Filed on behalf of: Mylan Laboratories Limited
`By: Steven W. Parmelee
`
`Michael T. Rosato
`
`Jad A. Mills
`WILSON SONSINI GOODRICH & ROSATI
`
`Paper No. _________
`Filed: _________
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MYLAN LABORATORIES LIMITED,
`Petitioner,
`
`v.
`
`AVENTIS PHARMA SA,
`Patent Owner.
`_____________________________
`
`IPR2016-00712
`
`Patent No. 8,927,592
`_____________________________
`
`PETITIONER’S OPPOSITION TO PATENT OWNER’S
`MOTION TO AMEND UNDER 37 C.F.R. § 42.121
`
`

`

`
`
`I. 
`
`TABLE OF CONTENTS
`
`Page
`
`OVERVIEW OF WHY AVENTIS’S MOTION SHOULD BE
`DENIED.......................................................................................................... 1 
`
`II. 
`
`AVENTIS’S VARYING CLAIM CONSTRUCTIONS ................................ 1 
`
`III.  CLAIM CONSTRUCTION ........................................................................... 2 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`Claim 31: “administering to a patient in need thereof” ....................... 2 
`
`Aventis’s Construction: “a method that prolongs the life
`of a patient as compared to no treatment or palliative
`treatment” ............................................................................................. 5 
`
`Aventis’s Construction: Clinically Proven Survival
`Benefit .................................................................................................. 6 
`
`Claims 31, 33: Administration of the pretreatment
`regimen “prior to said dose” of cabazitaxel ......................................... 6 
`
`IV.  AVENTIS’S MOTION FAILS TO OVERCOME THE PRIOR
`ART ................................................................................................................ 7 
`
`A.  Aventis’s Erroneous “Increasing Survival” Analysis .......................... 7 
`
`1. 
`
`2. 
`
`The Prior Art Need Not Disclose Inherent Results ................... 8 
`
`The Prior Art Teaches the Method Is Intended to
`Increase Survival ........................................................................ 9 
`
`B. 
`
`The Premedication Regimen is Obvious in View of the
`Prior Art .............................................................................................. 10 
`
`1.  Winquist/TROPIC Listing in view of Pivot and
`NCCN ....................................................................................... 10 
`
`a. 
`
`b. 
`
`Pivot discloses antihistamine/antiemetic
`pretreatment regimen in combination with
`cabazitaxel ..................................................................... 11 
`NCCN discloses a conventional antiemetic
`protocol comprising a corticosteroid and an H2
`antagonist ....................................................................... 12 
`
`- i -
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`2.  Winquist/TROPIC Listing in view of Pivot and
`any one of Takenaka, Hudis, Trudeau, or the Taxol
`Label ......................................................................................... 15 
`
`3. 
`
`Consent Form in view of Pivot and any one of
`NCCN, Takenaka, Hudis, Trudeau, or the Taxol
`Label ......................................................................................... 19 
`
`4. 
`
`The TROPIC Study Anticipates Claims 31-34. ....................... 21 
`
`5.  Mita further renders the substitute claims obvious
`in combination with any of the above Grounds ....................... 22 
`
`6. 
`
`The Prior Art Does Not Teach Away From H2
`Antagonists ............................................................................... 23 
`
`V. 
`
`PATENT OWNER’S “OBJECTIVE INDICIA” ARE
`UNAVAILING. ............................................................................................ 24 
`
`VI.  CONCLUSION ............................................................................................. 25 
`
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`- ii -
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`
`I.
`
`OVERVIEW OF WHY AVENTIS’S MOTION SHOULD BE DENIED
`Petitioner opposes Aventis Pharma S.A.’s (“Aventis”) Contingent Motion to
`
`Amend (Paper 22 (“Mot.”)). Aventis fails to meet its burden to show it is entitled
`
`to amended claims. 37 C.F.R. § 42.20(e)); Synopsys, Inc. v. Mentor Graphics
`
`Corp., 814 F.3d 1309, 1323 (Fed. Cir. 2016). Neither the proposed amendment of
`
`the preamble nor the prior art pretreatment regimen render the proposed amended
`
`claims patentable. Accordingly, Aventis’s Motion should be denied.
