UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________
`
`WOCKHARDT BIO AG
`Petitioner,
`v.
`
`JANSSEN ONCOLOGY, INC.
`Patent Owner.
`
`_______________________
`
`Case IPR2016-01582
`Patent 8,822,438 B2
`
`_______________________
`
`DECLARATION OF RICHARD AUCHUS, M.D., Ph.D.
`IN SUPPORT OF JANSSEN ONCOLOGY, INC.’S
`PATENT OWNER RESPONSE
`
`
`
`
`
`
`
`JANSSEN EXHIBIT 2040
`Wockhardt v. Janssen IPR2016-01582
`
`
`
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________
`
`WOCKHARDT BIO AG
`Petitioner,
`v.
`
`JANSSEN ONCOLOGY, INC.
`Patent Owner.
`
`_______________________
`
`Case IPR2016-01582
`Patent 8,822,438 B2
`
`_______________________
`
`DECLARATION OF RICHARD AUCHUS, M.D., Ph.D.
`IN SUPPORT OF JANSSEN ONCOLOGY, INC.’S
`PATENT OWNER RESPONSE
`
`
`
`
`
`
`
`JANSSEN EXHIBIT 2040
`Wockhardt v. Janssen IPR2016-01582
`
`
`
`
`
`
`
`I, Richard Auchus, M.D., Ph.D. hereby declare as follows:
`
`I.
`
`ENGAGEMENT
`
`1.
`
`I have been retained by counsel for Patent Owner Janssen Oncology,
`
`Inc. (“Janssen”) to provide expert testimony as background for the panel of
`
`Administrative Patent Judges of the Patent Trial and Appeal Board of the United
`
`States Patent and Trademark Office (“Panel”) as it considers issues relating to the
`
`patentability of U.S. Patent No. 8,822,438 (the ’438 Patent) (Ex. 1001) in an inter
`
`partes review requested by Wockhardt Bio AG (hereinafter “Wockhardt”) in Case
`
`No. IPR2016-01582.
`
`2.
`
`I am being compensated at my customary rate of $350 per hour for
`
`work in connection with this proceeding. I am also being reimbursed for
`
`reasonable and customary expenses associated with my work in this proceeding.
`
`My compensation is in no way contingent upon the outcome of this proceeding or
`
`the specifics of my testimony.
`
`3.
`
`I understand that a person of ordinary skill (“POSA”) is a hypothetical
`
`person who has the characteristics of an ordinary practitioner, including ordinary
`
`creativity. For purposes of my analysis in this case, I have considered the issues in
`
`the context of a POSA, which would have been a physician specializing in urology
`
`or medical oncology who has significant practical experience in the treatment of
`
`
`
`
`
`patients with prostate cancer. A POSA would have worked in a team or setting
`
`
`that includes access to one or more individuals who have expertise in
`
`endocrinology, biochemistry, pharmacology, and/or molecular biology or a related
`
`field of science, and who has experience in prostate cancer treatments or androgen
`
`synthesis and action. I have been informed that Wockhardt defines a POSA as
`
`someone who is a treating clinician specializing in oncology, typically holding an
`
`M.D. degree, with at least five years of experience specializing in medical
`
`oncology; or, alternatively, a person with an M.D. and at least five years of
`
`experience specializing in urology and at least two years of clinical experience, and
`
`that a POSA could have consulted with a biochemist, an endocrinologist, and a
`
`pharmaceutical scientist. My analysis and the opinions set forth herein would
`
`remain unchanged under Wockhardt’s proposed definition.
`
`II. QUALIFICATIONS AND EXPERIENCE
`4.
`
`I am a physician, Board Certified in endocrinology, diabetes, and
`
`metabolism. I am currently Professor of Internal Medicine, Division of
`
`Metabolism, Endocrinology and Diabetes (“MEND”) at the University of
`
`Michigan Medical School. I am also Program Director of the MEND Fellowship
`
`Program, which provides training in clinical endocrinology and offers specialized
`
`clinics in pituitary diseases, endocrine tumors and genetics, endocrinopathies in
`
`
`
`3
`
`
`
`pregnancy, intensive diabetes care, bariatrics, and metabolic bone diseases. I am
`
`
`also Professor in the Department of Pharmacology, University of Michigan.
`
`5.
