UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`MYLAN LABORATORIES LIMITED,
`Petitioner,
`
`v.
`
`AVENTIS PHARMA, S.A.,
`Patent Owner.
`
`_____________________________
`
`Patent No. 8,927,592
`
`_____________________________
`
`
`
`DECLARATION OF DR. RAHUL SETH
`
`
`
`MYLAN - EXHIBIT 1002
`
`

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`
`
`
`
`TABLE OF CONTENTS
`TABLE OF CONTENTS
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`I.
`
`QUALIFICATIONS ........................................................................................... 1
`QUALIFICATIONS ......................................................................................... .. 1
`
`II.
`
`SCOPE OF WORK ............................................................................................ 2
`SCOPE OF WORK .......................................................................................... ..2
`
`III. OVERVIEW OF THE ’592 PATENT .................................................................... 2
`III.
`OVERVIEW OF THE ’592 PATENT .................................................................. ..2
`
`IV. FILE HISTORY OF THE ’592 PATENT ................................................................ 7
`IV.
`FILE HISTORY OF THE ’592 PATENT .............................................................. ..7
`
`V.
`
`LEGAL STANDARDS ..................................................................................... 10
`LEGAL STANDARDS ................................................................................... .. 10
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................................ 13
`VI.
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ...................................... .. 13
`
`VII. CLAIM CONSTRUCTION ................................................................................ 14
`VII.
`CLAIM CONSTRUCTION .............................................................................. .. 14
`
`VIII. THE STATE OF THE ART................................................................................ 21
`VIII.
`THE STATE OF THE ART .............................................................................. ..21
`
`IX. PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`FEATURES OF THE ’592 PATENT ................................................................... 33
`FEATURES OF THE ’592 PATENT ................................................................. ..33
`
`X.
`
`THE RESULTS OF THE TROPIC STUDY WERE NOT UNEXPECTED ..................... 99
`THE RESULTS OF THE TROPIC STUDY WERE NOT UNEXPECTED ................... ..99
`
`XI. REASONABLE EXPECTATION OF SUCCESS ................................................... 100
`XI.
`REASONABLE EXPECTATION OF SUCCESS ................................................. .. 100
`
`XII. CONCLUDING STATEMENTS ........................................................................ 105
`XII.
`CONCLUDING STATEMENTS ...................................................................... .. 105
`
`XIII. APPENDIX – LIST OF EXHIBITS ................................................................... 106
`XIII.
`APPENDIX — LIST OF EXHIBITS ................................................................. .. 106
`
`
`-i-
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`

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`
`
`I.
`
`I, Rahul Seth, declare as follows:
`
`QUALIFICATIONS
`
`1.
`
`I am currently an Assistant Professor of Medicine at SUNY Upstate
`
`Medical University, and I am a practicing oncologist at Upstate University
`
`Hospital in Syracuse, NY. My practice includes treatment of prostate cancer
`
`patients as a member of the Upstate Specialty Services Prostate Cancer Program. I
`
`have been a member of the faculty of SUNY Upstate Medical University since
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`2009. I am a physician licensed for independent practice in New York, where I
`
`have practiced medicine since 2005. I completed my residency in internal medicine
`
`in 2002 at Stony Brook University Hospital, where I further completed a
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`fellowship in hematology and oncology in 2005.
`
`2.
`
`I obtained my Bachelor of Science degree in Biology in 1991 from
`
`Carnegie Mellon University and my Master of Science degree in Biochemistry and
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`Toxicology in 1995 from Brown University. In 1999, I received my Doctor of
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`Osteopathy degree from the New York College of Osteopathic Medicine. I have
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`been board-certified in oncology since 2006.
`
`3. My research and clinical practice is focused on urological oncology
`
`and gastrointestinal cancers. I have extensive experience dating back to 2002 in the
`
`administration of taxanes for the treatment of prostate cancer. My practice has
`
`included treating over 60 patients with metastatic prostate cancer using active
`
`chemotherapy, and such treatment typically includes administering taxane drugs. I
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`have also participated in several clinical drug studies, including Phase III clinical
`
`trials involving administration of taxane drugs for the purpose of treating cancers.
`
`1
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`

