Paper No. _
`Date Filed: December 23, 2016
`
`Filed on behalf of: Aventis Pharma S.A.
`
`By:
`
`Dominick A. Conde
`dconde@fchs.com
`(212) 218-2100
`
`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
`________________
`
`PATENT OWNER’S CONTINGENT MOTION TO AMEND
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`Introduction......................................................................................................1
`
`Claim Listing ...................................................................................................1
`
`III. Written Description Support For Substitute Claims........................................2
`
`IV.
`
`V.
`
`VI.
`
`A.
`
`B.
`
`C.
`
`D.
`
`Claim 31 ................................................................................................3
`
`Claim 32 ................................................................................................5
`
`Claim 33 ................................................................................................5
`
`Claim 34 ................................................................................................6
`
`Level Of Ordinary Skill In The Art.................................................................6
`
`Claim Construction..........................................................................................6
`
`A.
`
`The Preamble of Claim 31 Is Limiting .................................................6
`
`1.
`
`2.
`
`Claim Language Shows that the Preamble Is
`Limiting.......................................................................................7
`
`Patent Owner Is Relying on Increased Survival to
`Distinguish Prior Art...................................................................8
`
`B.
`
`C.
`
`“A method of increasing survival”........................................................8
`“antihistamine,” “corticoid,” and “H2 antagonist”................................9
`The Substitute Claims Are Patentable Over The Prior Art ...........................10
`
`A.
`
`B.
`
`The Substitute Claims Are Novel .......................................................10
`
`1.
`
`The Substitute Claims Are Nonobvious..............................................10
`No Prior Art Disclosed or Suggested 20-25 mg/m2
`of Cabazitaxel in Combination with Prednisone or
`Prednisolone Would Increase Overall Survival........................10
`
`a.
`
`There Is No Cabazitaxel Survival Data in
`the Prior Art ....................................................................11
`
`i
`
`

`

`b.
`
`c.
`
`Partial Responses in Tumor Size and
`Changes in PSA Levels Do Not Provide
`Evidence of Increased Survival ......................................13
`
`Docetaxel’s Survival Benefit in
`Chemotherapy- Naïve Patients Is of Little
`Relevance to Whether Claims 31-34 Were
`Obvious...........................................................................17
`
`2.
`
`A POSA Would Not Have Been Motivated to Use
`the Claimed Premedication Regimen with
`Cabazitaxel................................................................................18
`
`a.
`
`b.
`
`The Prior Art Teaches Away from the
`Claimed Premedication Regimen Prior to
`Cabazitaxel .....................................................................18
`
`A POSA Would Not Have Been Motivated
`to Employ the Claimed Premedication
`Based on Docetaxel and Paclitaxel.................................20
`
`c.
`
`The Prior Art Teaches Away from the Use
`of H2 Antagonists with Cabazitaxel................................23
`Objective Indicia Support Nonobviousness..............................24
`
`3.
`
`VII. Conclusion .....................................................................................................25
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Cases
`In re Omeprazole Patent Litig.,
`536 F.3d 1361 (Fed. Cir. 2008) .....................................................................19
`
`Jansen v. Rexall Sundown Inc.,
`342 F.3d 1329 (Fed. Cir. 2003) .......................................................................7
`
`MBO Labs., Inc. v. Becton, Dickinson & Co.,
`474 F.3d 1323 (Fed. Cir. 2007) .......................................................................8
`
`Rapoport v. Dement,
`254 F.3d 1053 (Fed. Cir. 2001) .......................................................................7
`
`Sanofi v. Glenmark Pharms. Inc.,
`No. 14-264, 2015 WL 5092631 (D. Del. Aug. 28, 2015) ...............................7
`
`Vas-Cath Inc. v. Mahurkar,
`935 F.2d 1555 (Fed. Cir. 1991) .......................................................................3
`
`Statutes
`
`35 U.S.C. § 316(d) .....................................................................................................1
`
`Rules
`
`37 C.F.R. § 42.121 .....................................................................................................1
`
`37 C.F.R. § 42.22(a)(2)..............................................................................................1
`
`iii
`
`