`
`I received my Bachelor’s degree in Chemistry at the Massachusetts
`
`Institute of Technology in 1982, and my M.D./Ph.D. in Pharmacology at
`
`Washington University School of Medicine in St. Louis in 1988. I completed my
`
`residency in internal medicine at the University of Iowa in 1991, and my
`
`fellowship in endocrinology at Wilford Hall U.S. Air Force Medical
`
`Center/UTHSC San Antonio in 1993, where I also served in the U.S. Air Force’s
`
`medical corps. My curriculum vitae can be found at Ex. 2041.
`
`6.
`
`From 1996-1999, I conducted postdoctoral research and served on the
`
`faculty in pediatrics and internal medicine at the University of California, San
`
`Francisco. Prior to joining the University of Michigan, I held the positions of
`
`Assistant Professor (1999-2005), Associate Professor (2005-2008), and Full
`
`Professor (2008-2011) at the University of Texas Southwestern Medical Center in
`
`Dallas, where I was also Acting Chief of the Division of Endocrinology and
`
`Metabolism and the Division of Translational Research.
`
`7. My research interests include investigation of the basic mechanisms
`
`underlying steroid hormone biosynthesis, as well as the clinical and translational
`
`investigation of disorders of the pituitary, adrenals, ovaries, and testes that cause
`
`hypertension, infertility, and obesity. The common theme of my work is steroid
`
`
`
`4
`
`
`
`and sterol biosynthesis and action with an emphasis on human diseases. In my
`
`
`clinical practice I also focus on diseases involving changes in steroid hormone
`
`production.
`
`8.
`
`I have been a principal or co-investigator on several clinical trials and
`
`studies sponsored by the National Institutes of Health, March of Dimes, Robert A.
`
`Welch Foundation, and pharmaceutical companies. I am active in physician
`
`training and education, as well as efforts to improve the health of patients with
`
`endocrine diseases.
`
`9.
`
`I am a named author on over 208 original peer-reviewed medical
`
`journal articles and book chapters, and have presented at a diverse range of
`
`national and international conferences. I am a Council Member of the American
`
`Professors of Diabetes, Endocrinology, and Metabolism organization as well as a
`
`member of the American Heart Association, American Association of Clinical
`
`Endocrinologists, and the Endocrine Society. I am on the editorial board of several
`
`professional journals. I have also served as an ad hoc referee for the New England
`
`Journal of Medicine and the Proceedings of the National Academy of Sciences
`
`(PNAS), among others. I have been the recipient of numerous awards including
`
`the CARES Foundation’s Pioneer Award, The Charles A. and Elizabeth Ann
`
`Sanders Chair in Translational Research, and the Burroughs Wellcome Clinical
`
`Scientist Award in Translational Research.
`
`
`
`5
`
`
`
`
`
`10. My opinions are based on my education, research, and medical
`
`practice and experience in the field of endocrinology as well as my investigation
`
`and study of the relevant materials. A list of the documents that I relied on in
`
`connection with the development of my opinions set forth in this declaration is
`
`attached as Appendix A. I have also reviewed the declaration of Dr. Paul A.
`
`Godley and documents cited therein as discussed below.
`
`III. CORTISOL LEVELS AND THE SYNACTHEN TEST
`11. Cortisol is the major glucocorticoid in humans. Cortisol has multiple
`
`functions in the body, including the control of cellular metabolism and glucose
`
`levels in the blood. Glucocorticoids such as cortisol are also necessary for the
`
`body to respond to stress (e.g., surgery, trauma, pain, infection, hypoglycemia, and
`
`hemorrhage).
`
`12. Cortisol is produced and secreted by the adrenal glands. Cortisol
`
`production is regulated by the hypothalamus and the pituitary gland. If cortisol
`
`levels fall, the hypothalamus signals to the pituitary to produce adrenocorticotropic
`
`hormone (“ACTH”), which stimulates the adrenal glands to produce and release
`
`cortisol. Cortisol production is tightly regulated to maintain its concentration in
`
`the physiologic range. This occurs not only through stimulation of cortisol
`
`production and secretion by ACTH, but also through the negative feedback of
`
`glucocorticoids on the hypothalamus and pituitary, which lowers ACTH and
`
`
`
`6
`
`
`
`prevents cortisol overproduction. As of August 2006, it was known that cortisol
`
`
`levels varied throughout the day and are subject to a diurnal rhythm, with peak
`
`levels in the morning that decrease throughout the day, reaching very low
`
`concentrations at midnight. (Ex. 2085 (Sephton) at 996) (“healthy cortisol rhythms
`
`[are characterized] by high morning and lower evening [cortisol] levels”).