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`
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`4.
`
`A summary of my education, experience, awards and honors,
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`publications, and presentations is provided in my CV, a copy of which is submitted
`
`separately. Ex. 1003.
`
`II.
`
`SCOPE OF WORK
`
`5.
`
`I understand that a petition is being filed with the United States Patent
`
`and Trademark Office for Inter Partes Review of U.S. Patent No. 8,927,592
`
`(hereinafter, “the ’592 patent,” Ex. 1001). I have been retained as a technical
`
`expert to provide analysis and opinions regarding the ’592 patent. I have reviewed
`
`the ’592 patent and relevant sections of its prosecution history in the United States
`
`Patent and Trademark Office (Ex. 1004). I have also reviewed and considered
`
`various other documents in arriving at my opinions, and I cite to them in this
`
`declaration. For convenience, documents cited in this declaration are listed in the
`
`Appendix in Section XI.
`
`6.
`
`I am being compensated at the rate of $670/hour for my work. I have
`
`no financial interest in the outcome of this matter.
`
`III. OVERVIEW OF THE ’592 PATENT
`
`7.
`
`The ’592 patent is entitled “Antitumoral Use of Cabazitaxel.” The
`
`first page of the patent states that an application for the ’592 patent (U.S.
`
`Application No. 13/456,720, hereinafter “the ’720 application”) was filed on April
`
`26, 2012, and is a continuation of International Application No.
`
`PCT/IB2010/054866, which was filed on October 27, 2010 and claims priority to
`
`seven different U.S. Provisional Patent Applications, the earliest of which dates to
`
`October 29, 2009. I have also been advised that claims 7, 8, and 9 of the ’592
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`-2-
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`

`
`
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`patent may not be entitled to a priority date earlier than June 17, 2010, the filing
`
`date of provisional application 61/355,834 (“the ’843 application”), as explained in
`
`further detail below.
`
`8.
`
`The ’592 patent is generally directed to methods of treating prostate
`
`cancer, such as metastatic castrate- (or hormone-) resistant prostate cancer
`
`(“mCRPC”), by administering cabazitaxel (also referred to as XRP6258; see, e.g.,
`
`Ex. 1004 at 02224). For convenience, the structure of cabazitaxel, as disclosed in
`
`the specification of the ’592 patent, is shown below:
`
`9.
`
`Independent claim 1 of the ’592 patent recites the following:
`
`
`
`1. A method for treating a patient with prostate cancer that has
`
`progressed during or after treatment with docetaxel, comprising
`administering to said patient a dose of 20 to 25 mg/m2 of
`cabazitaxel, or a hydrate or solvate thereof, in combination with
`
`a corticoid.
`
`10. Dependent claim 2 depends from claim 1 and recites that the prostate
`
`cancer is an advanced metastatic disease. Dependent claim 3 depends from claim 1
`
`and recites that the cabazitaxel is in the form of an acetone solvate. Claim 4
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`-3-
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`

