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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
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`NEPTUNE GENERICS, LLC
`Petitioner
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`v.
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`CORCEPT THERAPEUTICS, INC.
`Patent Owner
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`________
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`Patent No. 8,921,348
`Issued: December 30, 2014
`Filed: October 29, 2013
`Inventor: Joseph K. Belanoff
`Title: “Optimizing mifepristone levels in plasma serum of patients suffering from
`mental disorders treatable with glucocorticoid receptor antagonists”
`____________________
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`Inter Partes Review No.—not yet assigned
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`__________________
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`DECLARATION OF MIKKO A. OSKARI HEIKINHEIMO,
`M.D., Ph.D.
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`U.S. Patent No. 8,921,348
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`I, Mikko A. Oskari Heikinheimo, M.D., Ph.D., declare as follows:
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`1. I received an M.D. degree from the University of Helsinki in 1989, and my
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`M.D. and Ph.D. as a Doctor of Medicine and Surgery from the University of Helsinki
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`in 1990. Subsequently, I completed a post-doctoral fellowship at the Jones Institute
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`for Reproductive Medicine at the Eastern Virginia Medical School in Norfolk,
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`Virginia from 1992-1994, and my specialist training in obstetrics and gynecology at
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`the University of Helsinki, Finland, in 2000.
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`2. Since 2009, I have been the Physician-in-chief at the Kätilöopisto Hospital
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`Department of Obstetrics and gynecology (part of Helsinki University Hospital), and
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`since 2014 also a Professor in the Department of Obstetrics and Gynecology at the
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`University of Helsinki.
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`3. I have more than 130 original publications in scientific journals. Six (6) of
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`them are discussed in this declaration and the Petition it accompanies. A more
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`thorough summary of my education, experience, publications, awards, honors and
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`presentations is provided in my curriculum vitae, a copy of which is attached to this
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`declaration as Exhibit A.
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`4. Mifepristone is the active ingredient in Corcept’s Korlym product
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`(previously referred to as Corlux) and is also known as RU-486, a key component in
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`medical abortion (in combination with synthetic prostaglandin), and the active
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`U.S. Patent No. 8,921,348
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`ingredient in the “early option” birth control pill, first marketed as Mifegyne® (by
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`Exelgyn, Paris, France) and marketed as Mifeprex (first FDA-approved in 2000) in
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`the US.
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`5. A POSA (person of skill in the art) may have collaborated with others having
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`expertise in, for example, methods of treating diseases and administering medicines.
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`6. The arguments that Applicant proffered to rebut the assertions of the
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`Examiner for the ‘114 application were based on partial and incomplete information
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`of what was known in the prior art at the time of the invention.
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`7. There were many studies available at the time of filing of the application that
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`became the ‘348 Patent that used detection methods capable of distinguishing
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`mifepristone from its metabolites. These same studies have indicated clearly that the
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`oral administration of mifepristone doses of greater than or equal to 200mg would
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`indeed result in blood serum levels at the levels claimed. Documents teaching the
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`detection of mifepristone (and differentiation of its metabolites) as well as the
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`pharmacokinetics of administration include at least:
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`“Quantitation of RU486 in human plasma by
`HPLC and RIA after column chromatography.”
`Heikinheimo et al.
`“Clinical Pharmacokinetics
`of Mifepristone”
`Heikinheimo
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`Contraception 1986; 34: 613-
`624.
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`Clin. Pharmacokinet. 1997
`July, 33 (I): 7-17 (Ex. 1011)
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`“Plasma concentrations and receptor binding
`of RU 486 and its metabolites in humans.”
`Heikinheimo, et al.
`“Pharmacokinetics of the Antiporgesterone RU
`486 in Women During Multiple Dose
`Administration”
`Heikinheimo, et al.
`“Pharmacokinetics of Mifepristone After Low
`Oral Doses”
`Kekkonen, et al.
`“A Study of the Effect of Mifepristone
`(Antiprogesterone) Followed by Prostaglandin
`on Uterine Activity and Fetal Heart Rate in
`Patients Having a Termination of Pregnancy”
`Pulkkinen, et al.
`“Pharmacokinetic study of RU 486 and its
`metabolites after oral administration of single
`doses to pregnant and non-pregnant women”
`Shi, et al.
`Alterations in the pituitary-thyroid and
`pituitary-adrenal axis - Consequences of long-
`term mifepristone treatment.
`Heikinheimo et al.
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`U.S. Patent No. 8,921,348
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`J. Steroid Biochem Vol. 26:
`279-284, 1987 (Ex. 1012)
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`J. Steroid Biochem. Vol. 32,
`No. 1A, pp. 21-25, 1989. (Ex.
`1013)
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`Contraception 1996; 54:229-
`234. (Ex. 1014)
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`Arch Gynecol Obstet (1989)
`244:75-78 (Ex. 1015)
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`Contraception August 1993:48,
`133-149 (Ex. 1016)
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`Metabolism, 1997; 46: 292-
`296.