`
`13. The Synacthen test is a laboratory test used to evaluate adrenal
`
`function in patients, specifically, the adrenal gland’s ability to respond to a stress
`
`stimulus. In clinical practice, Synacthen tests are typically performed and
`
`interpreted by an endocrinologist, and are not indicated unless a patient presents
`
`with clinical symptoms1 that lead a clinician to suspect the patient could be
`
`producing insufficient amounts of glucocorticoids, i.e., adrenal insufficiency.
`
`Synacthen (or cosyntropin) is a synthetic analogue of ACTH.2 During the test, a
`
`
`1 Clinical symptoms frequently associated with a clinical state of adrenal
`
`insufficiency are hypotension (low blood pressure), fatigue, hypoglycemia,
`
`hyponatremia and hyperpigmentation. (See Ex. 1009 (Harrison’s) at 2142).
`
`2 Synacthen is a brand name for the compound tetracosactide, which is also known
`
`as tetracosactrin, and cosyntropin. These substances were also available as the
`
`brand name Cortrosyn. (See Ex. 2050 (Medline)). As of August 2006, these terms
`
`were used interchangeably in the literature.
`
`
`
`7
`
`
`
`bolus amount of Synacthen is administered by intramuscular or intravenous
`
`
`injection to stimulate the adrenal gland, and then serum or plasma cortisol levels
`
`are typically measured 30 and 60 minutes later. (Ex. 2051 (Dorin) at 195).
`
`14. As of August 2006, Synacthen tests results were typically reported as
`
`a “pass”/“fail” or “positive”/“negative” for each individual patient based upon
`
`whether or not the cortisol level rose above or remained below a specific
`
`concentration at any point during the test. The definition of a “pass” was not
`
`consistent in clinical practice, and a range of post-Synacthen cortisol cutoff levels
`
`had been applied for the diagnosis of adrenal insufficiency, generally
`
`approximately 500 nmol/L. (See, e.g., id. at 195). Dorin notes that “if the
`
`diagnostic application of the cosyntropin test can be restricted to primary adrenal
`
`insufficiency…it may be useful to use a lower cortisol cutoff level.” (Id. at 197).
`
`15. As of August 2006, it was also known that Synacthen test results
`
`reported as an absolute or percentage change from the basal level were not useful.
`
`(See id. at 195 (“In patients with suspected adrenal insufficiency, a basal level
`
`plasma cortisol level is not usually necessary because neither the absolute nor the
`
`percentage change from the basal level is useful as a diagnostic criterion for the
`
`cosyntropin test”); see also Ex. 2052 (Grinspoon) at 927 (“the increase in cortisol
`
`following Cortrosyn [Synacthen] administration is an unreliable index of adrenal
`
`function because it fails to distinguish normal patients from those with adrenal
`
`
`
`8
`
`
`
`insufficiency…The peak cortisol response to Cortrosyn, which is unaffected by the
`
`
`time of day, is thus a more useful measure of adrenal function than the
`
`increment.”)).
`
`16. Because the basic Synacthen tests typically measure only cortisol
`
`levels in response to a stress stimulus, they do not account for all glucocorticoids
`
`being made in the body. As a result, the Synacthen test result can be below a
`
`threshold value, without there being a glucocorticoid deficiency state. A physician
`
`would not make a prescribing decision based solely on the Synacthen test,
`
`particularly when the results were borderline, but would do a full work up of the
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`patient, with a focus on their clinical symptoms.
`
`17.
`
`It was also known as of August 2006 that because cortisol levels vary
`
`substantially throughout the day, the timing of cortisol level measurement is very
`
`important. For example, because cortisol levels are typically very low in the
`
`evening, evening cortisol levels do not provide any meaningful information about
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`whether a patient’s cortisol production is insufficient.
`
`IV. O’DONNELL
`18.