`
`II. AVENTIS’S VARYING CLAIM CONSTRUCTIONS
`Aventis may propose only one substitute claim for each canceled claim
`
`unless Aventis demonstrates good cause for multiplicative substitutions. 37 C.F.R.
`
`§42.121(a)(3), (c); Idle Free Sys., Inc. v. Bergstrom, Inc., Case IPR2012-00027,
`
`Paper 26 at 11 (“Idle Free”). Aventis acknowledges this limit (Mot., 1), but
`
`functionally ignores it by providing at least four different preamble meanings:
`
`Reflecting a purpose of the treatment:
` “A method of increasing survival….” [Appendix 1]
` “a method for increasing the survival of a patient in need thereof” [3]
` “[T]he preamble is a statement of intentional purpose ….” [7]
`Requiring a particular result in an individual patient:
` “method that prolongs the life of a patient as compared to no treatment….” [8].
` “prior art must teach…method increases the survival of a patient.” [10-11].
`Requiring knowledge of statistical population data:
` “No Prior Art Disclosed…Cabazitaxel…Would Increase Overall Survival.”[10]
` “clinical study with sufficient [statistical] power was necessary….” [13].
`
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`
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` Drug must “increase overall survival in a phase III…study.” [14-15].
`Requiring FDA approval:
` Drug must “succeed[] in phase III…study and receiv[e] approval. [15].
`
`This strategy attempts to draft ambiguity into the claims to further Aventis’s
`
`strategy of asserting that present-day performance of the Winquist/TROPIC Listing
`
`regimen infringes the claims while arguing that prior art disclosure of the same
`
`regimen fails to invalidate the claims. The Board should hold Aventis to proving
`
`the proposed claims, as drafted and under their broadest reasonable interpretation,
`
`are patentable.
`
`III. CLAIM CONSTRUCTION
`In a motion to amend, a Patent Owner must ensure that the metes and
`
`bounds of the proposed claims are clearly set forth. Idle Free at 7. The Board
`
`interprets unexpired claims using the “broadest reasonable construction in light of
`
`the specification of the patent in which [they] appear[].” 37 C.F.R. § 42.100(b);
`
`Cuozzo Speed Technologies, LLC v. Lee, 136 S. Ct. 2131, 2134-35 (2016).
`
`A. Claim 31: “administering to a patient in need thereof”
`The Board already construed “a method of increasing the survival of a
`
`patient” as “a non-limiting statement of the purpose of the claimed method.” Paper
`
`9 at 10. This same construction should be applied to the language “a method of
`
`increasing survival.” EX1043, ¶40. The Board should adopt the plain meaning:
`
`“thereof” refers to the elements of the “administering” step that surround it as
`
`opposed to the preamble that is more distant. Thus, the plain meaning of the phrase
`
`“administering to a patient in need thereof (i) [A], (ii) [B], (iii) [C], and [D]”
`
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`
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`means administering to a patient in need of the administration of (i) [A], (ii) [B],
`
`(iii) [C], and (iv) [D].
`
`Even if “thereof” refers to the preamble, this would simply mean that [A],
`
`[B], [C], and [D] should be administered to a patient in need of a method of
`
`increasing survival. The claim further specifies that “said patient” in need thereof
`
`has mCRPC that has progressed during or after treatment with docetaxel. Both Dr.
`
`Sartor and Dr. Seth have testified that this disease inevitably leads to death of the
`
`patient and that any post-docetaxel mCRPC patient in 2008 had a recognized need
`
`for increased survival. EX2173, ¶162; 1043, ¶10. Thus, the preamble at most gives
`
`a more generic description of the patient, not some required mental state. Under
`
`either interpretation, the preamble is not limiting because none of it is necessary to
`
`provide antecedent basis for any step or to breathe life into the claim. Pet., 18.
`
`Aventis asserts that the preamble is limiting if a phrase in the body “gives
`
`life and meaning to the preamble.” Mot., 7. Even if correct, this does not mean that
`
`the claims at issue here import the same intentionality requirement that existed in
`
`Jansen. The Jansen construction applied to the issued claim language and
`
`specification of that patent based on the doctrine of prosecution history estoppel in
`
`a district court. Jansen v. Rexall Sundown, Inc., 342 F.3d 1329, 1332 (Fed. Cir.