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`
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`depends from claim 3 and further recites that the acetone solvate contains between
`
`5% and 8% by weight of acetone. Claim 5 depends from claim 1 and recites that
`
`the administration of cabazitaxel is repeated as a new cycle every 3 weeks. Claim 6
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`depends from claim 1 and recites that the cabazitaxel is in base form.
`
`11. Claims 7, 8, and 9 each recite limitations to claim 1 in which
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`“cabazitaxel, or hydrate or solvate thereof, is administered in an amount to
`
`provide” certain specified pharmacokinetic values in patients. Claim 7 recites “an
`
`AUC of about 991 ng· h/mL (CV 34%),” claim 8 recites “an Cmax of about 226
`
`ng· h/mL (CV 107%),” and claim 9 recites “a plasma clearance of 48.5 L/h (CV
`
`39%).” Ex. 1001, claims 7-9.
`
`12.
`
`I reviewed provisional patent applications 61/256,160 (“the ’160
`
`application”) (Ex. 1005), filed October 29, 2009, and provisional patent application
`
`61/293,903 (“the’903 application”) (Ex. 1006), filed January 11, 2010, and find
`
`that neither application describes the pharmacokinetic parameters recited in claims
`
`7-9. In particular, neither application discloses any values for AUC, Cmax, or
`
`plasma clearance rates of cabazitaxel.
`
`13.
`
`I reviewed the ’834 application and found that material was included
`
`in the ’834 application (Ex. 1007) that recites “an AUC of about 991 ng· h/mL (CV
`
`34%),” “an Cmax of about 226 ng· h/mL (CV 107%),” and “a plasma clearance of
`
`48.5 L/h (CV 39%)” at 11, ll.25-32 of Ex. 1007. This language was not present in
`
`either the ’160 application or the ’903 application, nor were these pharmacokinetic
`
`values deducible from the disclosures provided therein, either separately or in
`
`combination.
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`-4-
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`

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`
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`14.
`
`I have been informed that a claim is entitled only to the effective
`
`filing date of the earliest application in which all of the claimed subject matter is
`
`described in writing in sufficient detail that one of ordinary skill in the art can
`
`reasonably conclude that the inventor had possession of the claimed invention,
`
`along with sufficient disclosure to enable a person of ordinary skill in the art to
`
`make or use the claimed subject matter without undue experimentation. Applying
`
`this standard, claims 7, 8, and 9 of the ’592 patent are entitled, at best, to a priority
`
`date no earlier than June 17, 2010, the filing date of the ’834 application.
`
`15. The “Cmax of about 226 ng· h/mL” recited in claim 8 appears to contain
`
`a technical error. Cmax means maximum blood plasma concentration of drug
`
`observed during or after administration, and is conventionally expressed in units of
`
`mass/volume, not units of mass· time/volume. For the analysis provided herein, I
`
`assume that “Cmax of about 226 ng· h/mL” as recited in claim 8 was intended to
`
`mean “Cmax of about 226 ng/mL.”
`
`16. Claim 10 depends from claim 1 and recites monitoring blood counts
`
`and measuring neutrophil levels in the patient. Claim 11 depends from claim 10
`
`and further recites discontinuing cabazitaxel treatment in a patient with a
`
`neutrophil count of ≤ 1,500 cells/mm3. Claim 12 depends from claim 1 and recites
`
`that cabazitaxel is administered at a dose of 25 mg/m2.
`
`17. Claim 13 depends from claim 1 and recites that the corticoid is
`
`selected from the group consisting of prednisone and prednisolone. Claim 14
`
`depends from claim 13 and further recites that the prednisone or prednisolone is
`
`administered at a dose of 10 mg/day. Claims 15 and 16 depend from claim 14 and
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`-5-
`
`