`
`I understand that Wockhardt’s expert, Dr. Paul A. Godley, has stated
`
`in his declaration that O’Donnell, A. et al., “Hormonal Impact of the 17α-
`
`hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in patients with
`
`prostate cancer,” Br. J. Cancer, 90:2317-2325 (2004) (“O’Donnell,” Ex. 1005)
`
`
`
`9
`
`
`
`teaches that “co-administration of a glucocorticoid, such as prednisone, would
`
`
`likely be necessary to prevent mineralocorticoid excess when administering
`
`abiraterone acetate” and that based upon this alleged teaching, a POSA would have
`
`been motivated to co-administer 10 mg/daily of prednisone with abiraterone
`
`acetate. (See, e.g., Ex. 1002 at ¶¶ 64, 79). For the reasons set forth below, I
`
`disagree.
`
`19. O’Donnell describes the results of a series of three Phase I toxicity
`
`studies conducted to investigate the ability of abiraterone acetate to suppress
`
`testosterone synthesis in castrate and non-castrate males with prostate cancer. (Ex.
`
`1005 at Abstract). This was the first report of the use of a specific 17α –
`
`hydroxylase/C17,20-lyase inhibitor in humans. (Id.) According to O’Donnell, “[t]he
`
`studies were conducted to determine the dose of abiraterone acetate that will result
`
`in maximum suppression of testosterone and to obtain safety, pharmacokinetic
`
`(PK) and endocrine data.” (Id. at 2318.)
`
`A. Clinical Results Reported in O’Donnell
`
`20. O’Donnell describes three studies: (1) Study A (a single dose study in
`
`males with castrate levels of testosterone following surgical or medical castration);
`
`(2) Study B (a single dose study in non-castrate males); and (3) Study C (a
`
`multidose study in non-castrate males). (Id. at 2319-22, Figs. 3-5). In each of
`
`
`
`10
`
`
`
`these three studies, only the endocrine effects of abiraterone acetate were
`
`
`examined. (See id. at 2322).
`
`21. Concerning overall toxicity, O’Donnell (2004) reports that “[i]n all
`
`three trials, abiraterone acetate was very well tolerated and no serious adverse
`
`events attributable to treatment were recorded. No haematologic or biochemical
`
`effects were observed at any dose level or schedule evaluated. No alteration in
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`resting heart rate or blood pressure was seen.” (Ex. 1005 at 2322 (emphasis
`
`added); see also id. at Abstract (“The study drug was well tolerated”); id. at 2324
`
`(“as abiraterone [acetate] is well tolerated”)).
`
`22. O’Donnell reports with respect to each of the three studies that
`
`treatment with abiraterone acetate did not result in any significant change in cortisol
`
`levels, which remained within normal limits. (See generally id. at 2320-22).
`
`23. With regard to Study A, O’Donnell states that the results “showed no
`
`effect on 17α -OH-progesterone production,” indicating that “any inhibition of
`
`17α–hydroxylase by abiraterone acetate is overridden by compensatory
`
`mechanisms related to cortisol feedback. … Supportive evidence for this is
`
`provided by the observation that there was no significant effect on cortisol levels in
`
`these patients.” (Id. at 2322-23) (emphasis added). Although a reduction in serum
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`cortisol levels was seen in one patient treated at 500 mg, O’Donnell reports that
`
`this reduction was not considered to be due to abiraterone acetate. (Id. at 2320).
`
`
`
`11
`
`
`
`
`
`24. Similarly, with regard to Study B, O’Donnell (2004) reports that
`
`“[a]gain, there was no indication in this component study of the series that there
`
`was any effect on baseline cortisol levels despite what would appear[] to be a
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`persistent block in C17,20-lyase activity.” (Id. at 2323) (emphasis added).
`
`25. With regard to Study C, O’Donnell reports for an initial cohort of
`
`three patients who received treatment at 500 mg abiraterone acetate that “serum
`
`cortisol levels remained within normal limits.” (Id. at 2321).
`
`26. O’Donnell does not discuss mineralocorticoid excess or report any
`
`measurement of mineralocorticoid levels following abiraterone acetate
`
`administration. O’Donnell also does not report any clinical symptoms that would
`
`suggest a clinical syndrome of mineralocorticoid excess.
`
`B.
`
`27.
`
`Synacthen Test Results Reported in O’Donnell
`
`In Study C, O’Donnell reports that Synacthen tests were performed on
`
`Day 11 in 3 patients receiving 500mg of abiraterone acetate and 3 patients
`
`receiving 800mg of abiraterone acetate. All three patients receiving 500 mg were
`
`reported to have “developed an abnormal response to Synacthen by Day 11.”