`
`2003). The intentionality limitation existed because it was necessary to define the
`
`patient population receiving the drug. Id.
`
`In contrast, here, to the extent the element “patient in need” gives life to the
`
`preamble phrase “a method of increasing survival,” it does so by describing whose
`
`survival is at issue: an individual patient, not a population of patients. In other
`
`- 3 -
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`
`
`words, Jansen precludes Aventis’s proposal that the preamble imposes claim
`
`requirements that the method result in an increase in overall survival in a
`population of patients. This is consistent with the language of the preamble
`
`referring to “increasing survival,” not “overall survival” or “median survival.”
`
`Neither Rapoport nor Glenmark are contrary. In Rapoport, there was no
`
`dispute that the preamble was limiting because otherwise the claim term “‘to a
`patient in need of such treatment’ would not have proper antecedent basis.”
`
`Rapoport v. Dement, 254 F.3d 1053, 1059 (2001). The intentionality requirement
`
`was based on the specific language of the claim and specification at issue and not
`
`based on an overgeneralization that limiting claim preambles necessarily imports
`
`intentionality as a limitation of the claim. Id. Similarly, the intentionality
`
`requirement in Glenmark was based on the specific language of that claim and the
`
`fact that the preamble provided necessary antecedent basis for several claim terms
`
`that otherwise lacked a complete description of the type of patient to be given the
`
`medication. Sanofi v. Glenmark Pharms. Inc., No. 14-264, 2015 WL 5092631, at
`
`*10 (D. Del. Aug. 28, 2015).
`
`Aventis also argues that the preamble is limiting because Aventis “relies on”
`
`increased survival to “distinguish prior art.” Mot., 8. Aventis thus invites the Board
`
`to treat its claim construction arguments prospectively as a prosecution disclaimer.
`
`However, such disclaimer does not arise from arguments made in the same
`
`proceeding. See Tempo Lighting, Inc. v. Tivoli, LLC, 742 F.3d 973, 978 (Fed. Cir.
`
`2014); see also In re Lockwood, 2017 U.S. App. LEXIS 2483 at *11 (Fed. Cir.
`
`Feb. 13, 2017). The Board should disregard Aventis’s circular logic.
`
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`
`
`Even if Aventis is correct that the preamble requires that the administrator
`
`have an intention to increase survival, the claim language does not specify that the
`
`mental intention be exclusive, based on a clinical study finding a statistically
`
`significant increase in survival, or based on FDA approval, as opposed to simply
`
`having “evidence of a diagnosis and a knowing need” of increasing survival, and
`
`that increasing survival is “desired or appreciated.” Jansen, 342 F.3d at 1335.
`
`B. Aventis’s Construction: “a method that prolongs the life of a patient
`as compared to no treatment or palliative treatment”
`Aventis’s proposed construction fails for lack of written description and
`
`enablement and renders claims 31-34 unpatentable. Pre-AIA 35 U.S.C.§112, ¶1.
`
`The specification provides no survival comparison of cabazitaxel versus “no
`
`treatment.” Likewise, Aventis’ assertion that mitoxantrone treatment is “equivalent
`
`to no therapy” with respect to prolonging life” is not taught by the patent.
`
`The specification also does not describe or enable comparing the survival of
`
`an individual patient against a counterfactual of receiving mitoxantrone or no
`
`treatment. Furthermore, at least some patients appear to have had their lives
`
`shortened by cabazitaxel. See Pet., 19-20. Dr. Sartor admits that even today, he
`
`cannot guarantee that the methods of the ’592 patent will increase the survival of
`
`any particular patient. EX1041, 115:19-116:2; see also EX1043, ¶38. Accordingly,
`
`the ’592 patent neither discloses a method that actually “prolongs the life of a
`
`patient,” as opposed to at most intending or hoping to do so, nor does it enable the
`
`practice of such a method.