`

`I.
`
`Introduction
`
`Aventis Pharma, S.A. moves pursuant to 37 C.F.R. § 42.121 to amend U.S.
`
`Patent No. 8,927,592 contingent upon the outcome of the instituted Grounds of
`
`IPR2016-00712. If original Claim 27 is found unpatentable, the Board is requested
`
`to replace it with proposed substitute Claim 31. If original Claim 28 is found
`
`unpatentable, the Board is requested replace it with proposed substitute Claim 32.
`
`If original Claim 29 is found unpatentable, the Board is requested to replace it with
`
`proposed substitute Claim 33. If original Claim 30 is found unpatentable, the
`
`Board is requested to replace it with proposed substitute Claim 34. See 37 C.F.R.
`
`§ 42.22(a)(2); 35 U.S.C. § 316(d).
`
`II.
`
`Claim Listing
`
`A complete listing of the proposed claim amendments is provided in
`
`Appendix 1 hereto. No more than one substitute claim is proposed for each
`
`canceled claim. 37 C.F.R. § 42.121(a)(3). The proposed substitute claims add
`
`elements to the claims and do not remove any limitations; therefore they are not
`
`broader than the original claims. 35 U.S.C. § 316(d)(3); 37 C.F.R. § 42.121(a)(2).
`
`Claim 31 has been amended so that the preamble (now a “method of
`
`increasing survival”) is a limitation of the claim. Claim 31 still requires
`
`administering a dose of 20-25 mg/m2 of cabazitaxel, or hydrate or solvate thereof,
`
`in combination with prednisone or prednisolone to a patient with hormone-
`
`1
`
`

`

`refractory or castration resistant, metastatic prostate cancer that has progressed
`
`during or after treatment with docetaxel. Claim 31 is further limited over original
`
`Claim 27 by the requirement of administering an antihistamine, a corticoid, and an
`
`H2 antagonist prior to administering the 20-25 mg/m2 of cabazitaxel. Because
`
`Claim 31 adds limitations and does not remove any limitations, it is narrower than
`
`original Claim 27.
`
`Dependent Claims 32-34 incorporate new limitations by virtue of their
`
`dependence on substitute Claim 31. Claim 33 is further amended to require that
`
`administration of the antihistamine, corticoid, and H2 antagonist also occur as a
`
`new cycle every three weeks. Thus, Claims 32-34 are narrower than each
`
`corresponding original claim.
`
`III. Written Description Support For Substitute Claims
`
`Each of the proposed substitute claims are supported by the original
`
`disclosure of the ’592 patent (Exh. 1004 at 2360-403 (“’720 application”)) as well
`
`as International Application No. PCT/IB2010/054866 (“’866 application”) filed on
`
`October 27, 2010 (Exh. 2230), Provisional Application No. 61/293,903 (“’903
`
`application”) (Exh. 1006) filed on January 11, 2010, and Provisional Application
`
`No. 61/355,834 (“’834 application”) (Exh. 1007) filed on June 17, 2010. Based on
`
`the original disclosure of the ’720, ’866, ’834, and ’903 applications, one of
`
`2
`
`

`

`ordinary skill would understand that the inventor was in possession of Claims 31-
`
`34. Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1561-62 (Fed. Cir. 1991).
`
`A.
`
`Claim 31
`
`Claim 31 recites a method for increasing the survival of a patient in need
`
`thereof that has castration resistant or hormone-refractory metastatic prostate
`
`cancer that has progressed during or after docetaxel therapy. This method is
`
`described in detail in Example 1 of the specification of the ’720, ’866, ’834, and
`
`’903 applications. Example 1 describes a clinical study where patients with
`
`metastatic castration resistant prostate cancer (“mCRPC”) with progressive disease
`
`after docetaxel therapy received a statistically significant overall survival benefit
`
`when treated with cabazitaxel in combination with prednisone or prednisolone as
`
`compared to palliative mitoxantrone therapy. Exh. 1004 at 2385-86; Exh. 2230 at
`
`13:31-15:7; Exh. 1007 at 14:1-15:11; Exh. 1006 at 7:33-8:37; see also Exh. 1004
`
`at 2376-77; Exh. 2230 at 7:13-15; Exh. 1007 at 7:3-5; Exh. 1006 at 6:9-10 (“In
`
`another aspect, the patient has prostate cancer that progressed during or after
`
`treatment with docetaxel.”); Exh. 1004 at 2378; Exh. 2230 at 8:6-9; Exh. 1007 at 7:
`
`34-37 (“increasing the survival of a patient with hormone refractory metastatic
`
`prostate cancer, comprising administering a clinically proven effective amount of
`
`cabazitaxel to the patient in combination with prednisone or prednisolone. . . .
`
`[T]he patient has been previously treated with a docetaxel-containing regimen”).
`
`3
`
`