`
`
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`further recite that cabazitaxel is administered at a dose of 20 mg/m2 or 25 mg/m2,
`
`respectively.
`
`18. Claim 17 depends from claim 1 and recites that the prostate cancer is
`
`a castration resistant or hormone-refractory prostate cancer. Claim 18 depends
`
`from claim 17 and further recites that cabazitaxel is administered at a dose of 25
`
`mg/m2. Claim 19 depends from claim 17 and further recites that administration of
`
`cabazitaxel is repeated as a new cycle every 3 weeks.
`
`19. Claim 20 depends from claim 1 and recites that the prostate cancer is
`
`a castration resistant or hormone-refractory metastatic prostate cancer. Claims 21
`
`and 22 depend from claim 20 and further recite that cabazitaxel is administered at a
`
`dose of 20 mg/m2 or 25 mg/m2, respectively. Claim 23 depends from claim 20 and
`
`further recites that administration of cabazitaxel is repeated as a new cycle every 3
`
`weeks.
`
`20. Claim 24 depends from claim 1 and recites that the prostate cancer is
`
`a castration resistant or hormone-refractory metastatic prostate cancer, the
`
`corticoid is selected from the group consisting of prednisone and prednisolone, and
`
`that cabazitaxel is administered at a dose of 25 mg/m2. Claim 25 depends from
`
`claim 24 and further recites that administration of cabazitaxel is repeated as a new
`
`cycle every 3 weeks.
`
`21. Claim 26 depends from claim 1 and recites that cabazitaxel is
`
`administered at a dose of 20 mg/m2.
`
`22. Claim 27 of the ’592 patent is an independent claim and recites the
`
`following:
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`-6-
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`

`
`
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`27. A method of increasing the survival of a patient with a
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`castration resistant or hormone refractory, metastatic prostate
`
`cancer that has progressed during or after treatment with
`docetaxel, comprising administering a dose of 20 to 25 mg/m2
`of cabazitaxel, or hydrate or solvate thereof, to the patient in
`
`combination with prednisone or prednisolone.
`
`23. Claims 28 and 30 depend from claim 27 and recite that cabazitaxel is
`
`administered at a dose of 25 mg/m2 or 20 mg/m2, respectively. Claim 29 depends
`
`from claim 27 and further recites that administration of cabazitaxel is repeated as a
`
`new cycle every 3 weeks.
`
`24.
`
`In my opinion, and as explained in further detail below, each feature
`
`of claims 1-5 and 7-30 of the ’592 patent can be found in the prior art, and each of
`
`claims 1-5 and 7-30 would have been obvious to a person of ordinary skill in the
`
`art prior to October 29, 2009, the earliest claimed priority date of the ’592 patent.
`
`IV. FILE HISTORY OF THE ’592 PATENT
`
`25. The ’592 patent issued on January 6, 2015. I understand that during
`
`prosecution, claims directed to a method of treating hormone-refractory metastatic
`
`prostate cancer by administering cabazitaxel in combination with prednisone were
`
`twice rejected (Ex. 1004 at0 2220-31and 01870-85). In both Office actions, Mita
`
`et al. (Ex. 1012) and Tannock et al. (Ex. 1013) were relied upon to reject the
`
`method claims as obvious. Ex. 1004 at 01874, 02224. Mita discloses Phase I data
`
`evaluating safe dose ranges for administering cabazitaxel to patients with advanced
`
`solid tumors, including breast and prostate cancer. Ex. 1012 at 723. As discussed
`
`below, Mita also discloses pharmacokinetic properties of cabazitaxel. Id. Tannock
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`-7-
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`

`
`
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`discloses co-administering docetaxel, a close structural taxane analogue of
`
`cabazitaxel, with prednisone. Ex. 1013.
`
`26.
`
`In a final Office action, the examiner cited Mita’s teaching “that
`
`evidence of anticancer activity [of cabazitaxel] was noted in two patients,
`
`including one patient with ‘hormone- and docetaxel-refractory prostate cancer.’”
`
`Ex. 1004 at 01881. The examiner also stated, “[i]t is well-established in the art
`
`that Phase I clinical trials are used as a basis for continuing Phase II and Phase III
`
`clinical trials,” and “the skilled artisan would be imbued with at least a reasonable
`
`expectation of success in treating such prostate cancer.” Id. Mita did not disclose
`
`any Phase II clinical data for cabazitaxel and did not explicitly state that the
`
`patients had mCRPC that had progressed during or after treatment with docetaxel.
`
`Ex. 1012.
`
`27.
`
`In a subsequent Office action the claims were rejected as anticipated
`
`by Beardsley et al. (Ex. 1022), and as obvious over Beardsley in view of Mita (Ex.
`
`1012) and Tannock (Ex. 1013). Ex. 1004 at 00252-68. Beardsley is a review paper
`
`discussing treatments for castration- (or hormone-) resistant prostate cancer. Ex.
`
`1022. Beardsley teaches that castration resistant prostate cancer “is an incurable
`
`condition projected to cause also 30 000 deaths in America alone in 2008.” Id.
`
`Beardsley states: “The current first-line standard of care for patient with
`
`symptomatic or progressive disease is docetaxel-based chemotherapy.” Id.
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`Beardsley examined a variety of second-line treatments, i.e., treatments for patients
`
`with disease progression after or during docetaxel chemotherapy. Id. Beardsley
`
`reported that the Phase II clinical trial of cabazitaxel among patients with
`
`-8-
`
`

