. Sartor pronounces a failure due to its
`
`failure to obtain FDA approval. However, the clinical studies cited by Dr. Sartor
`
`-9-
`
`
`
`
`
`paint a different picture. Dr. Sartor identifies DN-101 as a failure due to its
`
`inability to demonstrate superiority as a combination treatment with weekly
`
`docetaxel, when compared to 3-weekly docetaxel. EX2176, ¶98, citing EX2043,
`
`1593. However, the ASCENT-1 trial demonstrated superior survival of DN-101
`
`plus docetaxel to placebo plus weekly docetaxel (p = 0.04). EX2006, 669. Weekly
`
`docetaxel was known to provide only a small (nonsignificant) improvement over
`
`mitoxantrone (see EX1013, 1502); accordingly, the superior overall survival
`
`demonstrated by the ASCENT-1 trial shows that the drug was useful, as it was
`
`superior to (an equivalent to) mitoxantrone treatment. That DN-101 was not
`
`sufficiently superior to garner FDA approval when facing the bar of the already-
`
`approved 3-weekly docetaxel does not imply that it lacks utility. Ultimately, the
`
`trials of DN-101 merely show that although DN-101 provides a significant
`
`improvement to the (known inferior) weekly docetaxel regimen, it does not
`
`provide enough to defeat 3-weekly docetaxel. Insofar as Dr. Sartor relies on the
`
`statements of Dr. Tannock made in 2010 (see EX2176, ¶99), after the “relevant
`
`timeframes” he identifies (see id., ¶17), such statements would not have informed a
`
`person of ordinary skill.
`
`22. Dr. Sartor similarly errs in lending weight to the failure of GVAX to
`
`obtain FDA approval. EX2176, ¶100. GVAX was an immunotherapy that used as a
`
`replacement for prednisone in docetaxel treatment. EX2027, 1. It was compared in
`
`a Phase III trial to docetaxel plus prednisone and failed to show superiority. Like
`
`DN-101, the failure of GVAX to defeat docetaxel does not imply it lacks utility;
`
`-10-
`
`
`
`
`
`after all, cabazitaxel also “failed” in the same comparison against docetaxel in the
`
`FIRSTANA study. EX2212, 1. The Medscape article Dr. Sartor relies upon for the
`
`results of the phase III GVAX trial posed the question of whether the sponsor
`
`“raised the bar too high in these phase 3 trials when we put GVAX up against an
`
`active chemotherapy drug,” referring to docetaxel. EX2027, 1. In a similar way,
`
`Dr. Sartor “raises the bar too high” when he judges drugs based on the FDA’s
`
`regulatory decisions to approve or deny approval.
`
`23. Due to the low degree of similarity between cabazitaxel and most of
`
`the “failed” drugs described by Dr. Sartor, a person of ordinary skill would
`
`attribute little weight to those examples, which ultimately amount to little more
`
`than anecdotal evidence. The only drug Dr. Sartor brings up that was similar in
`
`activity and indication to cabazitaxel was larotaxel, and even that drug had many
`
`differences (e.g., breast rather than prostate cancer, significantly worse Phase II
`
`side effects, lower single-arm survival in Phase II breast cancer) that would lead a
`
`person of ordinary skill to doubt its relevance. Phase III study published prior to
`
`2009 in which there was a failure in the relevant patient population: patients with
`
`post-docetaxel mCRPC. The most relevant evidence to the utility of cabazitaxel for
`
`mCRPC treatment was the clinical trial results reported by Pivot and Mita, and the
`
`clinical trial listings of Winquist and the TROPIC Listing detailing the TROPIC
`
`Protocol and indicating an ongoing Phase-III trial. None of these publications gave
`
`reason to doubt cabazitaxel’s usefulness in treating mCRPC. In my opinion, none
`
`of Dr. Sartor’s anecdotal evidence would undermine these teachings.