`

`The ’720, ’866, ’834 and ’903 applications also disclose administering a
`
`dosage of 20-25 mg/m2 of cabazitaxel, or a hydrate or solvate thereof, in
`
`combination with prednisone or prednisolone. Exh. 1004 at 2372 (“between 20
`
`and 25 mg/m2,” “anhydrous base, a hydrate or a solvate,” “in combination with a
`
`corticoid chosen especially from prednisone and prednisolone”); Exh. 2230 at 3:6-
`
`9, 3:18-20; Exh. 1007 at 3:6-21; Exh. 1006 at 3:6-16.
`
`The ’720, ’866, ’834, and ’903 applications also disclose administering a
`
`premedication regimen of an antihistamine, a corticoid, and an H2 antagonist. The
`
`applications state that “cabazitaxel may be administered in combination with a
`
`medication to prevent or control nausea and vomiting or to prevent or control
`
`hypersensitivity.” Exh. 1004 at 2378; Exh. 2230 at 8:11-14; Exh. 1007 at 8:1-2;
`
`Exh. 1006 at 7:2-3. “Preferably, a patient is pre-medicated . . . at least 30 minutes
`
`prior to administering each dose of cabazitaxel.” Exh. 1004 at 2378; Exh. 2230 at
`
`8:12-14; Exh. 1007 at 8:2-4; Exh. 1006 at 7:3-5. The ’720, ’866, ’834, and ’903
`
`applications list antihistamines and corticosteroids as examples of premedications
`
`to prevent hypersensitivity. Exh. 1004 at 2378; Exh. 2230 at 8:26-30; Exh. 1007 at
`
`8:16-20; Exh. 1006 at 7:9-12. These applications also list H2 antagonists as an
`
`example of a premedication that can be used to prevent nausea and vomiting. Exh.
`
`1004 at 2379; Exh. 2230 at 9:11-16; Exh. 1007 at 9:5-6; Exh. 1006 at 7:7-8.
`
`4
`
`

`

`Claim 32
`B.
`Claim 32 recites a 25 mg/m2 dose of cabazitaxel. Example 1 of the ’720,
`
`’866, ’834, and ’903 applications describes using a 25 mg/m2 dose of cabazitaxel
`
`in combination with prednisone or prednisolone to increase overall survival of
`
`mCRPC patients with progressive disease after docetaxel therapy as compared to
`
`patients receiving mitoxantrone therapy. Exh. 1004 at 2385-86; Exh. 2230 at
`
`13:31-15:7; Exh. 1007 at 14:1-15:11; Exh. 1006 at 7:36-8:37.
`
`C.
`
`Claim 33
`
`Claim 33 recites repeating the administration of the antihistamine, corticoid,
`
`H2 antagonist, and cabazitaxel every three weeks. The ’720, ’866, ’834, and ’903
`
`applications disclose administering cabazitaxel as a new cycle every three weeks in
`
`combination with prednisone or prednisolone, which can be administered daily.
`
`Exh. 1004 at 2376 (“cabazitaxel is administered by perfusion to the patient
`
`according to an intermittent program with an interval between each administration
`
`of 3 weeks”); Exh. 2230 at 7:3-5; Exh. 1007 at 6:31-32; Exh. 1006 at 5:38-6:4.
`
`Example 1 describes a study wherein cabazitaxel was given every three weeks in
`
`combination with daily prednisone. Exh. 1004 at 2385; Exh. 2230 at 13:31-15:7;
`
`Exh. 1007 at 14:1-15:11; Exh. 1006 at 7:36-8:2. As described above for Claim 31,
`
`the ’720, ’866, ’843, and ’903 applications also describe premedicating patients
`
`with an antihistamine, a corticoid, and an H2 antagonist before “each dose of
`
`5
`
`

