`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`NEPTUNE GENERICS, LLC
`Petitioner
`
`
`v.
`
`
`
`
`
`
`
`
`
`CORCEPT THERAPEUTICS, INC.
`Patent Owner
`
`________
`
`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”
`____________________
`
`Inter Partes Review No.—not yet assigned
`
`
`
`
`
`
`__________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,921,348 AND
`MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`
`
`
`

`

`U.S. Patent No. 8,921,348
`
`
`TABLE OF CONTENTS
`
`CONTENTS
`
`I.
`
`II.
`
`Introduction ............................................................................................................... 1
`
`Grounds for Standing ................................................................................................. 1
`
`III. Mandatory Notices .................................................................................................... 1
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`IV.
`
`V.
`
`Real Party-In-Interest ........................................................................................... 1
`
`Notice of Related Matters .................................................................................... 1
`
`Lead and Backup Counsel .................................................................................... 1
`
`Service Information ............................................................................................. 2
`
`Payment of Fees ................................................................................................... 2
`
`Threshold Requirement for Inter Partes Review ........................................................ 2
`
`Identification of Challenge ......................................................................................... 2
`
`a.
`
`Overview of the ‘348 Patent ................................................................................. 2
`
`VI.
`
`Level of Skill in the Art ........................................................................................... 12
`
`VII. Claim Construction .................................................................................................. 12
`
`a.
`
`b.
`
`c.
`
`d.
`
`“mifepristone” .................................................................................................. 13
`
`“optimizing levels of mifepristone” ................................................................. 13
`
`“adjusting the daily dose of the patient” ......................................................... 13
`
`“a plasma sampling collection device suitable for detecting
`mifepristone serum levels”............................................................................... 14
`
`VIII. State of the Art at the Time of Filing of the ‘348 Patent ........................................... 15
`
`IX.
`
`Detailed Explanation of the Challenge ..................................................................... 23
`
`a.
`
`Ground 1: Claims 1, 2, 4, 6, and 7 of the ‘348 Patent are obvious
`under 35 U.S.C. § 103 over Belanoff ‘848 ....................................................... 25
`
`
`
`ii
`
`

`

`U.S. Patent No. 8,921,348
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`Ground 2: Claims 1, 2, 4, 6, and 7 of the ‘348 Patent are unpatentable
`as obvious under 35 U.S.C. § 103 over Belanoff 2002 in view of Chu
`and Belanoff and Sitruk-Ware. ......................................................................... 32
`
`Ground 3: Claim 3 of the ‘348 Patent is unpatentable as obvious
`under 35 U.S.C. § 103 over Belanoff 2002, Chu and Belanoff, and
`Sitruk-Ware in further view of Belanoff ‘953. ................................................. 42
`
`Ground 4: Claim 5 of the ‘348 Patent is unpatentable as obvious
`under 35 U.S.C. § 103 over Belanoff 2002, Chu and Belanoff and
`Sitruk-Ware in further view of Murphy. .......................................................... 43
`
`Ground 5: Claim 3 of the ‘348 Patent is unpatentable as obvious
`under 35 U.S.C. § 103 over Belanoff ‘848 in further view of Belanoff
`‘953. .................................................................................................................. 45
`
`Ground 6: Claim 5 of the ‘348 Patent is unpatentable as obvious
`under 35 U.S.C. § 103 over Belanoff ‘848 in further view of Murphy. ........... 46
`
`X.
`
`XI.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Secondary Considerations ........................................................................................ 47
`
`Conclusion............................................................................................................... 50
`
`
`
`
`
`iii
`
`

`

`U.S. Patent No. 8,921,348
`
`
`
`TABLE OF AUTHORITIES
`
`CASES
`
`Biomarin v. Genzyme, IPR2013-00534, Paper 81, p12-13, (PTAB 2015) ............. 26
`
`Cuozzo Speed Technologies, LLC v. Lee, 579 U. S. ____ (2016) .......................... 12
`
`In re Aller, 42 C.C.P.A. 824, 220 F.2d 454, 456 (1955)........................................ 29
`
`In re Boesch, 617 F.2d 272, 276 (C.C.P.A. 1980) ................................................. 29
`
`In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) ............................................. 29
`
`In re Kulling, 897 F.2d 1147, 1149 (Fed. Cir. 1990) ............................................. 29
`
`In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)........................................... 29
`
`KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) ......................... 26
`
`Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368-69 (Fed. Cir. 2007) ................... 29
`
`Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) ....................................... 14
`
`Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012) ............ 30
`
`
`STATUTES
`
`35 U.S.C. § 103(a) .................................................................................................. 7
`
`35 U.S.C. § 314(a) .................................................................................................. 2
`
`
`REGULATIONS
`
`37 C.F.R. § 42.100(b) ........................................................................................... 12
`
`37 C.F.R. § 42.8 ..................................................................................................... 1
`
`
`
`
`iv
`
`

