UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`MYLAN LABORATORIES LIMITED
`Petitioner,
`v.
`AVENTIS PHARMA S.A.
`Patent Owner.
`________________
`
`Case IPR2016-00712
`U.S. Patent No. 8,927,592
`________________
`
`REPLY DECLARATION OF ALTON OLIVER SARTOR, M.D.
`
`Aventis Exhibit 2259
`Mylan v. Aventis, IPR2016-00712
`
`
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`MYLAN LABORATORIES LIMITED
`Petitioner,
`v.
`AVENTIS PHARMA S.A.
`Patent Owner.
`________________
`
`Case IPR2016-00712
`U.S. Patent No. 8,927,592
`________________
`
`REPLY DECLARATION OF ALTON OLIVER SARTOR, M.D.
`
`Aventis Exhibit 2259
`Mylan v. Aventis, IPR2016-00712
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`Qualifications and Scope.................................................................................1
`
`“increasing survival” .......................................................................................1
`
`III. Nonobviousness...............................................................................................5
`
`A.
`
`B.
`
`It Would Not Have Been Obvious to a POSA to Use the
`Claimed Premedication Regimen to Prevent
`Hypersensitivity Reactions....................................................................6
`
`It Would Not Have Been Obvious to a POSA to Use the
`Claimed Premedication Regimen to Prevent or Treat
`Nausea .................................................................................................13
`
`1.
`
`2.
`
`To Prevent Nausea/Vomiting....................................................17
`
`To Treat Nausea/Vomiting .......................................................19
`
`IV. Declaration.....................................................................................................23
`
`i
`
`
`
`I.
`
`Qualifications and Scope
`
`1.
`
`I am the same Dr. Sartor who previously submitted declarations filed on
`
`June 24, 2016 (“First Declaration,” Exh. 2001) and December 23, 2016 (“Second
`
`Declaration,” Exh. 2176) in IPR2016-00712.
`
`2.
`
`I understand that Dr. Rahul Seth submitted declarations on March 15, 2016
`
`(“Petition Declaration,” Exh. 1002) addressing the validity of the claims of U.S.
`
`Patent No. 8,927,592 (“the ’592 patent”) and on March 14, 2017 (“Reply
`
`Declaration,” Exh. 1043) addressing the validity of the current claims of the ’592
`
`patent and substitute Claims 31-34 from Patent Owner’s Motion to Amend. I have
`
`been asked by counsel for Aventis Pharma S.A. (“Aventis”) to respond to Dr.
`
`Seth’s opinions regarding only Claims 31-34.
`
`II.
`
`“increasing survival”
`
`3. Dr. Seth argues that because it is impossible to know whether a drug will
`
`or has resulted in an increase in survival of a patient, “a method of increasing
`
`survival” means “administration of cabazitaxel with the intention of increasing
`
`survival of the patient, regardless of whether the intended survival actually
`
`results.” Exh. 1043 at ¶¶36-40.
`
`4.
`
`I disagree with Dr. Seth that it is impossible to know whether a drug will
`
`or has resulted in an increase in survival in a patient. As discussed in my Second
`
`Declaration, overall survival is a key endpoint for clinical studies in prostate cancer
`
`1
`
`
`
`that is measured by a randomized and controlled clinical study. Exh. 2176 at ¶231;
`
`Ramiah et al.,Clinical Endpoints for Drug Development in Prostate Cancer, 18
`
`Curr. Opin. Urol. 303-08 (2008) (Exh. 2030) at 306; Armstrong & George, New
`
`Drug Development in Metastatic Prostate Cancer, 26 Urologic Oncology:
`
`Seminars & Original Investigations 430-37 (2008) (Exh. 2005) at 431 (discussing
`
`power necessary to detect an overall survival advantage); Pazdur, Endpoints for
`
`Assessing Drug Activity in Clinical Trials, 13 (suppl. 2) The Oncologist 19-21
`
`(2008) (Exh. 2080) at 19-20.
`
`5. The purpose of measuring overall survival in clinical studies is to
`
`determine whether that regimen prolongs the life of individual patients. Once a
`
`study shows a statistically significant increase in overall survival as compared to
`
`no therapy or palliative therapy, a POSA can reasonably conclude that another
`
`patient with the same characteristics as in the clinical study has an increased life
`
`expectancy when given the study drug, and can treat the patient with the studied
`
`regimen with the intent to increase the survival of that patient.