`
`O’Donnell (2004) reports that for these patients, “[t]he mean change in cortisol in
`
`response to Synacthen was 294.3 nmol l-1 (i.e.+ 77%) at baseline . . . falling to
`
`only 42 nmol l-1 (+ 10%) by Day 11.” O’Donnell also reports for the three patients
`
`who received 800 mg of abiraterone acetate, “[t]he mean change in cortisol levels
`
`
`
`12
`
`
`
`in response to Synacthen was 385 nmol l-1 (120%) at baseline . . ., falling to an
`
`
`increment of 65.3 nmol l-1 (23%) by Day 11. (Id. at 2321).
`
`28. As of August 2006, a POSA would understand the Synacthen test
`
`results reported in O’Donnell to be inconclusive because patients’ individual peak
`
`cortisol values were not reported and there was no indication whether an individual
`
`patient’s peak cortisol level was above or below the test’s cutoff level. In addition,
`
`a POSA would understand that the cortisol levels reported in O’Donnell were not
`
`very useful because they were reported as a mean change, in cortisol level across
`
`multiple patients. Further, no information was provided concerning how the test
`
`was performed, including the dose of Synacthen administered, the time after
`
`Synacthen administration that cortisol levels were measured, or the time of day that
`
`the measurements being compared were taken, or what was considered a “normal”
`
`versus “abnormal” test result.
`
`29. O’Donnell also states that “[s]erum cortisol levels were themselves
`
`reduced by the evening of Day 1 in three patients but all other assessments
`
`remained within normal limits. Evening cortisol falling by 60, 71, and 69%,
`
`respectively, from baseline evening cortisol in these patients.” (Ex. 1005 at 2321).
`
`In my clinical practice, it is not unusual for a healthy patient to have an evening
`
`cortisol measurement of almost 0. As a result, a POSA would understand that
`
`
`
`13
`
`
`
`changes in evening cortisol levels provide no useful information in evaluating
`
`
`whether a patient has glucocorticoid deficiency.
`
`C.
`
`Analysis of Endocrine Data Provided in O’Donnell
`
`30.
`
`In my opinion, although O’Donnell states in the Abstract that
`
`“[a]drenocortical suppression may necessitate concomitant administration of
`
`replacement glucocorticoid,” a POSA would understand from the clinical results
`
`reported in O’Donnell that administration of abiraterone acetate would not require
`
`concomitant replacement glucocorticoid.
`
`31. First, O’Donnell does not describe any adverse clinical symptoms that
`
`would suggest a need for glucocorticoid replacement therapy due to cortisol
`
`suppression or the over-production or under-production of any other steroids. To
`
`the contrary, O’Donnell reports that abiraterone was “very well tolerated” (Id. at
`
`2322) and that cortisol levels of patients in all three studies remained within
`
`normal limits. (Id. at 2320-21). O’Donnell also reports that “[n]o alteration in
`
`resting heart rate or blood pressure was seen.” (Id. at 2322).
`
`32. Second, although O’Donnell reports that patients in Study C
`
`developed an “abnormal response to a short Synacthen test by day 11” (Id. at 2321,
`
`2323), a POSA as of August 2006 would not be able to reach any meaningful
`
`conclusions concerning the need for glucocorticoid replacement based upon the
`
`
`
`14
`
`
`
`Synacthen test results reported in O’Donnell alone, because they were improperly
`
`
`reported, as discussed above, and, as such, are uninterpretable and inconclusive.
`
`33. Third, even if a POSA accepted that the incorrectly reported
`
`Synacthen test results were “abnormal” without any meaningful supportive data
`
`provided by O’Donnell, which he or she would not, a POSA would understand that
`
`the Synacthen test is only a measure of cortisol in response to stress and does not
`
`measure the total amount of glucocorticoids being produced by a patient. For
`
`example, corticosterone, a steroid with glucocorticoid activity, was not measured
`
`in the Synacthen test reported in O’Donnell. The Synacthen test therefore is an
`
`incomplete picture of the total glucocorticoids being produced by a patient and,
`
`therefore, can be an unreliable indicator of whether a patient is producing a
`
`sufficient amount of glucocorticoids, particularly in instances in which it is
`
`expected that corticosterone is still made. A more relevant indicator is the degree
`
`to which patients experienced symptoms indicative of adrenal insufficiency. The
`
`patients who received abiraterone acetate in the O’Donnell studies did not evidence
`
`any symptoms suggestive of adrenal insufficiency.