`
`-11-
`
`
`
`
`
`24. Dr. Sartor additionally describes several drugs with Phase III studies
`
`published after 2009: Avastin (EX2176, ¶104), Sunitinib (id., ¶105), Yervoy (id.,
`
`¶106), Curtisen (id., ¶107), Orteronel (id., ¶108), and four other drugs (id., ¶109)
`
`discussed by Antonarakis and Eisenberger. None of these studies would have been
`
`relevant to the reasonable expectations of a person of ordinary skill, as none was
`
`published prior to 2009. Dr Sartor also argues that failure would have been
`
`expected based on the success rates of Phase II trials reported in Booth (see
`
`EX2176, ¶89), but as I explained in my original declaration, cabazitaxel was at
`
`Phase III. EX1002, ¶¶219-223. To base analysis of the likelihood of success on
`
`statistics for Phase II or I would be to artificially lower that likelihood of success,
`
`as most oncology drugs fail in Phase I or II, but most oncology drugs (such as
`
`cabazitaxel) that reach Phase III succeed in obtaining FDA approval. Id.; see also
`
`EX1015 at 610 (Figure 1) (60% of oncology drugs succeed if they reach Phase III).
`
`25. Dr. Sartor bases some of his arguments on the fact that paclitaxel had
`
`not received FDA approval for treatment of mCRPC in combination with
`
`prednisone. EX2176, ¶175. For example, Dr. Sartor uses this difference to imply
`
`that breast and prostate cancer were so dissimilar that data showing efficacy in
`
`breast cancer (e.g., that shown in Pivot) would be discounted by a person of
`
`ordinary skill. See EX2176, ¶¶138-39, 132. However, Dr. Sartor again misapplies a
`
`standard of FDA approval to determine whether a drug has a use. In fact, it was
`
`known to use paclitaxel in combination with prednisone (and further in
`
`combination with carboplatin) to treat mCRPC. A Phase II clinical trial by
`
`-12-
`
`
`
`
`
`Cabrespine et al. (EX1050) was published in 2006, reporting on a Phase II trial
`
`comparing paclitaxel+carboplatin to mitoxantrone. EX1050, 354. Both arms were
`
`administered in combination with prednisone. Id. The study reported significantly
`
`greater PSA response and 3.4 months longer overall survival (14.5 vs 11.1 months)
`
`for the paclitaxel arm than the mitoxantrone arm. Id. A 3.4 month survival benefit,
`
`as reported by Cabrespine, is a substantial clinical benefit, although the patient
`
`population was insufficiently large to prove statistical significance. Id. ,357. The
`
`study also reported a 23% objective response rate for paclitaxel vs 0% for
`
`mitoxantrone, which reached the edge of statistical significance (p = 0.06). Id.,
`
`354. Each of these findings indicates a clinical benefit to paclitaxel+carboplatin
`
`treatment. Accordingly, although paclitaxel was not FDA approved for mCRPC, it
`
`was nonetheless used for the treatment of mCRPC, in combination with
`
`prednisone, and showed clinical benefit in that indication.
`
`26.
`
`I understand that Dr. Sartor has suggested that “a POSA would not
`
`have been motivated to administer cabazitaxel to provide a palliative benefit to
`
`help patients to live more comfortably,” and that because the FDA was not
`
`expected to approve cabazitaxel based on, e.g., an improvement in pain, a person
`
`of ordinary skill would not consider such benefits sufficient to justify using
`
`cabazitaxel. EX2176, ¶164. With regard to pain, the reason the FDA would not
`
`approve on that basis is not because cabazitaxel was not reasonably expected to
`
`provide such a benefit, but because the TROPIC study was open-label. EX2211,
`
`11-12. A person of ordinary skill would understand that an open-label study would
`
`-13-
`
`
`
`
`
`have difficulty demonstrating a subjective benefit such as decrease in pain, as the
`
`patients’ knowledge of which treatment they received could skew the results. The
`
`Novantrone label also indicates that mitoxantrone causes side effects, including a
`
`10 to 11 percent rate of febrile or infectious neutropenia when treating mCRPC
`
`patients. EX2111, 30-31. Notably, this is higher than the 3% febrile neutropenia
`
`rate disclosed by Pivot for cabazitaxel (as well as the 4% neutropenic infection
`
`rate, or even the sum of the two). EX1010, 1550, Table 2. Thus, mitoxantrone was
`
`known to provide palliative benefits despite having a higher rate of febrile
`
`neutropenia than reported for cabazitaxel. A person of ordinary skill would not rule
`
`out the possibility of palliative benefit form cabazitaxel based on its reported rate
`
`of neutropenia. Accordingly, a person of ordinary skill could reasonably expect
`
`cabazitaxel to provide a benefit in pain, while also expecting the TROPIC study to
`
`be incapable of proving this benefit.