`
`
`
`docetaxel-resistant metastatic breast cancer found an objective response rate of
`
`14%, meaning, according to RECIST guidelines, that 14% of the patients in the
`
`Phase II trial had a reduction in tumor diameter by about 30% or more (see, e.g.,
`
`Ex. 1001 at col. 11, ll. 1-9, citing the RECIST guidelines), and that based on this
`
`result, a Phase III study had been initiated among patients with mCRPC previously
`
`treated with docetaxel. Ex. 1022 at 163. Beardsley did not disclose the dose of
`
`cabazitaxel being administered in the Phase III trial and did not explicitly state that
`
`the patients had mCRPC that had progressed during or after treatment with
`
`docetaxel. Id.
`
`28.
`
` The Examiner’s rejection stated: “Mita et al. clearly and
`
`unequivocally suggests that one skilled in the art should in fact use cabazitaxel for
`
`the treatment of taxane-refractory prostate cancer.” Id. at 00264. The examiner
`
`also cited Beardsley for teaching the use of cabazitaxel with prednisone. Id.
`
`According to the examiner, “all Applicant has done is take the next logical step . . .
`
`expressly suggested by Mita et al. and in fact stated by Beardsley et al. as
`
`‘currently being investigated’. . . more than 1 year before the Applicant’s
`
`invention.” Id. at 00267.
`
`29. The applicant held an in-person interview with the examiner on July
`
`10, 2014. Id. at 00143. During this interview, Dr. Alton Sartor, a principle
`
`investigator on the Phase III TROPIC study (id. at 00166), and other
`
`representatives of the applicant discussed the rejections with the examiner. Id.
`
`According to the applicant’s interview summary, the examiner agreed during the
`
`interview that the claims would be allowable if they were: “amended to recite (1)
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`-9-
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`

`
`
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`treatment of prostate cancer in patients who had progressed during or after
`
`docetaxel treatment and (2) administering a dose of 20 to 25 mg/m2 cabazitaxel . .
`
`. in combination with a corticoid.” Id. The applicant thereafter repeatedly argued
`
`that the absence of the 20 to 25 mg/m2 dosage range in the prior art was important
`
`evidence rebutting the examiner’s rejections. Id. at 00145 (“Importantly, the doses
`
`of cabazitaxel and prednisone are not disclosed in Beardsley. . . . Beardsley does
`
`not describe any dose of cabazitaxel, let alone an effective amount of cabazitaxel.”
`
`(emphasis in original)); see also id. at 00148 (“As previously noted, the doses of
`
`cabazitaxel and prednisone are not disclosed.”).
`
`30. On July 16, 2014, the applicant submitted an amendment making the
`
`changes agreed to during the interview, accompanied by the §1.132 declaration by
`
`Dr. Sartor (id. at 00164-92). I discuss the Sartor declaration in detail below. On
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`August 4, 2014, a Notice of Allowance was mailed.
`
`V. LEGAL STANDARDS
`
`31.
`
`I have been informed that a claimed invention is not patentable under
`
`35 U.S.C. §103, for obviousness, if the differences between the invention and the
`
`prior art are such that the subject matter as a whole would have been obvious at the
`
`time the invention was made to a person having ordinary skill in the art to which
`
`the subject matter pertains. I have been advised that “a person of ordinary skill in
`
`the art” is a hypothetical person who is presumed to have known the relevant art at
`
`the time of the invention. As discussed above, I understand that prior art for the
`
`purpose of this declaration includes references that were published at least before
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`-10-
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`