`
`34. Fourth, although O’Donnell speculates that “[s]ome impact on adrenal
`
`reserve was predictable from the steroid synthesis pathway” (Ex. 1005 at 2323), no
`
`further details are provided. Laboratory changes in hormone levels in the steroid
`
`synthesis pathway do not necessarily result in a clinical disorder requiring medical
`
`
`
`15
`
`
`
`intervention because of the complex feedback mechanisms and overlapping
`
`
`functions of many of the steroids in the adrenal steroid synthesis pathway. In
`
`O’Donnell, there was no clinical evidence of any disorder.
`
`35. As of August 2006, a POSA would have evaluated whether
`
`glucocorticoid replacement was necessary with abiraterone acetate based upon the
`
`clinical evidence in O’Donnell that abiraterone acetate was “very well tolerated”
`
`and “serum cortisol levels remained within normal limits.” (See Ex. 1005 at 2320-
`
`21, 2322). Based upon the clinical evidence, the POSA would have concluded that
`
`glucocorticoid replacement was not required during administration of abiraterone
`
`acetate.
`
`V. KETOCONAZOLE
`36.
`
`I understand that Dr. Godley has stated in his declaration that [i]t was
`
`known that a block in cortisol synthesis...resulted in an increase of
`
`mineralocorticoids. An increase in mineralocorticoids above normal levels, known
`
`as “mineralocorticoid excess (or hypermineralocorticoidism),” was known to have
`
`adverse effects, including hypertension and hypokalemia (reduction in circulating
`
`potassium levels). As discussed above, ketoconazole was known to have an effect
`
`on cortisol production. For this reason, glucocorticoids were commonly
`
`administered in combination with ketoconazole to inhibit ACTH secretion through
`
`the negative feedback loop. By suppressing the ACTH drive, the adverse side
`
`
`
`16
`
`
`
`effects caused by the mineralocorticoid excess are reduced.” (Ex. 1002 at ¶ 40).
`
`
`Dr. Godley’s opinion, based on the assumption that ketoconazole causes
`
`mineralocorticoid excess, is scientifically incorrect. To the contrary, because it
`
`was known that ketoconazole’s mechanism of action suppressed adrenal steroid
`
`production, ketoconazole was used to decrease corticosteroids (including
`
`mineralocorticoids) in conditions characterized by over-production of
`
`corticosteroids. (See Ex. 1040 (Sonino) at 815 (“Since ketoconazole…is a more
`
`potent inhibitor of cholesterol side-chain cleavage activity, it can be expected that
`
`patients treated with the agent will be free of side effects such as mineralocorticoid
`
`excess.”).
`
`37. More specifically, as of August 2006, the drug ketoconazole was
`
`known to be a non-selective inhibitor of adrenal and gonadal steroid synthesis.
`
`(See Ex. 1004 (Gerber) at 1177 (“[ketoconazole] is a potent inhibitor of gonadal
`
`and adrenocortical steroid synthesis”); Ex. 1011 (Harris) at 544 (“ketoconazole is a
`
`potent inhibitor of all adrenal steroid synthetic pathways”)).
`
`38. Because ketoconazole is a potent inhibitor of all adrenal steroids,
`
`ketoconazole was sometimes used off-label to manage symptoms associated with
`
`clinically significant over-production of glucocorticoids and/or mineralocorticoids.
`
`For example, it was known that ketoconazole was used off-label to decrease
`
`mineralocorticoids in patients who experienced symptoms associated with
`
`
`
`17
`
`
`
`mineralocorticoid excess. (Ex. 2066 (Mantero) at Abstract, 82; see also Ex. 2067
`
`
`(Palmer) at 587-589 (“The azole antifungals, such as ketoconazole, interfere with
`
`the biosynthesis of adrenal steroids and therefore can predispose patients to
`
`aldosterone [the primary mineralocorticoid in humans] deficiency.”), Ex. 1040
`
`(Sonino) at 815). In addition, high doses of ketoconazole were used to manage
`
`symptoms of Cushing disease, which is characterized by over-production of
`
`glucocorticoids, because of its ability to “give[…] near total suppression of cortisol
`
`excretion with the initial dose.” (Ex. 2065 (Farwell) at 1065).