`
`6. The TROPIC study described in Example 1 of the ’592 patent is an
`
`example of such a clinical trial designed to determine whether cabazitaxel plus
`
`prednisone would result in an increase in overall survival as compared to
`
`mitoxantrone plus prednisone. The TROPIC study randomized 755 patients with
`
`mCRPC that had progressed during or after a docetaxel-containing regimen. Exh.
`
`2
`
`
`
`1001 at Example 1. The results of the study showed that the cabazitaxel plus
`
`prednisone arm had statistically significantly longer overall survival as compared
`
`to the mitoxantrone plus prednisone arm, with a p-value of <0.0001. Id. Based on
`
`the results of TROPIC, another mCRPC patient that has progressed during or after
`
`docetaxel has an increased life expectancy when he receives cabazitaxel plus
`
`prednisone therapy as compared to mitoxantrone plus prednisone therapy.
`
`7. A POSA would understand that in an ideal world an experimental
`
`medication could be compared to no therapy to determine whether the
`
`experimental medication prolongs life. However, such a clinical trial could be
`
`considered unethical for mCRPC patients who are very sick. Accordingly, instead
`
`of no therapy, an appropriate comparator is palliative therapy, such as the
`
`mitoxantrone plus prednisone arm of the TROPIC study described in the ’592
`
`patent. The palliative mitoxantrone therapy is essentially a surrogate for no
`
`therapy with respect to survival because an increase in survival as compared to
`
`mitoxantrone is necessarily an increase in survival as compared to no therapy.
`
`8. Dr. Seth also asserts that the investigators of the TROPIC study intended to
`
`prolong the lives of their patients and that patients entering phase III studies intend
`
`themselves to live longer. Exh. 1043 at ¶39. I disagree. Patients in the TROPIC
`
`study were randomized to receive either cabazitaxel and prednisone or
`
`mitoxantrone and prednisone. Mitoxantrone had not been shown to prolong life.
`
`3
`
`
`
`See August 2008 Novantrone® Label (Exh. 2111) at 9-12. Therefore, before
`
`randomization, doctors and patients could not know which therapy they would
`
`receive, and thus, could not have intended for survival to be increased.
`
`9.
`
`From an ethical standpoint, a POSA understood that in order for the
`
`TROPIC study to be run, it must have been unknown whether the cabazitaxel arm
`
`would prolong survival as compared to the mitoxantrone arm; equipoise is
`
`required. Otherwise the study would have failed to enroll patients because
`
`physicians would not have wanted their patients to receive mitoxantrone.
`
`Accordingly, a POSA would have understood that even once patients were
`
`receiving cabazitaxel therapy on the TROPIC study, investigators could not have
`
`intended for those patients to have increased survival, nor could those patients have
`
`expected increased survival.
`
`10. At most, patients and investigators hoped that cabazitaxel therapy would
`
`turn out to be life-prolonging. I, and many other oncologists, have hoped that
`
`many drugs tested in mCRPC in the past 15 years would prolong life and provide a
`
`risk-benefit ratio that was favorable, particularly as compared to previously
`
`available therapies. However, an intention of increasing survival is different than a
`
`hope that it will occur.
`
`11. An intention of increased survival is only possible where there is data
`
`supporting the efficacy of that regimen with respect to survival. This is true in
`
`4
`
`
`
`particular for prostate cancer where, as discussed in my Second Declaration, there
`
`were no validated surrogate endpoints for survival. Exh. 2176 at ¶¶84, 86. Such
`
`data on survival did not exist for cabazitaxel prior to the results of TROPIC. There
`
`had never been a study in combination with prednisone, a controlled study
`
`measuring survival, or a study in more than eight prostate cancer patients, let alone
`
`mCRPC patients that had progressed during or after treatment with docetaxel.
`
`12. TROPIC was an experimental clinical study conducted to evaluate the
`
`safety and efficacy of cabazitaxel in combination with prednisone in patients with
`
`mCRPC that had progressed during or after treatment with docetaxel. No one
`
`could have known whether cabazitaxel therapy would prolong the life of these
`
`patients until the study was completed and the results were analyzed. Indeed, a
`
`POSA would not have reasonably expected cabazitaxel therapy to prolong overall
`
`survival, and therefore a POSA could not have given the cabazitaxel regimen of
`
`Claim 31 with an intention of increasing survival before the results of TROPIC.