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`
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`June 17, 2010, with respect to claims 7-9 of the ’592 patent, and at least before
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`October 29, 2009, for the remaining claims of the ’592 patent.
`
`32.
`
`I have been instructed that a determination of obviousness requires
`
`inquiries into (i) the scope and content of the art when the invention was made; (ii)
`
`the differences between the art and the claims at issue; (iii) the level of ordinary
`
`skill in the pertinent art when the invention was made; and, to the extent they exist,
`
`any secondary considerations of non-obviousness.
`
`33.
`
`I understand that a claim can be found to be obvious if all the claimed
`
`elements were known in the prior art and one skilled in the field could have
`
`combined the elements as claimed by known methods with no change in their
`
`respective functions, and the combination would have yielded nothing more than
`
`predictable and expected results to one of ordinary skill in the art.
`
`34.
`
`I understand that improper hindsight must not be used when
`
`comparing the prior art to the invention for obviousness. Thus, a conclusion of
`
`obviousness must be firmly based on knowledge and skill of a person of ordinary
`
`skill in the art at the time the invention was made.
`
`35.
`
`I have been informed that obviousness may be established by showing
`
`that it would have been obvious to combine more than one teaching to result in the
`
`claimed combination. I understand that in order for a claimed invention to be
`
`considered obvious, there must be some supporting rationale for combining cited
`
`references as proposed.
`
`36.
`
`I am informed that the following are examples of principles that may
`
`indicate that it would have been obvious to combine multiple teachings, resulting
`
`-11-
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`

`
`
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`in the claimed combination, if the claimed combination involves: (i) the
`
`combination of prior art elements according to known methods to yield predictable
`
`results; (ii) the simple substitution of one known element for another to obtain
`
`predictable results; (iii) the use of a known technique to improve similar methods
`
`or products in the same way; (iv) the application of a known technique to a known
`
`method or product ready for improvement to yield predictable results; (v) the
`
`application of a technique or approach that would have been “obvious to try” (e.g.,
`
`choosing from a finite number of identified, predictable solutions, with a
`
`reasonable expectation of success); (vi) predictable variations of a known work in
`
`one field of endeavor prompted for use in either the same field or a different field
`
`based on design incentives or other market forces; or (vii) some teaching,
`
`suggestion, or motivation in the prior art that would have led one of ordinary skill
`
`to modify the prior art reference or to combine prior art reference teachings to
`
`arrive at the claimed invention.
`
`37.
`
`I also understand that evidence of “secondary considerations” may be
`
`weighed against evidence of the scope and content of, and the level of skill in, the
`
`art where appropriate.
`
`38.
`
`I understand that such secondary considerations, where in evidence,
`
`may include: (i) the commercial success of a product due to the merits of the
`
`claimed invention; (ii) a long-felt, but unsatisfied need for the invention; (iii)
`
`failure of others to find the solution provided by the claimed invention; (iv)
`
`deliberate copying of the invention by others; (v) unexpected results achieved by
`
`the invention; (vi) praise of the invention by others skilled in the art; (vii) lack of
`
`-12-
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`