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`8. Because of its clinical use as an effective abortifacient beginning more than
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`25 years before the priority date of the ‘348 Patent, the pharmacokinetics of
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`mifepristone were extremely well studied and understood (see references above).
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`Dosing from ranges of less than a milligram to 1200 mg daily or more had been
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`investigated and studied in both single dose administrations and prolonged
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`administrations for years prior to the filing of the ‘348 Patent application. For
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`example, Belanoff 2002 (Ex. 1007) reports daily dosing of both 600 mg and 1200 mg.
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`U.S. Patent No. 8,921,348
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`9. The FDA-approved dose of Korlym is between 300mg and 1200mg oral
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`mifepristone daily.
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`10. Under the broadest reasonable interpretation of the claim, the term
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`“adjusting the daily dose of the patient” should be construed to mean “changing the
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`daily dose of the patient.”
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`11. The ‘348 specification describes “plasma collection devices” as those well
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`known in clinical labs, such as “vacutainers”. However, “vacutainers” are not
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`“suitable for detecting mifepristone serum levels.” (In every example in the ‘348
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`specification, the device that is used to collect the plasma (e.g., vacutainer) is different
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`than the device used to detect the mifepristone level)
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`12. A “suitable” device “for detecting mifepristone” is one that is capable of
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`actually sensing or identifying mifepristone in a serum sample. A “vacutainer” is only
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`a blood collection device, not a device for sensing or detecting components in blood.
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`Accordingly “a plasma sampling collection device suitable for detecting mifepristone
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`serum levels” must be a device capable of identifying or revealing mifepristone in a
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`blood serum sample. Such devices include instruments like mass spectrometers and
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`chromatography such as high pressure liquid chromatography (HPLC). In addition,
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`techniques based on radioimmunoassay, preceded by separation of mifepristone from
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`its metabolites have been employed. Before such analytical methods or instruments
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`can be applied, mifepristone must be separated from other components of
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`serum/plasma sample. This can be done for example by means of chromatography, or
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`extraction of serum samples using organic solvents (such as diethyl ether).
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`13. The term “optimizing levels of mifepristone” means, in the broadest
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`reasonable interpretation, “a method or process of making the level of mifepristone in
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`blood as functional or effective as possible”.
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`14. Optimization is a direct result of the performance of the three steps included
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`in claim 1. There is absolutely nothing new in “optimizing” blood levels of a drug in
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`order to assure efficacy – this is at the heart of all drug development. Measuring the
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`serum level of mifepristone and also its metabolites, and the resulting serum levels of
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`these compounds of a patient/study subject in order to optimize dosing and treatment
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`protocols were established and well known in the art at the time of the invention.
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`Measurement of serum levels of mifepristone would have been obvious to one of
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`ordinary skill in the art in order to correlate those levels to an effective dose of the
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`drug as a standard drug development protocol. Determining the dose-response
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`behavior of a compound that is already known to be therapeutically effective is a
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`standard part of developing new drugs in Europe, Japan, and the United States.
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`15. Nothing in the ‘348 Patent rises to the level of novel or non-obvious in light
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`of the prior art which instructs a person skilled in the art that monitoring blood serum
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`levels and adjusting the dosage to achieve a target serum level could have been
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`performed routinely and with a reasonable expectation of success.
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`16. Belanoff ‘848 teaches that mifepristone dosages should be adjusted for
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`individual patients due to a wide variety of factors – the very same factors that make
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`it desirable to monitor the mifepristone serum levels. The skilled person, using these
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`teachings, would monitor serum mifepristone levels, and adjust the dosages based on
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`the measured levels of mifepristone in order to optimize the desired clinical effect(s).
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`17. The mean plasma concentration discussed in Sitruk-Ware of 2000 ng/mL
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`(2.0 mg/L), following a single 600 mg dose of mifepristone, demonstrates that the
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`‘348 Patent’s target level of “greater than 1300 ng/mL” was known, attainable, and
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`reached. In fact, Figure 3 of Sitruk-Ware shows that any mifepristone dosage level
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`from 200-800 mg would have reached or exceeded the target range of 1300 ng/mL in
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`the patient. (Ex. 1008 Figure 3) In view of this dosing study, it would have been
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`obvious to one of ordinary skill in the art that 600 mg daily would have had a
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`reasonable expectation of success in attaining the target level of approximately 1300
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`ng/mL.
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`18. The Mifeprex label – as FDA-approved in 2000 - reports “Following oral
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`administration of a single dose of 600 mg, mifepristone is rapidly absorbed, with a
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`peak plasma concentration of 1.98 mg/L occurring approximately 90 minutes after
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`ingestion.” This report is fully consistent with Sitruk-Ware’s data reporting 2.0 mg/L.