`
`27.
`
`I also note that Dr. Sartor suggests that a person of ordinary skill
`
`would not expect a palliative benefit from cytotoxic chemotherapy because
`
`docetaxel had certain undesirable side effects. EX2176, ¶163. However, Tannock
`
`actually demonstrated a statistically significant improvement in pain reduction and
`
`quality of life for docetaxel + prednisone compared to mitoxantrone + prednisone
`
`in mCRPC. EX1013, 1508 (Table 3). Each also showed similar rates of febrile
`
`neutropenia to the rate disclosed in Pivot and Mita. Compare id., 1509 (Table 4,
`
`line 4) with EX1010, 1550 (Table 2, line 10); see also EX1012, 723 (one patient
`
`showed febrile neutropenia at 25 mg/m2, none reported at 20 mg/m2). Accordingly,
`
`-14-
`
`
`
`
`
`a person of ordinary skill would understand that a taxane such as docetaxel or
`
`cabazitaxel was entirely capable of providing palliative benefits. Even if a person
`
`of ordinary skill would believe that overall survival was the most likely outcome
`
`to lead to FDA approval, or indeed the most likely positive outcome overall for
`
`cabazitaxel, a person of ordinary skill could also reasonably expect cabazitaxel to
`
`produce other benefits desirable to patients and their doctors, such as palliation or
`
`improved progression-free survival. Any or all of these goals could motivate a
`
`person of ordinary skill to practice the method disclosed in the prior art Winquist
`
`and TROPIC Listing publications.
`
`28. Dr. Sartor also suggests that Ratain & Sargent (“Ratain,” EX1029)
`
`teach that “single-arm, non-randomized trials like Pivot should be the exception,
`
`not the rule in oncology trials.” EX2176, ¶133 (internal quotation omitted). In
`
`particular, Dr. Sartor suggests that Pivot’s successful result treating docetaxel-
`
`resistant metastatic cancer would be discounted because the study was not
`
`randomized, used objective response measures, and had “differing
`
`recommendations regarding dose from phase I studies.” Id. However, these
`
`arguments misrepresent the teachings of Ratain.
`
`29. Ratain states that non-randomized phase II trials in oncology are
`
`“appropriate for trials in which the desired outcome (e.g., a partial response) will
`
`not occur in the absence of the investigational agent, and the rate of that outcome
`
`for existing agents or regimens is historically highly reliable,” in which case “a
`
`positive phase II trial, defined as a response rate greater than some predefined
`
`-15-
`
`
`
`
`
`threshold, would be evidence for activity.” EX1029, 277. This accurately
`
`describes Pivot’s study, as Pivot measured objective (i.e. partial and complete)
`
`responses, which will generally “not occur in the absence of the investigational
`
`agent,” and which were known to correlate with Phase III success. I understand Dr.
`
`Sartor has criticized my discussion of El-Maraghi’s teaching that higher objective
`
`response rates, such as the 14% rate of Pivot, were indicative of greater likelihood
`
`of success. EX2176, ¶¶114-18. In particular, Dr. Sartor suggests that El-Maraghi’s
`
`findings were limited to targeted agents. Id., ¶115. However, on the same pages I
`
`cited in my declaration (see EX1002, ¶71), El-Maraghi clearly states that “phase II
`
`design for targeted agents is similar to that for cytotoxics” and that “[t]hese results
`
`… are similar to a recent review of cytotoxic agents.” EX1023, 1346, 1351. Ratain
`
`& Sargent “acknowledge that many experienced investigators continue to advocate
`
`the utility response rate as assessed in single-arm phase II trials,” citing to the El-
`
`Maraghi paper. EX1029, 277. Although they suggest that measuring further
`
`variables such as PFS further improve reliability (id., 278), they admit response
`
`rate “may be appropriate” for single-arm phase II oncology trials. Id., 277.