`
`Moreover, there is no way to actually know whether the survival of an
`
`individual patient has been prolonged by the administration of the claimed
`
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`

`
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`protocol. Pet., 20; EX1043, ¶¶36-39. Thus, Aventis’s proposed claim construction
`
`is indefinite under Pre-AIA 35 U.S.C. §112, ¶2. See Telebrands Corp. v. Tinnus
`
`Enter., LLC, PGR2015-00018, Paper 75, at 16-19 (“a claim is indefinite when it
`
`contains words or phrases whose meaning is unclear.” (quoting In re Packard, 751
`
`F.3d 1307, 1313 (Fed. Cir. 2014))); Ex Parte Miyazaki, 2008 WL5105055, 89
`
`USPQ2d 1207, 1211-12 (PTAB Nov. 19, 2008 (precedential) (claim is indefinite in
`
`PTO proceedings if “amenable to two or more plausible claim constructions”).
`
`C. Aventis’s Construction: Clinically Proven Survival Benefit
`According to Aventis, the preamble “a method of increasing survival” adds a
`
`limitation to the claims requiring proof of a statistical survival benefit in a phase III
`human clinical trial. See Mot., 13 (“clinical study with sufficient [statistical] power
`
`was necessary….” As Aventis asserts that this proof element distinguishes over the
`
`prior art, Aventis takes the position that the inventive step is the knowledge that the
`
`prior art method works. However, this construction renders claims 31-34
`
`unpatentable under 35 U.S.C. § 101. When the “inventive step” of a method is
`
`simply knowing about a correlation between the steps of the method and the effect
`
`of the method, the claim is directed to patent ineligible subject matter. See Mayo
`
`Collaborative v. Prometheus Labs., 132 S. Ct. 1289, 1297-98 (2012). Accordingly,
`
`claims 31-34, as construed by Aventis, are unpatentable.
`
`D. Claims 31, 33: Administration of the Pretreatment Regimen “Prior
`to Said Dose” of Cabazitaxel
`Claim 31 recites a method comprising administration of cabazitaxel and
`
`three other drugs, wherein the three other drugs are administered “prior to said
`
`dose” of cabazitaxel. The claim uses the open-ended term “comprising” and thus
`
`- 6 -
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`

`

`
`
`does not exclude methods comprising each of these steps in addition to others.
`
`Thus, under the broadest reasonable interpretation, claim 31 is satisfied by
`administration of the three other drugs before a dose of 20- 25 mg/m2 of
`cabazitaxel, even if the patient has previously received an earlier dose of
`
`cabazitaxel without first receiving all three of the other drugs. EX1043, ¶42.
`
`Claim 33 depends from claim 31 and adds the further limitation that the
`
`administration steps in claim 31 are repeated in a new cycle every three weeks.
`
`Claim 33 also uses the open-ended term “comprising,” permitting the method to be
`
`practiced even when other elements are also included. Thus, under the broadest
`
`reasonable interpretation, claim 33 is satisfied by administration of the three other
`drugs before a dose of 20 to 25 mg/m2 of cabazitaxel when these steps are repeated
`as a new cycle every three weeks, even if the patient has previously received an
`
`earlier dose of cabazitaxel without first receiving all three of the other drugs.
`
`EX1043, ¶43.This construction is consistent with the specification. See In re Am.
`
`Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1369 (Fed. Cir. 2004) (preferred
`
`embodiment not to be read into broader claim language).
`
`IV. AVENTIS’S MOTION FAILS TO OVERCOME THE PRIOR ART
`As demonstrated below and as further supported by the Declarations of Dr.
`
`Rahul Seth and Robert McSorley (EX1043 and EX1044), Aventis has failed to
`
`demonstrate that the amended claims are patentable in view of the prior art.
`
`A. Aventis’s Erroneous “Increasing Survival” Analysis
`As discussed in Section III.B, Aventis incorrectly construes the preamble as
`
`“a method that prolongs the life of a patient as compared to no treatment or
`
`- 7 -
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`

`

`
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`palliative treatment.” Based on this incorrect construction, Aventis further errs in
`
`concluding that “for the amended claims to be found obvious, the prior art must
`
`teach that the claimed method increases the survival of a patient” and in arguing
`
`that the teachings of the prior art are insufficient . Mot., 11-18. Aventis’s argument
`
`fails because (1) the prior art need not teach an inherent property of a claimed
`
`method; (2) the prior art provided sufficient disclosure to perform the method as
`
`claimed.