`

`cabazitaxel.” Exh. 1004 at 2378; Exh. 2230 at 8:12-14; Exh. 1007 at 8:2-4; Exh.
`
`1006 at 7:3-5. Thus, each application describes administering a premedication
`
`before each dose of cabazitaxel as a new cycle every three weeks.
`
`Claim 34
`D.
`Claim 34 recites a 20 mg/m2 dose of cabazitaxel. The ’720, ’866, ’834, and
`
`’903 applications disclose administering a dose of 20-25 mg/m2 of cabazitaxel.
`
`Exh. 1004 at 2372; Exh. 2230 at 3:18-19; Exh. 1007 at 3:20-21; Exh. 1006 at 3:15-
`
`16. Example 2 in the ’720, ’866, and ’834 applications also describe dosage
`
`modification to 20 mg/m2 of cabazitaxel for adverse reactions. Exh. 1004 at 2394;
`
`Exh. 2230 at 21:5-12; Exh. 1007 at 18:17-19:10.
`
`IV. Level Of Ordinary Skill In The Art
`
`A POSA would be an oncologist or medical doctor specializing in oncology
`
`and would have experience in the treatment of prostate cancer, including metastatic
`
`prostate cancer, in evaluating therapies for prostate cancer, and would have access
`
`to information regarding pharmacokinetics and mechanisms of drug resistance.
`
`Exh. 2176 at ¶28.
`
`V.
`
`Claim Construction
`
`A.
`
`The Preamble of Claim 31 Is Limiting
`
`By virtue of the claim language and Patent Owner’s reliance to distinguish
`
`prior art, the preamble of Claim 31 is a claim limitation.
`
`6
`
`

`

`1.
`
`Claim Language Shows that the Preamble Is Limiting
`
`The body of the claim refers to administering a treatment “to a patient in
`
`need thereof.” “Thereof” in the body of the claim refers to “increasing survival” in
`
`the preamble. The Federal Circuit has held that where the preamble sets forth the
`
`objective of the method and the body of claim directs that the method be
`
`performed on someone “in need,” the preamble is a statement of intentional
`
`purpose for how the method is to be performed, and is therefore limiting. Jansen
`
`v. Rexall Sundown Inc., 342 F.3d 1329, 1333 (Fed. Cir. 2003); see also Sanofi v.
`
`Glenmark Pharms. Inc., No. 14-264, 2015 WL 5092631, at *5 (D. Del. Aug. 28,
`
`2015) (finding the preamble gives life and meaning to “a patient in need thereof”
`
`in the body of the claim). The Jansen court found the preamble was limiting
`
`because the language “to a human in need thereof” gave “life and meaning” to the
`
`preamble’s statement of purpose. 342 F.3d at 1333; see also Rapoport v. Dement,
`
`254 F.3d 1053, 1059-60 (Fed. Cir. 2001) (“Moreover, without treating the phrase
`
`‘treatment of sleep apneas’ as a claim limitation, the phrase ‘to a patient in need of
`
`such treatment’ would not have a proper antecedent basis.”). Therefore, Claim
`
`31’s requirement that the drugs described in the claim be administered to a patient
`
`“in need thereof” gives life and meaning to the preamble, and indicates that the
`
`preamble is part of the claim.
`
`7
`
`

`

`2.
`
`Patent Owner Is Relying on Increased Survival to
`Distinguish Prior Art
`
`Where an applicant relies on the preamble language for patentability, the
`
`preamble is limiting. MBO Labs., Inc. v. Becton, Dickinson & Co., 474 F.3d 1323,
`
`1330 (Fed. Cir. 2007). Here, Aventis is expressly amending the language of claim
`
`27 to add the preamble as a limitation of the claim contingent upon a potential
`
`future finding by the Board that the original claim is unpatentable. The
`
`amendment relies on the finding of increased survival with 20-25 mg/m2 of
`
`cabazitaxel in combination with prednisone administered in the TROPIC study to
`
`mCRPC patients that had progressed during or after treatment with docetaxel to
`
`distinguish prior art cited by the Board and Petitioner. This provides further
`
`support that the preamble of Claim 31 is a limitation of the claim.
`
`B.
`
`“A method of increasing survival”
`
`Example 1 of the specification demonstrates that in a phase III clinical trial,
`
`cabazitaxel therapy provided a statistically significant increase in overall survival
`
`compared to palliative mitoxantrone therapy, a therapy that is equivalent to no
`
`therapy at all with respect to prolonging the life of a patient. Exh. 1001 at Table 1;
`
`see Exh. 2176 at ¶¶36, 87. In light of this data, a POSA would understand the
`
`phrase “a method of increasing survival” to mean “a method that prolongs the life
`
`of a patient as compared to no treatment or palliative treatment.” See also Exh.
`
`2176 at ¶¶230-33.
`
`8
`
`