`
`30. Dr. Sartor also suggests that there were “differing recommendations
`
`regarding dose from phase I studies,” which might lead a person of ordinary skill
`
`in the art to question Pivot’s validity. Although it is true that Ratain cautions
`
`against using non-randomized trials when “there is an uncertainty regarding the
`
`optimal dose,” Dr. Sartor does not point to any examples to support his suggestion
`
`that there was uncertainty in the optimal dose. Pivot’s two doses (20 and 25
`
`-16-
`
`
`
`
`
`mg/m2) were in agreement with the Phase I data regarding safe doses reported in
`
`Mita, as well as the Phase III doses reported in Winquist and the TROPIC Listing.
`
`Moreover, Pivot determined that the “safety profile of [cabazitaxel] was very
`
`favorable” with low rates of both non-hematological and hematological adverse
`
`events. EX1010, 1551. Moreover, Mita reports objective responses in mCRPC
`
`including with a cabazitaxel dose as low as 15 mg/m2. EX1012, 727. A person of
`
`ordinary skill would take this as evidence that cabazitaxel retained anticancer
`
`activity in combination with its favorable side effect profile not only at a 25 mg/m2
`
`dose, but also at lower doses such as 20 mg/m2. In light of this favorable side-
`
`effect profile, a person of ordinary skill would conclude that Pivot’s favorable
`
`objective response rate and safe dose were reasonable indicators of probable
`
`clinical efficacy.
`
`31. Dr. Sartor asserts that it was unexpected that, according to Omlin et
`
`al. (EX2220), cabazitaxel had lower rates of alopecia, nail changes, neuropathy,
`
`and dysgeusia than docetaxel. However, it would not be surprising that different
`
`taxane drugs exhibit the same side effects to different degrees, and cabazitaxel is
`
`no exception to this. Moreover, I note that the same table (EX2220, Table 1),
`
`indicates that cabazitaxel had significantly higher rates of neutropenia and febrile
`
`neutropenia in that trial, which are both more significant and dangerous side effects
`
`than alopecia, nail changes, neuropathy, and dysgeusia. Similarly, cabazitaxel also
`
`had a higher (though not statistically significant) rate of death within 30 days of
`
`last chemotherapy dose. Id. In my opinion, the higher incidence of these serious
`
`-17-
`
`
`
`
`
`negative side effects weigh against the lower incidence of the less serious side
`
`effects highlighted by Dr. Sartor. Taken together, these benefits and drawbacks are
`
`unlikely to make a material difference in treatment decisions. Indeed, the FDA
`
`determined that the results were insufficiently beneficial to merit approval of
`
`cabazitaxel for use prior to docetaxel despite demonstrating that the two drugs had
`
`comparable efficacy. Moreover, Pivot had already disclosed a “very favorable”
`
`safety profile compared to docetaxel for various side effects, including for nausea,
`
`vomiting, and sensory neuropathy (see EX1010, 1551), so the existence of some
`
`side effects with lower rates of incidence would not be surprising. Accordingly, it
`
`is my opinion that Omlin et al. do not support Dr. Sartor’s assertion of unexpected
`
`results from cabazitaxel.
`
`32. Dr. Sartor also states that it was “further unexpected that some
`
`patients would prefer cabazitaxel and prednisone to docetaxel and prednisone,”
`
`citing to an on-going study by Sanofi (EX2221) that asserts without support that
`
`certain patients express a preference for cabazitaxel over docetaxel with regards to
`
`“general tolerance.” However, it is not unexpected that some patients would prefer
`
`one drug to another, just as some would have the opposite preference.
`
`33. When treating mCRPC patients, a doctor will commonly administer
`
`treatments in the order of their preference, with the more preferred treatments
`
`administered first, and the less preferred treatments administered later. Prior to
`
`2009, most doctors administered docetaxel as a first-line treatment for mCRPC.
`
`Second line treatment at that time would include mitoxantrone, if the treating
`
`-18-
`
`
`
`
`
`physician preferred its palliative benefits, or any other drug the treating physician
`
`felt, in his professional judgment, would provide a benefit to the patient. As a
`
`result of this pattern, most mCRPC patients at second-line or later would have been
`
`post-docetaxel patients. A treating physicia
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