`
`III. Nonobviousness
`
`13. I understand that Dr. Seth argues that proposed Claims 31-34 would have
`
`been obvious based on the opinions in his Petition Declaration, and that it further
`
`would have been obvious to use a premedication regimen consisting of an
`
`antihistamine, a corticoid, and an H2 antagonist prior to administering the 20-25
`
`5
`
`
`
`mg/m2 of cabazitaxel to prevent allergic reactions or to prevent and treat nausea
`
`and vomiting. Exh. 1043 at ¶¶48-49. I do not agree.
`
`A.
`
`It Would Not Have Been Obvious to a POSA to Use the Claimed
`Premedication Regimen to Prevent Hypersensitivity Reactions
`
`14. Dr. Seth argues that a POSA would have been motivated to use the
`
`claimed premedication regimen to prevent hypersensitivity reactions based on
`
`Winquist, the TROPIC Listing, Pivot, and any one of the Taxol® Label, Takenaka,
`
`Trudeau, and Hudis, with or without the TROPIC Minimum Information Required
`
`for Written Subject Information (“Written Subject Information Form”). In my
`
`opinion, a POSA considering all of these references either in combination or
`
`separately would not have been motivated to prevent hypersensitivity reactions by
`
`using the claimed premedication regimen of an antihistamine, a corticoid, and an
`
`H2 antagonist.
`
`15. Winquist and the TROPIC Listing do not disclose the use of any
`
`premedication regimen, and the Written Subject Information Form does not list
`
`any specific medications for hypersensitivity. Clinicaltrials.gov, XRP6258 Plus
`
`Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory
`
`Metastatic Prostate Cancer (TROPIC) (“TROPIC Listing”) (Exh. 1008); Winquist
`
`et al., Open Clinical Uro-oncology Trials in Canada, Canadian J. Oncol. 15(1),
`
`3942-49 (2008) (“Winquist”) (Exh. 1009) at 3948; Minimum Information
`
`6
`
`
`
`Required for Written Subject Information, XRP6258/EFC6193 (Oct. 16, 2006)
`
`(Exh. 2182) at 2. Therefore, these three references do not provide a POSA with
`
`information or a motivation regarding premedications.
`
`16. Dr. Seth disagrees with my opinions regarding Mita because Mita does not
`
`“forbid” premedication. Exh. 1043 at ¶74. But, Mita was designed specifically to
`
`measure the toxicities of cabazitaxel without a premedication. Mita et al., Phase I
`
`and Pharmacokinetic Study of XRP6258 (RPR 116258A), a Novel Taxane,
`
`Administered as a 1-Hour Infusion Every 3 Weeks in Patients with Advanced Solid
`
`Tumors, 15(2) Clin. Cancer Res. 723-30 (2009) (“Mita”) (Exh. 1012) at 724.
`
`Therefore, a POSA would not discount the teaching of Mita regarding the level of
`
`hypersensitivity reactions. Only two patients out of twenty-five had grade 1
`
`hypersensitivity reactions, which “did not reoccur on retreatment in the absence of
`
`premedication.” Id. at 727. Thus, no patient in Mita received any premedication
`
`for hypersensitivity reactions. In light of these results, Mita concluded that
`
`cabazitaxel “does not require premedication.” Id. at 729. Mita would have been
`
`particularly instructive to a POSA because it was the only study of cabazitaxel that
`
`included prostate cancer patients.
`
`17. Dr. Seth also asserts that the other phase I studies of cabazitaxel I
`
`discussed in my Second Declaration with no premedication or only an
`
`antihistamine add nothing over Pivot and Mita. Exh. 1043 at ¶75. I disagree.
`
`7
`
`
`
`Additional experience with cabazitaxel with low levels of low grade or no
`
`hypersensitivity reactions would have been important to a POSA considering
`
`whether any premedication should be given, and if so what it should be.
`
`18. Dr. Seth asserts that Pivot would have motivated a POSA to use further
`
`premedications for hypersensitivity beyond an antihistamine. Exh. 1043 at ¶¶48,
`
`69. I disagree. Pivot reports the rate of hypersensitivity reactions to exemplify
`
`that the “safety profile of [cabazitaxel] was very favorable when compared with
`
`the known safety profile of the marketed taxanes or other compounds under
`
`development.” Pivot et al., A Multicenter Phase II Study of XRP6258
`
`Administered as a 1-H I.V. Infusion Every 3 Weeks in Taxane-Resistant Metastatic
`
`Breast Cancer Patients, 19 Annals of Oncol. 1547-52 (2008) (“Pivot”) (Exh. 1010)
`
`at 1551. Pivot concludes that cabazitaxel was “well tolerated” and does not
`
`recommend the use of additional premedication. Id. at 1547. Only three patients
`
`had grades 3-4 hypersensitivity reactions, and only one of those patients
`
`discontinued cabazitaxel therapy for a grade 4 allergic reaction. Id. at 1550-51.