`

`C.
`“antihistamine,” “corticoid,” and “H2 antagonist”
`Antihistamines, corticoids, and H2 antagonists were all well understood
`
`classes of drugs to a POSA. Exh. 2176 at ¶234.
`
`Antihistamines were understood to be drugs that are antagonistic to the
`
`production of histamine through action on either the H1 or H2 receptors. Exh. 2223
`
`at 3. However, as explained by Dr. Sartor, “antihistamine” was commonly used in
`
`the art to specifically refer to drugs that target the H1 histamine receptor and were
`
`used to prevent or lessen the severity of allergic reactions. Exh. 2176 at ¶235.
`
`This is consistent with the specification, which lists “antihistamines” and “H2
`
`antagonists” separately and provides two examples of antihistamines,
`
`dexchlorpheniramine and diphenhydramine, both of which are H1 antagonists.
`
`Exh. 1001 at 6:56-60; Exh. 2213 at 664; Exh. 2144 at 667. Thus, a POSA
`
`reviewing the ’592 patent would understand that “antihistamine” as used in the
`
`claim is referring to a drug that is antagonistic to the H1 histamine receptor. Exh.
`
`1001 at 6:56-60, 7:19-22; Exh. 2176 at ¶235.
`
`A POSA would understand “H2 antagonist” as used in the claims to mean a
`
`drug that is antagonistic to the H2 histamine receptor. Exh. 2223 at 3; Exh. 2176 at
`
`¶236.
`
`A POSA would understand “corticoid” as used in the claims to mean a
`
`steroid produced in the adrenal cortex and synthetic analogues of these steroids.
`
`9
`
`

`

`Exh. 2223 at 4; Exh. 2176 at ¶237.
`
`VI. The Substitute Claims Are Patentable Over The Prior Art
`
`A.
`
`The Substitute Claims Are Novel
`
`Petitioner did not propose any Grounds based on anticipation, and Aventis is
`
`not aware of a single reference that discloses the method of independent Claim 31.
`
`For example, Aventis is not aware of a reference disclosing that cabazitaxel in
`
`combination with prednisone increases survival in patients with mCRPC. Aventis
`
`is also not aware of a reference that discloses administering an antihistamine, a
`
`corticoid, and a H2 antagonist prior to administration of cabazitaxel.
`
`B.
`
`The Substitute Claims Are Nonobvious
`
`As stated above, Aventis is not aware of prior art disclosing all the elements
`
`of Claim 31. See also Exh. 2176 at ¶229. For the reasons described below,
`
`considering the entirety of the prior art, including the references relied on in the
`
`Petition, a POSA would not have reasonably expected that the administration of
`
`20-25 mg/m2 of cabazitaxel in combination with prednisone or prednisolone
`
`according to Claim 31 would increase survival of mCRPC patients progressing
`
`during or after docetaxel. Additionally, a POSA would not have been motivated to
`
`use the three-component premedication regimen of Claim 31 with cabazitaxel.
`
`1.
`
`No Prior Art Disclosed or Suggested 20-25 mg/m2
`of Cabazitaxel in Combination with Prednisone or
`Prednisolone Would Increase Overall Survival
`
`Unlike original Claims 27-30 for which the Board found “a method of
`
`10
`
`

`

`increasing the survival of a patient” either nonlimiting or reflecting an intent of the
`
`treatment (Paper 9 at 10), here the preamble “a method of increasing survival” is
`
`clearly a limitation of Claims 31-34. Consequently, for the amended claims to be
`
`found obvious, the prior art must teach that the claimed method increases the
`
`survival of a patient. The obviousness analysis for Claims 31-34 therefore differs
`
`from that undertaken by the Board with respect to original Claims 27-30 in light of
`
`the Board’s claim construction.
`
`a.
`
`There Is No Cabazitaxel Survival Data
`in the Prior Art
`
`The phase I studies of cabazitaxel, including the study reported in Mita and
`
`Attard, were uncontrolled studies in patients with a variety of solid tumors. Exh.
`
`1012 at 723; Exh. 2147 at CabRef0002985; Exh. 2224 at 2. Phase I studies in
`
`general, and these studies in particular, were not designed to evaluate the activity
`
`of cabazitaxel in any particular indication or its effect on the survival of patients,
`
`which can only be measured in a comparative study. Id.; Exh. 2080 at 19-20; Exh.
`
`2176 at ¶¶71-72, 231; Exh. 2177 at 152:6-12 (Mylan’s expert, Dr. Rahul Seth
`
`agreeing that Mita was not designed to determine the efficacy of cabazitaxel in a
`
`specific patient population).
`
`Indeed, none of the phase I studies even discuss
`
`survival as an outcome. In fact, a patient in Lortholary died from neutropenic
`
`sepsis, indicating there was a risk that cabazitaxel could shorten life instead of
`
`prolonging it. Exh. 2147 at CabRef0002986; see also Exh. 2176 at ¶163.
`
`11
`
`