`
`VI. THE ‘213 PATENT (“BARRIE”)
`39.
`
`I understand that Dr. Godley has also stated in his declaration that
`
`U.S. Patent No. 5,604,213, Barrie S.E. et al. “17-Substituted Steroids Useful in
`
`Cancer Treatment (“Barrie,” Ex. 1030) teaches that “abiraterone acetate suppressed
`
`testosterone levels in vivo more effectively than ketoconazole,” and that “a POSA
`
`would have expected abiraterone acetate to be more effective than ketoconazole for
`
`treating prostate cancer.” (Ex. 1002 at e.g., ¶¶ 38, 67, 72). This is also
`
`scientifically incorrect.
`
`40. Barrie and Potter describe 17-substituted steroid compounds that are
`
`inhibitors of “[t]he 17α-hydroxylase/ C17, 20-lyase enzyme [“CYP17”] complex,”
`
`and their use in the treatment of androgen-dependent disorders such as prostate
`
`
`
`18
`
`
`
`cancer. Abiraterone acetate is one of numerous compounds disclosed in these
`
`
`references.
`
`41. The “Test Results” section of the Barrie patent describes in vitro tests
`
`measuring the half maximal inhibition concentration (“IC50”) of abiraterone acetate
`
`on C17,20-lyase and 17α-hydroxylase activities. (Ex. 1030 at 21:22-66; 22:1-66).
`
`The data in the Barrie patent show that abiraterone acetate has greater inhibitory
`
`activity for C17,20-lyase (IC50 = 0.0097 µM) than 17α-hydroxylase (IC50 = 0.0130
`
`µM). (Id. at 22:59-66). The data reported in Potter further confirm that
`
`abiraterone acetate has a greater inhibitory activity for C17.20-lyase than 17α-
`
`hydroxylase. (Ex. 1035 at 2466, Table 1).
`
`42. Barrie discloses the results of laboratory experiments in mice, which
`
`show that abiraterone acetate specifically targets the CYP17 enzyme in the steroid
`
`synthesis pathway and compares these to ketoconazole, which acts non-specifically
`
`on all steroid synthesis. In Table 3 in the section entitled “In vivo organ weight
`
`and endocrine test in mice,” Barrie reports post-mortem weights of various organs
`
`in mice after they were administered various doses of abiraterone acetate or
`
`ketoconazole via intraperitoneal injection (or injection into the body cavity, a
`
`method often used in in vivo animal tests but rarely if ever used when
`
`administering a drug to a human patient). (Id. at 25:14-48).
`
`
`
`19
`
`
`
`
`
`43. The in vivo mice experiments reported in Barrie show a marked
`
`increase in the adrenal weight of mice administered ketoconazole as compared
`
`with those administered abiraterone acetate. Barrie concludes that: “Ketoconazole
`
`caused an increase in adrenal weight at the two highest doses, where [abiraterone
`
`acetate] had no significant effect, suggesting that they did not inhibit corticosterone
`
`biosynthesis.” (Id. at 25:45-48). 3
`
`44. As of August 2006, a POSA would understand that the increase in
`
`adrenal weight from treatment with ketoconazole signifies an accumulation of
`
`cholesterol esters in the adrenal glands, which, in normal rodents, is converted to
`
`various adrenal steroids through the steroid synthesis pathway. This is consistent
`
`with the “nonspecific” or “nonselective” mechanism of action of ketoconazole,
`
`which inhibited the production of all adrenal steroids because of ketoconazole’s
`
`inhibition of desmolase (also called cholesterol side chain cleavage enzyme), the
`
`first step of the steroid synthesis pathway.
`
`
`3 The Potter reference discusses these same experiments and notes that abiraterone
`
`acetate “markedly reduced the weights of androgen-dependent organs, and [it]
`
`depressed testosterone to undetectable levels. The adrenals were unaffected,
`
`implying that [abiraterone] , unlike ketoconazole, do[es] not inhibit enzymes in the
`
`pathway leading to corticosterone.” (Ex. 1035 at 2467).
`
`
`
`20
`
`
`
`
`
`45.