`
`19. Dr. Seth speculates that a patient that died on day 9 of cycle 1 due to shock
`
`with respiratory failure might have had a hypersensitivity reaction. Exh. 1043 at
`
`¶69. But, Pivot discloses only that this might be treatment-related, and it would be
`
`highly unusual for a hypersensitivity reaction to occur nine days after cabazitaxel,
`
`as Dr. Seth admits. Id.; Exh. 1010 at 1550. A POSA would therefore not have
`
`8
`
`
`
`understood Pivot as disclosing a patient death from hypersensitivity reactions.
`
`Further, as previously noted in my Second Declaration, the hypersensitivity levels
`
`reported in Pivot (6% any grade) were lower than those reported for docetaxel in
`
`breast cancer (15% any grade), also with a single component premedication. Exh.
`
`2176 at ¶¶249, 252-54; Exh. 1010 at 1550. Thus, a POSA considering the results
`
`of Pivot would not have been motivated to use an antihistamine, a corticosteroid,
`
`and an H2 antagonist to prevent hypersensitivity reactions.
`
`20. Dr. Seth’s reliance on the Taxol® label is misplaced because, as discussed
`
`in my Second Declaration, the hypersensitivity associated with paclitaxel was
`
`commonly attributed to the presence of the Cremophor EL surfactant that was not
`
`necessary with cabazitaxel. Exh. 2176 at ¶256; Straub et al., Intravenous
`
`Hydrophobic Drug Delivery: A Porous Particle Formulation of Paclitaxel (AI-
`
`850), 22(3) Pharm. Res. 347-55 (2005) (Exh. 2089) at 347.
`
`21. Dr. Seth argues that since the premedication regimen from the Taxol® label
`
`had also been used with docetaxel, a POSA would consider this premedication
`
`regimen for use with cabazitaxel. Exh. 1043 at ¶66. I disagree. The three
`
`docetaxel studies Dr. Seth cites were outdated to a POSA by October 2009-January
`
`2010 and reinforce that a POSA would have thought less premedication was
`
`necessary for cabazitaxel than docetaxel.
`
`9
`
`
`
`22. As a preliminary matter, a POSA considering docetaxel practice to
`
`determine whether and what premedication should be used with cabazitaxel would
`
`have first looked to the Taxotere® label. The label provides information on the
`
`premedication to be used and on the clinical studies that led to approval. Exh.
`
`1024 at 1, 5, 11, 45-46. The Taxotere® label also provides information on the
`
`incidence of hypersensitivity in breast cancer patients regardless of premedication
`
`and with the premedication. Id. at 15. A POSA would not have looked to older,
`
`smaller studies that were not reported in the label to determine what premedication
`
`should be used for docetaxel, let alone cabazitaxel.
`
`23. The Takenaka study cited by Dr. Seth began enrolling patients in March
`
`2003, which is before docetaxel was approved for prostate cancer by the FDA.
`
`Takenaka et al., Combination Chemotherapy with Weekly Docetaxel and
`
`Estramustine for Hormone Refractory Prostate Cancer in Japanese Patients, 15
`
`Int’l J. Urol. 106-09 (2008) (“Takenaka”) (Exh. 1046) at 106. Takenaka evaluated
`
`weekly docetaxel at 30 mg/m2 instead of the approved 3-weekly regimen. Id. at
`
`106. By the time Takenaka was published, a POSA would have understood that
`
`dexamethasone alone had been determined to be safe as a premedication for much
`
`higher doses of docetaxel, 75 mg/m2, because the FDA approved that regimen.
`
`Exh. 1024 at 1. To the extent a POSA was interested in docetaxel for determining
`
`the premedication for cabazitaxel, he or she would have looked to the
`
`10
`
`
`
`dexamethasone regimen for the approved 3-weekly docetaxel schedule in
`
`combination with prednisone that was more similar to the 3-weekly schedule in
`
`combination with prednisone schedule in Winquist.