`

`Similarly the phase II study in breast cancer reported in Pivot was an
`
`uncontrolled single arm study. Exh. 1010 at 1547. As Dr. Seth acknowledged,
`
`Pivot was not designed to evaluate either the efficacy of cabazitaxel in metastatic
`
`prostate cancer patients after docetaxel progression or the associated risks. Exh.
`
`2177 at 152:20 -153:4. Although Pivot reports the median overall survival of the
`
`taxane resistant metastatic breast cancer patients as 12.3 months, Pivot does not
`
`conclude that cabazitaxel had any impact on how long the patients lived, nor could
`
`it have without a comparative arm. Exh. 1010 at 1551.
`
`As Dr. Seth agreed, a POSA in 2009 aware of the phase I and phase II data
`
`from Mita and Pivot would be looking for a larger study for the use of cabazitaxel
`
`in patients with mCRPC progressing after treatment with docetaxel in order to
`
`characterize the benefits versus risks of cabazitaxel in those patients. Exh. 2177 at
`
`153:12-25. Without having this information, a POSA could not have reasonably
`
`expected that cabazitaxel would increase survival in such patients.
`
`The Winquist and the TROPIC Listing also do not provide any data on
`
`increased survival with cabazitaxel. Exh. 1008; Exh. 1009; Exh. 2176 at ¶¶238-39.
`
`These references merely state that the primary endpoint of the TROPIC study is
`
`overall survival; in other words that the study is designed to determine whether
`
`cabazitaxel in combination with prednisone prolongs the life of mCRPC patients
`
`previously treated with docetaxel as compared to palliative mitoxantrone therapy.
`
`12
`
`

`

`Exh. 1008 at 1; Exh. 1009 at 3948. However, no results of the study were
`
`reported.
`
`b.
`
`Partial Responses in Tumor Size and Changes in PSA
`Levels Do Not Provide Evidence of Increased Survival
`
`It was well understood by January 2010 that a randomized controlled clinical
`
`study with sufficient power was necessary to determine whether a therapy provided
`
`a survival benefit. See Exh. 2080 at 19-20; Exh. 2005 at 431; Exh. 2176 at ¶231.
`
`Therefore, by definition the single arm uncontrolled phase I and II studies for
`
`cabazitaxel could not have determined whether cabazitaxel prolonged overall
`
`survival. It was also understood that tumor responses and PSA reductions were not
`
`validated surrogates for overall survival in CRPC. Exh. 2030 at 303; Exh. 2177 at
`
`94:7-16 (Dr. Seth agreeing that there are no surrogates). In fact, there were no
`
`validated surrogate endpoints because (i) measuring changes in bone scans was
`
`difficult, (ii) changes in prostate specific antigen (“PSA”) levels were not
`
`necessarily associated “with clinically important or approvable endpoints such as
`
`overall survival or pain palliation,” and (iii) systems for measuring solid tumor
`
`response were not applicable to the site of most prostate metastases, bone. Exh.
`
`2030 at 303; see also Exh. 2005 at 431 (“Overall survival remains the necessary
`
`primary endpoint in phase III clinical studies in men with CRPC, given the
`
`uncertain validity of other surrogate measures for clinical benefits.”).
`
`13
`
`