`
`In contrast, abiraterone acetate had “no significant effect” on adrenal
`
`weight “suggesting that [abiraterone acetate] did not inhibit corticosterone
`
`biosynthesis.” (Id. at 25:46-48; Ex. 1035 at 2467). A POSA would understand
`
`from this disclosure that corticosterone, the major glucocorticoid in mice,
`
`continues to be made when abiraterone acetate is administered. As of 2006, a
`
`POSA would understand the Barrie reference to teach that abiraterone acetate is a
`
`“specific” inhibitor of CYP17, in contrast to ketoconazole, which nonspecifically
`
`inhibited all adrenal steroid production.
`
`46. Further, the continued production of corticosterone in mice after
`
`abiraterone acetate was administered would suggest to a POSA that
`
`glucocorticoids continue to be made after administration of abiraterone acetate.
`
`Corticosterone is the major glucocorticoid in rodents; cortisol is the major
`
`glucocorticoid in humans; however, humans also produce corticosterone as well,
`
`though typically in lower amounts.
`
`47. A POSA would therefore understand from the results reported in
`
`Barrie and Potter that glucocorticoid deficiency would not occur because either: 1)
`
`cortisol, the major glucocorticoid in humans, could continue to be made when
`
`abiraterone acetate was administered to humans, or 2) that continued production of
`
`corticosterone in humans could compensate for any reduction in cortisol based on
`
`corticosterone’s glucocorticoid activity.
`
`
`
`21
`
`
`
`
`
`48. Because the in vivo mice experiments disclosed in Barrie and in Potter
`
`did not evaluate abiraterone acetate’s or ketoconazole’s effect on prostate cancer,
`
`let alone human prostate cancer, a POSA would not conclude based on these prior
`
`art teachings that “a POSA would have expected abiraterone acetate to be more
`
`effective than ketoconazole for treating prostate cancer” as Dr. Godley incorrectly
`
`suggests. (Ex. 1002 at e.g., ¶¶ 38, 67, 72).
`
`VII. PRIOR ART CONCERNING MINERALOCORTICOID EXCESS
`49. Citing to Costa-Santos, M., et al., “Two Prevalent CYP17 Mutations
`
`and Genotype-Phenotype Correlations in 24 Brazilian Patients with 17-
`
`Hydroxylase Deficiency,” J. Clin. Endocrin. & Metabol. (89)1:49-60 (2004)
`
`(“Costa-Santos,” Ex. 1014), Kasper, D.L., et al. (Eds.), Harrison’s Principles of
`
`Internal Medicine, 16th Ed. (2005) (“Harrison’s,” Ex. 1009), and Ganong, W. F.,
`
`“Review of Medical Physiology,” Los Altos, CA: Lange Medical Publications,
`
`277-300 (1979) (“Ganong,” Ex. 1033). Dr. Godley states in his declaration that
`
`“CYP17 inhibitors were known in the art to suppress both testicular and adrenal
`
`androgen production” (citing Ex. 1005 at 2318; Ex. 1011 at 542); that “it was
`
`known that a block in cortisol synthesis (e.g., by CYP17 inhibition or deficiency)
`
`resulted in an increase in mineralocorticoids,” (citing Ex. 1009 at 2145, 2145; Ex.
`
`1033 at 284); and that patients with 17α-hydroxylase deficiency secrete “large
`
`amounts of 10-deoxycorticosterone and corticosterone, but cortisol and androgens
`
`
`
`22
`
`
`
`cannot be produced . . . this excess corticosterone may . . . resul[t] in
`
`
`mineralocorticoid excess” (citing Ex. 1009 at 2145; Ex. 1033 at 284); and that
`
`“mineralocorticoid excess . . . was known to have adverse effects, including
`
`hypertension and hypokalemia.” (citing Ex. 1009 at 2143, 2145-46; Ex. 1014 at
`
`49). (Ex. 1002 at ¶¶ 35, 36, 40). Dr. Godley appears to be analogizing certain
`
`congenital diseases relating to the CYP17 enzyme to the actions of drugs that
`
`inhibit adrenal steroid synthesis pathways such as abiraterone acetate. For the
`
`reasons set forth below, I disagree with Dr. Godley’s characterizations of the prior
`
`art.
`
`50. The CYP17 enzyme is involved in the synthesis of steroid
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