`
`1.
`
`The Prior Art Need Not Disclose Inherent Results
`
`Identifying or disclosing an inherent result of a prior art method of
`
`administering a drug cannot confer patentability. In re Montgomery, 677 F.3d
`
`1375, 1381 (Fed. Cir. 2012) (efficacy requirement satisfied by prior art disclosure
`
`of the steps of the method because “efficacy is inherent in carrying out the claim
`
`steps”); King Pharmaceuticals, Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1275-76
`
`(Fed. Cir. 2010) ("[M]erely discovering and claiming a new benefit of an old
`
`process cannot render the process again patentable"); PharmaStem Therapeutics
`
`Inc. v. Viacell Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007) (“As we have explained,
`
`however, providing proof sufficient to justify conducting in vivo procedures on
`
`humans, while useful, is not a test of patentability.”).
`
`Moreover “informing someone of the correlation cannot confer patentability
`
`absent a functional relationship between the informing and administering steps.” In
`
`re Kao, 639 F.3d 1057, 1072 (Fed. Cir. 2011). To hold otherwise would
`
`- 8 -
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`
`
`improperly “remove from the public that which is in the public domain by virtue of
`
`its inclusion in, or obviousness from, the prior art.” Kao, 639 F.3d at 1073.
`
`The ’592 patent teaches that increasing survival is an inherent property of
`
`administering 25 mg/m2 of cabazitaxel to a patient previously treated with a
`
`docetaxel-containing regimen. See Pet., 2-3, 52; EX1002, ¶¶44, 46, 95-96, 121;
`
`EX1001 at 6:28-34, 11:29-32. Neither Aventis nor Dr. Sartor has disputed the
`
`inherency of the efficacy. Accordingly, even if claim 31 did require an increase in
`
`survival, this inherent property need not be taught in the prior art.
`
`The Prior Art Teaches the Method Is Intended to Increase Survival
`
`2.
`Even if the preambles of claims 31-34 required that a purpose of the method
`
`includes increasing survival, this too is satisfied by the prior art. For example,
`
`TROPIC Listing discloses that the “primary objective” of the open-label study was
`
`“survival.” EX1008. Tannock disclosed that docetaxel provided a survival benefit
`
`to mCRPC patients, and Mita, Attard, and Pivot disclosed that cabazitaxel had anti-
`
`cancer activity similar to docetaxel except that it retained greater potency in
`
`patients that had progressed during or after docetaxel. See EX1013, 1502; see also
`
`EX1010, 1547; EX1012, 727; EX1021, 75. Thus, as Dr. Seth explained, it would
`
`have been obvious to the POSA that a purpose of the Winquist/TROPIC Listing
`
`regimen was to prolong survival of the cabazitaxel-treated patients. EX1002, ¶132;
`
`see also EX1008, 1 (“primary objective is overall survival”); EX1009, 3948
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`(“primary endpoint … overall survival”). Performance of the trial and reporting the
`
`data were merely routine procedures. EX1041, 132:15-134:18; EX1002, ¶122.
`
`Both Dr. Sartor and Dr. Seth testified that when they administer a taxane to a
`
`patient, one objective is almost always that it increase survival. EX1041, 114:3-16;
`
`EX2177, 134:1-7. Dr. Sartor specifically testified that increased survival is his
`
`hope when he administers taxanes today, and that this was his same hope when he
`
`administered cabazitaxel in 2008. EX1041, 114:3-115:4. He testified that, even
`
`today, cabazitaxel merely has the potential to increase survival of a patient. Id. at
`
`115:19-116:9. Dr. Seth confirmed that patients entering a phase III trial for
`
`mCRPC generally intend to “live longer and better” from participating in the trial,
`
`particularly those patients who know they are receiving the sponsor’s drug because
`
`the treatment groups are unblinded. EX1043, ¶39. Dr. Seth testified that the POSA
`
`would have understood from TROPIC Listing that physicians were enrolling their
`
`patients in a phase III trial of the taxane cabazitaxel with an intention, but not a
`
`guarantee or promise, of prolonging the life of at least some patients. Id.