`

`That objective responses in tumor size and PSA reduction could not be used
`
`for a POSA to form a reasonable expectation regarding whether a therapy would
`
`increase survival is demonstrated by the large number of different therapies
`
`discussed below. These therapies led to reported reductions in PSA levels and
`
`tumor size, but failed to prolong overall survival in phase III studies. Tellingly,
`
`many of these studies had more patients with responses than reported for
`
`cabazitaxel in prostate cancer.
`
`For example, suramin reduced PSA levels in phase I and phase II studies
`
`with three patients having complete tumor responses, yet the drug did not increase
`
`overall survival in a phase III CRPC study. Exh. 2020 at 209-10.
`
`A phase I study of satraplatin reported an mCRPC patient with complete
`
`relief of tumour pain, and a phase II CRPC study reported 10 patients with a partial
`
`PSA response and 2 patients with tumor reductions, yet the drug did not increase
`
`overall survival in a phase III chemotherapy treated mCRPC study. Exh. 2194 at
`
`1319; Exh. 2110 at 79; Exh. 1022 at 162-63.
`
`Atrasentan reduced PSA levels in phase I and II mCRPC studies, yet failed
`
`to increase overall survival in a phase III mCRPC study. Exh. 2190 at 2171; Exh.
`
`2191; Exh. 2010 at 1960, 1962-63.
`
`DN-101 plus docetaxel significantly increased PSA response rate as
`
`compared to docetaxel plus placebo with a “promising improvement” in survival
`
`14
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`

`

`and no increase in toxicity, yet did not improve overall survival in a phase III
`
`mCRPC study. Exh. 2006 at 669, 672-73; Exh. 2043 at 1593; Exh. 2127 at 2.
`
`Phase I/II studies of GVAX in mCRPC reported a complete response and six
`
`patients with PSA decreases, but development was terminated after two phase III
`
`mCRPC studies failed to show an effect on overall survival. Exh. 2034 at 3884,
`
`3888, 3890; Exh. 2018 at 983; Exh. 2027 at 1.
`
`By 2006, more than 200 compounds had entered clinical development for
`
`use in advanced prostate cancer, but none other than docetaxel was shown to
`
`increase overall survival. See Exh. 2148 at 138. Even after the filing of the ’592
`
`patent, failure to show a benefit in overall survival in CRPC continued. Exh. 2176
`
`at ¶¶103-09. Antonarakis and Eisenberger report eight failed phase III trials in
`
`patients with mCRPC of different combination therapies with docetaxel. Exh.
`
`2004 at 1709-10. The authors state that “accurate prediction of a positive phase III
`
`study is an impossible endeavor.” Id. at 1711.
`
`Additionally, with respect to breast cancer, Ratain 2005 notes that for a
`
`breast cancer study with an objective response rate higher than 10%, such as for
`
`cabazitaxel reported in Pivot, the positive predictive value was only 25%. Exh.
`
`2145 at 5661, Table 1. A POSA would understand this to mean that there was only
`
`a 25% chance of succeeding in a phase III breast cancer study and receiving
`
`approval, let alone a study in patients with mCRPC. Id. at Table 1; Exh. 2177 at
`
`15
`
`

`

`84:6-18, 87:10-18; Exh. 2176 at ¶132. Three to one odds of failure in the same
`
`tumor type undermines any assertion that success is predictable in a different
`
`tumor type.
`
`In addition, the fact that cabazitaxel is a taxane does not mean that it
`
`provides a survival benefit. Indeed, Booth notes that survival is “exceedingly
`
`tough to prove in populations with refractory, progressive tumours.” Exh. 1015 at
`
`609. The taxane larotaxel, for example, produced tumor responses in both lung
`
`cancer and taxane-resistant metastatic breast cancer patients in phase I-II studies,
`
`yet failed to provide a survival benefit in three separate phase III trials: taxane
`
`resistant metastatic breast cancer, pancreatic cancer, and bladder cancer. Exh.
`
`1021 at 75; Exh. 2015 at 1255-56; Exh. 2040 at vi13; Exh. 2003 at 3; Exh. 2134 at
`
`45/305; Exh. 2036 at 210-11, 213. Thus, a POSA would not have reasonably
`
`expected cabazitaxel to prolong survival in mCRPC patients that had already failed
`
`docetaxel based on the fact that it was a taxane. Exh. 2176 at ¶¶56-69.
`
`These failed studies demonstrate that the partial responses in two mCRPC
`
`patients reported in Mita, only one of which was in a docetaxel-refractory patient,
`
`and the 14% tumor response rate from Pivot, if a POSA were to even consider
`
`breast cancer data to be informative for the treatment of mCRPC, failed to provide
`
`a POSA with a reasonable expectation that cabazitaxel therapy could prolong
`
`overall survival of mCRPC patients who had failed docetaxel therapy.
`
`16
`
`