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`
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`independent simultaneous invention within a comparatively short space of time;
`
`and (viii) teaching away from the invention in the prior art. Secondary
`
`considerations are relevant where there is a nexus between the evidence and the
`
`claimed invention.
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`39.
`
`I have been advised that “a person of ordinary skill in the art” is a
`
`hypothetical person who is presumed to have known the relevant art at the time of
`
`the invention. A person of ordinary skill in the art is also a person of ordinary
`
`creativity. As discussed above, I understand that the relevant timeframe for
`
`assessing validity of claims 1-5 and 10-30 of the ’592 patent is the time prior to
`
`October 29, 2009, and that the relevant timeframe for assessing validity of claims
`
`7-9 of the ’592 patent is the time prior to June 17, 2010. However, as set forth in
`
`greater detail below, I have determined that each of claims 1-5 and 7-30 of the
`
`’592 patent would have been obvious to a person of ordinary skill prior to either
`
`the October 29, 2009 or the June 17, 2010 priority dates.
`
`40. By virtue of my education, experience, and training, I am familiar with
`
`the level of skill in the art of the ’592 patent in the October 29, 2009, and June 17,
`
`2010, timeframes. In my opinion, a person of ordinary skill in the relevant field in
`
`October 2009 and June 2010 would be an oncologist, would hold a medical degree
`
`(e.g., a D.O. or an M.D.), and would have experience treating patients with prostate
`
`cancer by administering chemotherapeutic drugs. In particular, one of ordinary
`
`skill in the art would likely have experience with some combination of the
`
`following: a) treatment of metastatic prostate cancer by administering taxanes,
`
`-13-
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`