`
`24. Takenaka was also a combination study with estramustine. This was also
`
`different from the cabazitaxel regimen described by Winquist. Estramustine could
`
`also cause allergic reactions, which might have had an impact on the use of a 3-
`
`component premedication in Takenaka. June 2007 Emcyt® Label (Exh. 2260) at 4
`
`(“Allergic reactions and angioedema at times involving the airway have been
`
`reported.”).
`
`25.
`
`Furthermore, in Takenaka twelve out of eighteen patients had to
`
`discontinue therapy because of toxicity, leading the authors to conclude that “the
`
`regimen and/or the timing of the chemotherapy should be altered for Japanese
`
`patients.” Exh. 1046 at 108. Accordingly, a POSA would not have looked to this
`
`small, unsuccessful study of weekly docetaxel combination therapy in Japanese
`
`patients to determine what premedication to use with cabazitaxel.
`
`26. Dr. Seth also cites to two 1996 phase II breast cancer trials as examples of
`
`docetaxel studies that used the claimed premedication regimen. Hudis allowed a
`
`variety of premedication combinations: nine patients received no premedication,
`
`twenty-four patients received just an antihistamine, two patients received an
`
`antihistamine and a corticoid, one patient received an antihistamine and an H2
`
`11
`
`
`
`antagonist, and only a single patient received an antihistamine, a corticoid, and an
`
`H2 antagonist. Hudis et al., Phase II and Pharmacologic Study of Docetaxel as
`
`Initial Chemotherapy for Metastatic Breast Cancer, 14(1) J. Clin. Oncol. 58-65
`
`(1996) (“Hudis”) (Exh. 1048) at 61-62. The authors conclude that due to the small
`
`sample sizes and the fact that the different regimens were not randomized, “it is not
`
`possible to analyze the impact of specific pretreatment regimens on the incidence
`
`of HSR.” Id. at 61.
`
`27. Trudeau also used a variety of premedication regimens, including no
`
`premedication; an antihistamine and a corticoid; and an antihistamine, a corticoid,
`
`and an H2 antagonist. Trudeau et al., Docetaxel in Patients with Metastatic Breast
`
`Cancer: A Phase II Study of the National Cancer Institute of Canada-Clinical
`
`Trials Group, 14(2) J. Clin. Oncol. 422-28 (1996) (“Trudeau”) (Exh. 1047) at 423.
`
`When docetaxel was approved for mCRPC in 2004, the FDA approved a different
`
`premedication regimen using only dexamethasone. Rather than consider these two
`
`decade-old studies which used a variety of regimens, a POSA would look to the
`
`FDA-approved docetaxel premedication.
`
`28. Additionally, Hudis reported hypersensitivity reactions in 54% of patients
`
`regardless of the premedication received. Exh. 1048 at 61. Trudeau reported that
`
`when no premedication was given 74% of patients had hypersensitivity reactions.
`
`Exh. 1047 at 424. When corticosteroids and antihistamines were used as a
`
`12
`
`
`
`premedication, 55% of patients still experienced hypersensitivity reactions. Id.
`
`These levels of hypersensitivity are far higher than the 6% of patients in Pivot with
`
`any level of hypersensitivity reaction, leading a POSA to conclude that cabazitaxel
`
`required less premedication than docetaxel, not more as Dr. Seth asserts.
`
`29. The Trudeau and Hudis studies further confirm that a POSA would not
`
`have been motivated to use an antihistamine, a corticoid, and an H2 antagonist
`
`before cabazitaxel. In both studies the investigators originally chose not to employ
`
`a premedication, only adding one when a problem was noted. Exh. 1047 at 423;
`
`Exh. 1048 at 59. Even erring on the conservative side, a POSA would not have
`
`been motivated to use more than a single premedication for hypersensitivity
`
`reactions.
`
`30. In summary, nothing in Winquist, the TROPIC Listing, the Written Subject
`
`Information Form, Pivot, and any one of the Taxol® Label, Takenaka, Trudeau,
`
`and Hudis would have motivated a POSA to use a premedication regimen of an
`
`antihistamine, a corticoid, and an H2 antagonist to prevent hypersensitivity
`
`reactions prior to a dose of cabazitaxel.
`
`B.
`
`It Would Not Have Been Obvious to a POSA to Use the Claimed
`Premedication Regimen to Prevent or Treat Nausea
`
`31. Dr. Seth also asserts that a POSA would have been motivated to use the
`
`claimed premedication regimen to prevent or treat nausea arising from cabazitaxel.