`

`Lastly, the fact that the TROPIC study was being performed (as disclosed in
`
`Winquist and TROPIC Listing references relied on by Mylan) did not add any
`
`information regarding whether cabazitaxel therapy would prolong life. As Dr. Seth
`
`stated, the TROPIC study was to “determine ultimately what is better” between
`
`cabazitaxel and palliative mitoxantrone therapy. Exh. 2177 at 186:7-187:4. The
`
`numerous phase III failures discussed above show that merely running a phase III
`
`trial was not reasonably predictive of an increase in overall survival.
`
`c.
`
`Docetaxel’s Survival Benefit in Chemotherapy-
`Naïve Patients Is of Little Relevance to
`Whether Claims 31-34 Were Obvious
`
`The only survival data Mylan and Dr. Seth rely on to support allegations that
`
`a POSA would have reasonably expected an increase in overall survival by
`
`administering cabazitaxel in combination with prednisone is from a study of
`
`docetaxel in mCRPC patients. Petition at 33 (citing Attard’s discussion of the
`
`TAX327 trial); Exh. 1002 at ¶110 (citing Exh. 1013). Importantly, the survival
`
`benefit with docetaxel reported in the Tannock 2004 publication (the TAX327
`
`study) was in a different group of patients, i.e., patients who had not already
`
`progressed during or after docetaxel therapy. Exh. 1013 at 1503. Dr. Seth agreed
`
`that whether docetaxel provides a survival benefit in patients with metastatic
`
`prostate cancer who had disease progression during hormonal therapy is a different
`
`question from whether docetaxel would provide a survival benefit in patients with
`
`17
`
`

`

`metastatic prostate cancer who worsened during or after docetaxel treatment. Exh.
`
`2177 at 48:17-24. Dr. Seth also agreed that there are differences between patients
`
`who have only progressed on hormonal therapy as compared to patients who have
`
`progressed on docetaxel, and that chemotherapy-naïve (i.e., not previously treated
`
`with chemotherapy) patients will tolerate chemotherapy better than docetaxel-
`
`treated patients. Id. at 48:25-49:4, 50:7-24. Mylan does not explain why a similar
`
`survival benefit would be expected using a different drug in different patients.
`
`2.
`
`A POSA Would Not Have Been Motivated to Use the
`Claimed Premedication Regimen with Cabazitaxel
`
`No prior art reference, including Winquist and the TROPIC Listing, disclose
`
`the use of a premedication regimen with cabazitaxel, and a POSA would not have
`
`been motivated to combine either reference with the premedication regimen of
`
`Claim 31. Exh. 1008; Exh. 1009 at 3948. If anything, the prior art suggested such
`
`a combination would be unnecessary, or that a different combination should be
`
`used, as discussed below.
`
`a.
`
`The Prior Art Teaches Away from the Claimed
`Premedication Regimen Prior to Cabazitaxel
`
`Premedication regimens are employed to either reduce or lessen the
`
`incidence of certain side effects associated with intravenous administration of
`
`certain drugs. Exh. 2176 at ¶¶241-42. For example, premedications can be used
`
`when there is a concern over allergic responses to intravenous administration
`
`18
`
`

`

`referred to in the art as hypersensitivity reactions. Id. at ¶242. Additionally,
`
`corticoids can be used to reduce fluid retention.
`
`Id.; Exh. 1024 at 5.
`
`Because the art does not suggest a concern over hypersensitivity reactions or
`
`fluid retention with respect to cabazitaxel administration, a POSA would not have
`
`been motivated to administer a premedication. Where a problem had not been
`
`previously recognized in the art, the solution to that problem is not obvious. See In
`
`re Omeprazole Patent Litig., 536 F.3d 1361, 1380 (Fed. Cir. 2008) (use of
`
`subcoating not obvious where a POSA would not have inferred a need for it).
`
`In the phase I Mita and Fumoleau studies, no premedication was given for
`
`hypersensitivity reactions, and no severe hypersensitivity reactions occurred. Exh.
`
`1012 at 724, 728; Exh. 2224 at 2; Exh. 2176 at ¶¶243-45, 248. In Mita, two
`
`patients experienced transient hypersensitivity reactions that did not reoccur
`
`without premedication, and in the Fumoleau study there were 3 cases of mild
`
`h