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`
`
`including docetaxel; b) treatment of docetaxel-resistant prostate cancer; c)
`
`treatment of castration resistant, hormone-refractory prostate cancer; d) the ability
`
`to understand work presented or published by others in the field, including
`
`publications discussed in this declaration, such as disclosures relating to Phase I,
`
`Phase II and Phase III clinical studies of methods for treating prostate cancer. In
`
`particular, a person of ordinary skill in the art would understand how to administer
`
`taxanes, including cabazitaxel, to prostate cancer patients at a given dose; for
`
`example, by using the 1-hour intravenous infusion disclosed in the Taxotere Label.
`
`See ¶ 62, below. A person of ordinary skill would also understand that doses of
`
`corticoids such as prednisone can be administered orally to prostate cancer patients
`
`in combination with taxanes. Id. Such intravenous and oral administration would
`
`be a routine matter for a practicing oncologist.
`
`VII. CLAIM CONSTRUCTION
`
`41.
`
`I have been advised that, in the present proceeding, the ’592 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
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`specification. I also understand that, absent some reason to the contrary, claim
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`terms are typically given their ordinary and accustomed meaning as would have
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`been understood by one of ordinary skill in the art. I have followed these principles
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`in my analysis described throughout this declaration. The ’592 patent provides
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`definitions for certain claim terms. In my opinion, these definitions are
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`conventional. Certain claim terms are not defined in the ’592 patent. I discuss a
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`few terms below and what I understand as constructions of these terms.
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`42. The ’592 patent provides no definition for the claim term “dose.”
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`However, the ordinary and accustomed meaning of “dose” is the total amount of
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`drug administered during a defined cycle of administration, irrespective of how
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`many times the drug is administered to achieve the dose. Ex. 1016 at 00006. For
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`example, a dose of 10 mg per day can be provided as multiple administrations of
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`less than 10 mg each within the same 24 hour cycle, so long as the sum of the
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`individual administrations over the course of the 24-hour period sum to a total dose
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`of 10 mg (e.g., two doses of 5 mg administered within the same 24 hour period is a
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`dose of 10 mg/day).
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`43. Claim 1 includes the phrase “[a] method for treating a patient.” In the
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`context of prostate cancer, “treating a patient” includes treatments that provide no
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`therapeutic benefit; for example, palliative treatments. Further, “treating a patient”
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`includes treatments given with merely a hope of providing therapeutic benefit, but
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`with great uncertainty as to whether the benefit will result; for example,
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`experimental treatments. Indeed, experimental treatments could include treatment
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`of humans or animals, as the ’592 patent makes clear that “patient” refers to any
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`animal. Ex. 1001 at 4:6-7.
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`44. Even after FDA approval of a drug for a particular indication, the
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`activity intrinsic to a particular compound does not guarantee a particular result in
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`every patient (though the results would be expected to be predictable across the
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`same population of patients, and therefore intrinsic to the compound when
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`administered to that population). For example, anti-prostate cancer activity is
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`intrinsic to cabazitaxel because of its mechanism of action (discussed in more
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`detail in para. VIII.73 below). Yet, there is still great uncertainty as to whether
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`administration of the drug to a particular patient will achieve the desired result for
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`that patient. For example, the ’592 patent discloses that fewer than one in six
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`patients receiving cabazitaxel had an objective response. Ex. 1001 at Table 1. In
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`other words, five out of six patients receiving cabazitaxel had no objective
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`response. Assuming that the ’592 patent discloses data from a valid study of the
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`target population (patients with prostate cancer previously treated with docetaxel),
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`the objective response rate and other results reflect inherent characteristics of
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`cabazitazel when administered to the target population.
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`45. Thus, it is my opinion that a person of ordinary skill in the art would
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`reasonably understand the phrase “a method for treating a patient” in the context of
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`the ’592 patent according to its ordinary meaning, which, includes administration
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`of cabazitaxel with the intention of benefiting the patient, regardless of whether the
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`intended benefit actually results.
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`46. Claim 27 includes the phrase “[a] method of increasing the survival of
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`a patient.” In the context of prostate cancer, it is not known at the time of
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`administrating a drug whether that drug will result in any increase in survival of
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`the patient. Indeed, it may never be knowable whether the treatment increased the
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`survival of the patient, as the same patient cannot be both treated and not treated.
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`Clinical trials can measure the rates at which a drug is effective and safe among the
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`human population of mCRPC patients, as these rates are intrinsic properties of the
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`drug when administered to the target population.
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`47. Even after FDA approval, as discussed above, drugs are administered
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`with great uncertainty as to whether administration of the drug to a particular
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`patient will actually result in the intended result for that patient. For example,
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`during the first three months of treatment, overall survival was actually lower
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`among patients treated with cabazitaxel than among patients treated with
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`mitoxantrone. Ex. 1001 at Col. 3, ll. 36-37 & Figure 1. And, as mentioned before,
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`the chances of an objective response may be lower than one in six. Thus, it is my
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`opinion that a person of ordinary skill in the art would reasonably understand the
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`phrase “a method of increasing the survival of a patient” in the context of the ’592
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`patent according to its ordinary meaning, which includes administration of
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`cabazitaxel with the intention of increasing survival of the patient, regardless of
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`whether the intended increased survival actually results.
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`48. Claims 1 and 27 refer to “prostate cancer that has progressed.” The
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`’592 patent states that in Example 1, “progression” was evaluated as “at least [a]
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`20% increase in the sum of the largest diameter of the lesion or appearance of one
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`or more new lesions” or as “either an increase of the PSA [prostate-specific
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`antigen], or of the tumour, or of the pain.” Ex. 1001 at 11:10-25. The Patent Owner
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`has previously agreed that progression also includes any worsening of the cancer.
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`Ex. 1031 (Jt. Statement). Accordingly, I understand the phrase “prostate cancer
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`that has progressed,” as used in the ’592 patent for the purpose of this proceeding,
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`to include prostate cancer that exhibits an increase in PSA, tumor size, pain, the
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`appearance of new lesions, or any worsening of the cancer.
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`49. The term “advanced metastatic disease” is not defined in the ’592
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`patent. However, in the context of prostate cancer, “advanced metastatic disease”
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`would be understood by a person of ordinary skill in the art to include a prostate
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`cancer that has widely metastasized beyond the prostate, the surrounding tissue,
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`and the pelvic lymph nodes. See, e.g. Ex. 1030 at S11. This includes metastasis
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`into the visceral organs (i.e., the heart, lungs, liver, pancreas,