`
`B.
`
`The Premedication Regimen is Obvious in View of the Prior Art
`Aventis attempts to distinguish the prior art Winquist/TROPIC Listing
`
`regimen by adding a pre-treatment regimen. However, this pretreatment regimen
`
`was well-known in the art for use with both paclitaxel and docetaxel, the two
`
`previously-marketed members of cabazitaxel’s taxane class. EX1043, ¶¶44-46.
`
`1. Winquist/TROPIC Listing in view of Pivot and NCCN
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`As described in the Petition (6-7, 25-29, 32-34), Winquist (EX1009) and
`
`TROPIC Listing (EX1008) are two descriptions of the same cabazitaxel regimen,
`
`and together they disclose and enable a regimen for treating and increasing
`survival of a patient by administering 25 mg/m2 cabazitaxel in combination with
`prednisone to patients that have mCRPC that has progressed during or after
`
`treatment with docetaxel in a new cycle every three weeks. EX1008, 1-2; EX1009
`
`at 3948; EX1002, ¶¶115-22, 131-35. Pivot, Mita, Beardsley, and Attard further
`
`demonstrate the obviousness of the claimed regimen and also provide motivation
`to administer a 20 mg/m2 dose to patients having difficulty tolerating the 25 mg/m2
`dose. Pet., 43-44; EX1021, 74-75; EX1022, 163; EX1010, 1547; EX1012, 723,
`
`727, 729; EX1002, ¶¶155-58. These references are sufficient to render each of
`
`original claims 27-30 obvious.
`
`Proposed claims 31-34 would amend claims 27-30 to add a pretreatment
`regimen that includes a corticoid, an antihistamine, and an H2 antagonist — a
`limitation that adds nothing new or nonobvious to the existing claims that are
`
`invalid for reasons addressed in the Petition and Reply. The POSA would have had
`
`motivation to combine the Winquist/TROPIC Listing regimen with a pretreatment
`
`regimen that includes a corticoid, an antihistamine, and an H2 antagonist and would
`have had a reasonable expectation of successfully thereby practicing the claimed
`
`invention. EX1043, ¶¶44-46, 57-72.
`a.
`
`Pivot discloses antihistamine/antiemetic pretreatment regimen
`in combination with cabazitaxel
`Pivot teaches administration of an antihistamine as part of a premedication
`
`regimen: “Patients received i.v. antihistaminic anti-H1 premedication 30 min
`
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`
`
`before study drug administration.” EX1010 at 1548. Furthermore, Pivot discloses
`
`that additional premedications, such as antiemetics, were provided to patients in
`
`need thereof: “In case of nausea/vomiting, patients could receive preventive
`
`antiemetic treatment in compliance with the conventional antiemetic protocol of
`
`the center, for subsequent cycles.” Id. Pivot administers cabazitaxel in a 3 week
`
`cycle (id. at 1547), and administers premedication “before study drug
`
`administration” and “for subsequent cycles.” EX1043, ¶47.
`
`The POSA would have had good reason to use a premedication regimen
`
`including antihistamines and antiemetics, as disclosed in Pivot, to prevent allergic
`
`reactions and to treat nausea arising from cabazitaxel administration. EX1043, ¶48.
`
`Pivot discloses that “allergic reaction” was “the most frequent grade 3/4 non-
`
`hematological” adverse event, occurring in 4% of patients receiving cabazitaxel.
`
`EX1010 at 1551. Additionally, one patient had to be withdrawn from the study due
`
`to a grade 4 allergic reaction. Id. at 1550. A person of ordinary skill would
`
`understand that the use of pretreatments, as disclosed by Pivot, would be desirable
`
`to minimize the risk of allergic reactions. EX1043, ¶48.
`
`Pivot also discloses that nausea and vomiting were among the most frequent
`
`non-hematological adverse events. EX1010 at 1550. Thus, a person of ordinary
`
`skill would also have good reason to use an antiemetic protocol before cabazitaxel
`
`administration, as taught by Pivot. EX1043, ¶¶49, 63.
`b.
`
`NCCN discloses a conventional antiemetic protocol comprising
`a corticosteroid and an H2 antagonist
`Pivot does not limit the antiemetic regimens used to treat nausea and
`
`vomiting but states that any “conventional antiemetic protocol” could be used.