`
`13
`
`
`
`Exh. 1043 at ¶¶49, 63. But a POSA considering the stated purposes of
`
`premedication regimens for other taxanes at the time would not have had this
`
`motivation. The Taxol® label, for instance, requires premedication before
`
`paclitaxel “in order to prevent severe hypersensitivity reactions,” and the
`
`Taxotere® label states that the premedication regimen is given “in order to reduce
`
`the incidence and severity of fluid retention as well as the severity of
`
`hypersensitivity reactions.” February 2000 Taxol® Label (Exh. 2093) at 39; Exh.
`
`1024 at 5. Even today, the Jevtana® label recommends premedication of an
`
`antihistamine, a corticosteroid, and an H2 antagonist “to reduce the risk and/or
`
`severity of hypersensitivity,” and separately notes that “[a]ntiemetic prophylaxis is
`
`recommended and can be given orally or intravenously as needed.” September
`
`2016 Jevtana® Label (Exh. 2150) at 3. None of these labels discuss a
`
`premedication regimen containing an antihistamine, a corticoid, or an H2
`
`antagonist for the purpose of preventing or treating nausea.
`
`32. Dr. Seth asserts that the premedication regimen of Claims 31-34 would
`
`have been obvious to a POSA based on the combination of Winquist, the TROPIC
`
`Listing, Pivot, and the NCCN Guidelines, with or without Doenicke and the
`
`Written Subject Information Form. In my opinion, a POSA considering all of
`
`these references either in combination or separately would not have been motivated
`
`14
`
`
`
`to prevent or treat nausea arising from cabazitaxel by using the claimed
`
`premedication regimen of an antihistamine, a corticoid, and an H2 antagonist.
`
`33. Winquist and the TROPIC Listing do not disclose the use of any
`
`antiemetic premedication regimen, and the Written Subject Information form does
`
`not list any specific medications for nausea or vomiting. Exh. 1008; Exh. 1009 at
`
`3948; Exh. 2182 at 2. Therefore, these three references do not provide a POSA
`
`with information or a motivation regarding premedications.
`
`34. Pivot discloses using only an H1 antagonist as premedication, and states
`
`that “[n]o prophylactic antiemetic drugs were allowed at the first cycle.” Exh.
`
`1010 at 1548. Only in case of nausea or vomiting could patients receive antiemetic
`
`treatment in compliance with the conventional antiemetic protocol of the study
`
`center. Id. at 1548.
`
`35. Although the Pivot study took place in 39 centers between Europe, North
`
`America, and South America, Pivot does not describe whether any patients
`
`ultimately received an antiemetic, what the antiemetic was, including whether it
`
`was more than one agent, or whether all patients developing nausea and vomiting
`
`received the same antiemetics. Id. at 1548.
`
`36. Docetaxel is described on the NCCN Guidelines as a low emetic risk drug,
`
`which is supported by the Taxotere® label that does not require antiemetic therapy.
`
`NCCN Clinical Practice Guidelines in Oncology: Antiemesis V.3.2008 (“NCCN
`
`15
`
`
`
`Guidelines”) (Exh. 1045) at 11 (10-30% frequency of emesis considered low risk);
`
`Exh. 1045 at 11.1 Pivot reports no severe adverse events for nausea or vomiting,
`
`and finds that cabazitaxel was “well tolerated.” Exh. 1010 at 1547, 1550-51. Pivot
`
`concludes that the “safety profile of [cabazitaxel] was very favorable when
`
`compared with the known safety profile of the marketed taxanes or other
`
`compounds under development,” and does not recommend the use of additional
`
`antiemetic premedication or any further premedication. Id. at 1547, 1551. Dr.
`
`Seth agrees that Pivot teaches that cabazitaxel has a favorable profile with respect
`
`to nausea and vomiting as compared to docetaxel. Exh. 1043 at ¶31. Therefore,
`
`there is no reason to motivate a POSA to use an antiemetic premedication for
`
`cabazitaxel therapy.
`
`37. Dr. Seth spends little time discussing preventative therapy. Exh. 1043 at
`
`¶58 (stating only that the NCCN Guidelines suggest dexamethasone before
`
`chemotherapy). Instead, Dr. Seth focuses on breakthrough antiemetic treatments.