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`19. It would have been readily obvious to one of ordinary skill in the art,
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`knowing that: (1) mifepristone was useful to treat conditions associated with excess
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`glucocorticoid activity (such as Cushing’s disease) administered in at least 600 mg
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`daily dosing (as disclosed by Belanoff 2002); and (2) administration of mifepristone
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`at 600 mg gave serum levels of mifepristone of greater than 1300 ng/mL, to test the
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`serum levels of a patient to determine if blood levels of mifepristone were greater than
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`1300 ng/mL since it was known that such dosages were efficacious in the treatment
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`of stress disorders. Absent any guidance as to why any level greater than 1300 ng/mL
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`mifepristone is the preferred genus, the species of around 2000 ng/mL as disclosed by
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`Sitruk-Ware is encompassed by the claimed range. It would have been further obvious
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`to one of ordinary skill in the art to adjust the daily dosing of the patient for treating
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`psychotic disorders in order to achieve mifepristone blood levels greater than 1300
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`ng/mL so that efficacy could be maintained.
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`20. Administration of mifepristone at the dosage levels taught by Belanoff ‘848
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`would necessarily and inevitably result in a range of blood serum concentrations that
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`achieve mifepristone blood levels greater than 1300 ng/mL as claimed. It would have
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`been readily obvious to one of ordinary skill in the art with a very high expectation of
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`success that the daily dosing of the patient could be adjusted to optimize mifepristone
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`blood levels. This could be done by changing (increasing) the daily dose if necessary.
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`21. Mifepristone administered in tablet form constitutes oral administration.
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`Oral administration was the routine and customary mode of dosing for mifepristone
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`at the time of the filing of the ‘348 Patent.
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`22. It would have been readily obvious to one of ordinary skill in that art with
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`a reasonable expectation of success that any stress disorder selected from the group of
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`acute stress disorder, post-traumatic stress disorder and brief psychotic disorder with
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`marked stressor(s) could have been monitored as required in claim 2 because both
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`Belanoff ‘953 and Belanoff 2002 teach mifepristone useful for treating patients with
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`similar stress disorders.
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`23. It would have been obvious to one of ordinary skill in the art that treatment
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`with mifepristone would have been reasonably expected to have been successful over
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`a period of at least 28 days in light of at least Murphy which teaches the usefulness
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`and efficacy of dosing for periods up to 56 days saying the patient receiving the 56-
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`day regimen “tolerated the dosing well.”
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`24. Both the patients in Belanoff 2002 and those in Murphy were being assessed
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`on a similar scale to monitor effectiveness of the mifepristone treatment. Therefore,
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`any untoward side effects apparent in Murphy would have also been seen by Belanoff
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`2002. Neither Belanoff 2002 nor Murphy report unwanted side effects due to the
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`dosing regimens.
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`25. It is in no way surprising that administration of the same dose of
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`mifepristone can produce widely varying blood serum levels in different patients.”
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`Table 2 of Shi is of demonstrates unequivocally that there is nothing surprising about
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`the same dose of mifepristone producing varying levels of blood mifepristone.
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`Shi was published well over a decade before the filing of the ‘348 Patent, and there is
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`absolutely nothing “surprising” about variations in dosing levels as shown by Shi.
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`26. The Shi 1993 publication shows mifepristone plasma levels well above
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`1300 ng/mL at hours 1 and 4 after administration of a single 600 mg oral dose. The
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`Shi 1993 publication shows mifepristone plasma levels at about 800 ng/mL remaining
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`at hour 24.
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`27. I understand the patent applicant summarized the Shi 1993 publication data
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`on mifepristone plasma levels to the Patent Office in the following table excerpt:
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`See Amendment C dated September 25, 2012 submitted to the United States Patent
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`and Trademark Office during prosecution of U.S. Application Serial Number
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`12/199,114.
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`28. It is my opinion that, if a subject took a subsequent daily dose of 600 mg
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`oral mifepristone, a person of skill in the art in 2006 or earlier would expect -- based
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`on data starting from the Heikinheimo et al. 1986 and Shi 1993 publications and the
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`nonlinear pharmacokinetics of mifepristone as published in the literature identified
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`above -- the mifepristone plasma levels would be above 1300 ng/mL at more points
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`in time by hour 48 (day 2).
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`29. I believe that in the Nieman et al. 1985 paper, researchers had already
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`shown that Cushing’s Syndrome) could be successfully treated with daily
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`mifepristone. The doses that the researchers tested and showed to be effective in
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`Neiman et al. 1985 were among the very doses approved in 2012 for Korlym to
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`improve Cushing’s syndrome
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`30. It is my opinion that, if a subject took a seven (7) or more sequential daily
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`doses of 600 mg oral mifepristone, a person of skill in the art in 2006 or earlier would
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`expect -- based on data from the Shi 1993 publication and the nonlinear
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`pharmacokinetics of mifepristone as published in the literature identified above --
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`plasma mifepristone levels would be sustained above 1300 ng/mL after such dosing
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`for at least 24 hours after the last dose of mifepristone.
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`31. I declare that all statements made in this declaration are of my own
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`knowledge and are true and that all statements made on information and belief are
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`believed to be true. I also declare that these statements were made with the knowledge
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`that willful false statements and the like so made are punishable by fine or
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`imprisonment, or both under Section 1001 of Title 18 of the United States Code.
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`Date: July 30, 2018
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`Respectfully Submitted,
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`By: Mikko A. Oskari Heikinheimo, MD, PhD
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