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`EX1010 at 1548. As discussed below, it would have been obvious to use an
`antiemetic protocol comprising an H2 antagonist and a corticoid because both
`drugs had known uses in antiemetic treatment and because both drugs had
`
`previously been used in pretreatment regimens for the two FDA-approved taxanes
`
`on the market, paclitaxel and docetaxel.
`
`For example, the 2008 National Comprehensive Cancer Network Antiemetic
`
`Guidelines (“NCCN,” EX1045) detail common treatment options used in cancer
`
`centers’ conventional antiemetic protocols. EX1043, ¶¶51, 57. NCCN recommends
`
`the use of dexamethasone (a corticoid) and H2 antagonists in the treatment of
`chemotherapy-related nausea and vomiting. As described by Dr. Seth, NCCN was
`
`published in 2008, more than 1 year before the earliest claimed priority date for the
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`’592 patent. Id. Accordingly, NCCN is prior art under 35 U.S.C. 102(b).
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`NCCN expressly identifies the use of dexamethasone for high, moderate,
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`and even low emetic risk chemotherapy, and recommends that the antiemetic
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`treatment “start before chemotherapy.” EX1045, 6-8; EX1043, ¶58. NCCN also
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`describes a method of antiemetic treatment called “breakthrough treatment,” to be
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`used in subsequent cycles when nausea or vomiting is induced in an earlier cycle.
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`EX1045, 15. Breakthrough treatment involves giving a combination of drugs
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`chosen from a set of equivalents. Id. at 22. NCCN explains that “Multiple
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`concurrent agents … may be necessary,” and lists “corticosteroids” among the
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`drugs that “may be required.” Id., 22-23; EX1043, ¶59.
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`NCCN also suggests the addition of H2 antagonists to the same antiemetic
`regimen: “If patient has dyspepsia consider antacid therapy (H2 blocker or proton
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`pump inhibitor).” EX1045 at 15. As explained by Dr. Seth, H2 antagonists are a
`form of anti-heartburn medication that reduce the production of gastric acid.
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`EX1043, ¶59. NCCN explains that H2 antagonists should be used in an antiemetic
`regimen “because patients sometimes have difficulty discriminating heartburn
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`from nausea.” EX1045 at 23. As Dr. Seth further explains, excess stomach acidity
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`can increase pain when vomiting occurs, as the higher acid concentration interacts
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`with the patient’s esophagus. EX1043, ¶60. This benefit would further encourage
`use of an H2 antagonist in patients receiving nausea-inducing cabazitaxel therapy.
`The combined antiemetic use of antihistamine H1 and H2 antagonists was
`also known more generally. See EX1049 at S154 (“[p]remedication with H1 and
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`H2 blocking agents significantly reduces the incidence of postoperative nausea and
`vomiting.”). Two common H2 antagonists—ranitidine (Zantac®) and cimetidine
`(Tagamet®)—were shown to provide antiemetic benefit. Id. Accordingly, the
`antiemetic effect of H2 antagonists and their combinability with H1 antihistamine
`was corroborated through controlled studies. EX1043, ¶61; see also EX1045 at 20
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`(describing use of “antihistamines” in antiemetic treatments).
`The POSA would have been motivated to use dexamethasone and an H2
`antagonist in a conventional antiemetic protocol, as suggested by NCCN, in
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`combination with an antihistamine, disclosed in Pivot, prior to administration of
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`cabazitaxel. EX1010, 1548. Moreover, the POSA would have had a reasonable
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`expectation of success in adding an H2 antagonist and a corticoid to Pivot’s
`antihistamine premedication regimen, as this combination was well-known for
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`taxane pretreatment regimens. EX1043, ¶62; see also EX2093, 24; EX1046, 106;
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`1047, 425; EX1048, 59. Accordingly, use of the claimed premedication regimen in
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`combination with cabazitaxel and prednisone for the treatment of mCRPC as
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`recited in substitute claims 31-34 would have been obvious in view of any of the
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`instituted grounds in further view of Pivot and NCCN.