`
`The breakthrough treatment discussed by Dr. Seth is a post-chemotherapy regimen
`
`given when a patient receives chemotherapy and then still suffers from nausea or
`
`vomiting, thereby “breaking through” any prior antiemetic regimen. That means it
`
`1 The Taxotere® label discusses antiemetics when docetaxel is given in
`
`combination with cisplatin, which is a high emetic risk drug. Exh. 1024 at 4, 6;
`
`Exh. 1045 at 10.
`
`16
`
`
`
`is not given “prior to” the dose of chemotherapy as required by Claim 31. See
`
`Exh. 1045 at 15. Regardless, in my opinion a POSA would not have been
`
`motivated to use the claimed premedication regimen either to prevent or to treat
`
`nausea.
`
`1.
`
`To Prevent Nausea/Vomiting
`
`38. For low emetic risk drugs, the NCCN Guidelines recommend giving before
`
`chemotherapy either dexamethasone, or prochlorperazine (brand name
`
`Compazine®) or metoclopramide (brand name Reglan®) with or without either
`
`lorazepam (brand name Ativan®) or diphenhydramine (brand name Benadryl®).
`
`Exh. 1045 at 8, 21-22. The NCCN Guidelines do not suggest that dexamethasone
`
`is preferred over the other options. Instead, the Guidelines state that
`
`“[d]examethasone should not be added when the chemotherapy regimen already
`
`includes a corticosteroid.” Exh. 1045 at 14. Since Winquist and the TROPIC
`
`Listing disclosed cabazitaxel given with prednisone, a corticosteroid, and since
`
`there are other options, a POSA would have been discouraged by the NCCN
`
`Guidelines from using dexamethasone to prevent nausea or vomiting with
`
`cabazitaxel.
`
`39. Additionally, the NCCN Guidelines recommend dexamethasone on a daily
`
`basis, not as part of a new cycle every three weeks as stated in Claim 33. Dr. Seth
`
`agrees that the doses of Claim 33 must be “separated by a 3-week interval.” Exh.
`
`17
`
`
`
`1043 at ¶43. The daily schedule of dexamethasone recommended by the NCCN
`
`Guidelines for nausea further indicates that the purpose of dexamethasone in the
`
`Taxol® and Taxotere® labels was not for nausea or vomiting. The Taxol® label
`
`recommends dexamethasone only 12 and 6 hours before Taxol® administration,
`
`which occurs either once every two weeks or once every three weeks. Exh. 2093
`
`at 39-41. The Taxotere® label recommends dexamethasone the day before, the day
`
`of, and the day after the infusion, which only occurs once every three weeks. Exh.
`
`1024 at 3-5. For prostate cancer, the Taxotere® label only recommends
`
`dexamethasone at 12, 3, and 1 hour before the Taxotere® infusion. Id. at 5.
`
`40. Diphenhydramine, an H1 antagonist, is not recommended by the NCCN
`
`Guidelines for emesis, but rather is optionally recommended if the patient is given
`
`prochlorperazine or metoclopramide premedication and has a dystonic reaction.
`
`Exh. 1045 at 22. Dystonic reactions are uncontrollable muscle spasms. See id.
`
`Prochlorperazine and metoclopramide are not antihistamines or corticoids.
`
`41. Dr. Seth does not address the use of H2 antagonists for a premedication
`
`beginning before each dose of chemotherapy, and the NCCN Guidelines do not
`
`suggest the use of an H2 antagonist as antiemetic premedication for low emetic risk
`
`drugs. See Exh. 1045 at 8.
`
`42. As a preventative treatment, the NCCN Guidelines would not have
`
`motivated a POSA to use a premedication regimen of an antihistamine, a corticoid,
`
`18
`
`
`
`and an H2 antagonist because the Guidelines discourage using dexamethasone with
`
`another corticoid, suggest diphenhydramine only for dystonic reactions occurring
`
`after non-corticoid drugs, and do not recommend H2 antagonists.
`
`2.
`
`To Treat Nausea/Vomiting
`
`43. A POSA also would not have been motivated to use the claimed
`
`premedication regimen to treat nausea arising from cabazitaxel administration.