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`2. Winquist/TROPIC Listing in view of Pivot and any one of Takenaka,
`Hudis, Trudeau, or the Taxol Label
`Contrary to Aventis’s arguments, a person of ordinary skill would also have
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`been motivated to use the prior art taxane premedication regimen to decrease the
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`risk of hypersensitivity reactions (“HSRs”). Aventis admits that it was known to
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`administer an antihistamine, a corticoid, and an H2 antagonist to prevent HSR in
`patients undergoing taxane treatment. Mot., 22. For example, the Taxol Label
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`states that “to avoid the occurrence of severe hypersensitivity reactions, all patients
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`treated with TAXOL should be premedicated with corticosteroids (such as
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`dexamethasone), diphenhydramine [an antihistamine] and H2 antagonists (such as
`cimetidine or ranitidine).” EX2093 at 24. Dr. Sartor agrees that this “broad type of
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`regimen had been kicked around” by 2008. EX1041, 211:22-23; EX1043, ¶55, 64.
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`Aventis argues that the need for this regimen was solely “attributable to the
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`presence of Cremophor in the formulation” of paclitaxel; however, this is not the
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`case. In fact, multiple references that qualify as §102(b) prior art teach the use of
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`the same regimen to prevent HSRs to docetaxel, the formulation of which (like
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`cabazitaxel) contains polysorbate 80 instead of Cremophor. Mot., 22 EX1043, ¶65.
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`For example, Takenaka et al. (“Takenaka,” EX1046), published in January
`of 2008, describes a study administering 30 mg/m2 docetaxel for the treatment of
`mCRPC. EX1043, ¶52; EX1046 at 106. Takenaka states that “[d]examethasone 24
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`mg, diphenhydramine 50 mg, and ranitidine 50 mg were administered before the
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`[docetaxel] infusion to prevent a hypersensitivity reaction.” Id. These constitute a
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`corticoid, an antihistamine, and an H2 antagonist, respectively. EX1043, ¶66;
`EX1001, 6:56-61, 7:15-21. Notably, the full, three-part pretreatment regimen was
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`indicated and used despite a nearly two-third reduction in docetaxel dose
`(compared to 75 mg/m2), contradicting Aventis’s argument that the POSA would
`not use the pretreatment regimen with a 25 mg/m2 of cabazitaxel because of a
`presumed lower concentration of polysorbate 80. EX1043, ¶¶65-66.
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`Premedication regimens comprising the same three categories of drug were
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`also reported in other prior art docetaxel publications. For example, Trudeau
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`(EX1047) reported HSRs were common without pretreatment, but “the use of [the
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`paclitaxel-type] premedication regimen of oral dexamethasone and IV H1 and H2
`blockers prevented significant HSRs.” Id. at 422, 425. EX1043, ¶¶53, 67.
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`Hudis et al. (EX1048) similarly studied docetaxel in metastatic breast
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`cancer. EX1048 at 58. After observing two HSRs, “a variety of pretreatment
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`regimens that incorporated diphenhydramine [an antihistamine], corticosteroids,
`and cimetidine [an H2 blocker] were used.” Id. at 59. Accordingly, a person of
`ordinary skill would have considered the use of the claimed pretreatment regimen
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`of a corticosteroid, an antihistamine, and an H2 antagonist as a well-known option
`for prevention of taxane-induced HSRs. EX1043, ¶¶54, 65.
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`Aventis incorrectly contends that Mita and the side effects of the
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`pretreatment regimen would have taught away from the pretreatment regimen. This
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`argument ignores that a larger phase II study of cabazitaxel was disclosed in Pivot.
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`Notwithstanding the earlier statement in Mita, Pivot expressly used a pretreatment
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`regimen to reduce allergic reactions. Pivot discloses that when administering
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`cabazitaxel, the most common grade 3–5 non-hematological adverse event was
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`HSR. EX1010 at 1550. As Dr. Seth explains, a 4% rate of serious (grade 3 or
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`higher) HSR would be of concern to a person of ordinary skill, and would warrant
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`the use of the claimed pretreatment regimen. EX1043, ¶68. Furthermore, Pivot
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`discloses a treatment-related death “due to shock with respiratory failure” and a
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`patient withdrawal