`
`Even considering the breakthrough antiemetic recommendations, a POSA would
`
`not have any reason to choose the combination of an antihistamine, a corticoid, and
`
`an H2 antagonist. The Guidelines suggest using prochlorperazine or
`
`metoclopramide with or without diphenhydramine for dystonic reactions,
`
`lorazepam, ondansetron2 (brand name Zofran®), granisetron (brand name Kytril®),
`
`dolasetron (brand name Anzemet®), haloperidol (brand name Haldol®), dronabinol
`
`(brand name Marinol®), nabilone (brand name Cesamet™), dexamethasone,
`
`olanzapine (brand name Zyprexa®), or promethazine (various brand names), and
`
`explicitly note that “[n]o one treatment is better than the other for managing
`
`breakthrough emesis.” Exh. 1045 at 9, 15.
`
`44. As with preventative antiemetic treatment, diphenhydramine is
`
`recommended only if the patient is given prochlorperazine or metoclopramide and
`
`has a dystonic reaction. Exh. 1045 at 9.
`
`2 The “setron” drugs are 5-HT3 receptor antagonists.
`
`19
`
`
`
`45. H2 antagonists are not included in the flowchart for breakthrough drugs
`
`(Exh. 1045 at 9), but are later mentioned as something to “consider” for patients
`
`with dyspepsia. Exh. 1045 at 23. Since Mita and Pivot do not report patients with
`
`dyspepsia from cabazitaxel, and the emesis levels are relatively low, a POSA
`
`would not be motivated to choose an H2 antagonist before cabazitaxel for concerns
`
`about stomach acid. Exh. 1010 at 1550; Exh. 1012 at 726-27. Dr. Seth argues that
`
`H2 antagonists would provide a further benefit of “decreased pain from vomiting-
`
`induced acid reflux,” without citing to any source. Exh. 1043 at ¶60. But again,
`
`cabazitaxel had shown low levels of emesis in Mita and Pivot, so a POSA would
`
`have no reason to choose an H2 antagonist over any other antiemetic. Exh. 1045 at
`
`11; Exh. 1012 at 726; Exh. 1010 at 1550.
`
`46. A POSA would not have been motivated to use a combination of H1 and
`
`H2 antagonists for cabazitaxel-induced emesis based on Doenicke, which discusses
`
`H1 and H2 antagonists for postoperative nausea and vomiting (“PONV”). Exh.
`
`1049 at S154. A Doenicke states, anesthetic drugs may “stimulate histamine
`
`release,” motivating a POSA to use antihistamines, H1 and H2 antagonists, to treat
`
`or prevent PONV by countering that rise in histamines. Exh. 1049 at S156. In
`
`contrast, the NCCN Guidelines state that for chemotherapy-induced nausea and
`
`vomiting, the principle receptors involved are the serotonin and dopamine
`
`receptors. Exh. 1045 at 16.
`
`20
`
`
`
`47. Dr. Seth admits that PONV is a different “context[ ]” than chemotherapy-
`
`induced nausea and vomiting, but suggests that the “use of H2 antagonists in
`
`combination with H1 antihistamine was known . . . in chemotherapy” as well as
`
`PONV. Exh. 1043 at ¶ 61. In support of this, Dr. Seth cites to the NCCN
`
`Guidelines. Id. However, the section of the Guidelines Dr. Seth cites here is
`
`discussing the “advent of the 5-HT3-receptor antagonists,” “a significant advance
`
`in antiemetic therapy,” as compared to older regimens that might have included an
`
`antihistamine. Exh. 1045 at 18, 20. A POSA understood that 5-HT3-receptor
`
`antagonists such as odansetron were more effective therapies for nausea and
`
`vomiting than antihistamines. Id.; see also Exh. 1049 at S157 (“The 5-HT3
`
`receptor antagonists are superior to conventional antiemetic agents for the
`
`prevention of PONV.”). Furthermore, as noted above, the NCCN Guidelines do
`
`not recommend an antihistamine as an antiemetic for low emetic risk drugs. Exh.
`
`1045 at 8. Therefore, to the extent a POSA wanted to treat nausea and vomiting,
`
`he or she would have used more effective drugs than H1 antihistamines or H2
`
`antagonists.
`
`48. Additionally, although Dr. Seth is correct that combination therapy is
`
`noted as more effective than single-agent therapy, nothing in the Guidelines
`
`suggests using a combination of drugs from the same category, i.e., an H1 and an
`
`H2 antagonist (both generally antihistamines). Id. at 20. To the contrary, the
`
`21
`
`
`
`“general principle” of managing breakthrough emesis is to add an additional agent
`
`from a different class of drugs. Id. at 15.
`
`49. Furthermore, as noted in my Second Declaration, H2 antagonist
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