`

`U.S. Patent No. 8,921,348
`
`I.
`
`Introduction
`
`Neptune Generics, LLC (“Petitioner”) requests inter partes review (“IPR”) of
`
`claims 1-7 of U.S. Patent No. 8,921,348 (“the ‘348 Patent”) (Exhibit 1001).
`
`II. Grounds for Standing
`Petitioner certifies that the patent for which review is sought is available for
`
`inter partes review, and that Petitioner is not barred or estopped from requesting an
`
`inter partes review on the grounds identified in the petition.
`
`III. Mandatory Notices
`a. Real Party-In-Interest
`
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Neptune Generics,
`
`LLC has authority to direct or control (i) the timing of, filing of, content of, or any
`
`decisions or other activities relating to this Petition or (ii) any timing, future filings,
`
`content of, or any decisions or other activities relating to the future proceedings related
`
`to this Petition.
`
`b. Notice of Related Matters
`
`Petitioner is unaware of any other matters related to the ‘348 Patent.
`
`c. Lead and Backup Counsel
`
`Lead Counsel:
`Kenneth M. Goldman
`Reg. No. 34,174
`MASSEY & GAIL LLP
`50 E. Washington Street, Suite 400
`Chicago, IL 60602
` kgoldman@masseygail.com
`
`Backup Counsel:
`Christopher L. May
`Reg. No. 53,286
`MASSEY & GAIL LLP
`1325 G Street N.W., Suite 500
`Washington, DC 20005
` cmay@masseygail.com
`
`1
`
`

`

`U.S. Patent No. 8,921,348
`
`d. Service Information
`
`Please address all correspondence to the lead and backup counsel at the
`
`address shown above. Petitioner also consents to electronic service by e-mail at:
`
`kgoldman@masseygail.com and lgail@masseygail.com.
`
`e. Payment of Fees
`
`The required fees are submitted herewith in accordance with 37 C.F.R.
`
`§§ 42.103(a) and 42.15(a).
`
`
`
`IV. Threshold Requirement for Inter Partes Review
`A petition for inter partes review must demonstrate “a reasonable likelihood
`
`that the petitioner would prevail with respect to at least one of the claims challenged
`
`in the petition.” 35 U.S.C. § 314(a). This Petition meets that threshold. All of the
`
`elements of claims 1-7 of the ‘348 Patent are taught or suggested in the prior art, as
`
`explained below in the proposed grounds of unpatentability.
`
`V.
`
`Identification of Challenge
`a. Overview of the ‘348 Patent
`i.
`
`The ‘348 Specification
`
`The ‘348 Patent names Joseph K. Belanoff as the sole inventor. Belanoff has
`
`been the CEO of Corcept Therapeutics (the assignee of the ‘348 Patent) since 1999.
`
`2
`
`

`

`U.S. Patent No. 8,921,348
`
`Since its inception in 1998, Corcept has been developing mifepristone1, a compound
`
`that modulates the effects of cortisol by acting as a competitive antagonist at the
`
`glucocorticoid receptor (GR). (Ex. 1031 at 1) Mifepristone is the active ingredient
`
`in Corcept’s Korlym product (previously referred to as Corlux) as well as Mifeprex
`
`which was first FDA-approved in 2000. (Ex. 1004 ¶4; Ex. 1032; Ex. 1033)
`
`The ‘348 Patent is directed to a method for optimizing levels of the well-
`
`known drug mifepristone in a patient. The method comprises the simple steps of
`
`treating a patient with the drug, testing the serum of the patient to determine the level
`
`of the drug in the blood, then adjusting the dosage to achieve a desired level of the
`
`drug in the blood. (Ex. 1001 abstract)
`
`According to Belanoff, this method of optimizing serum levels of a drug is
`
`especially useful for a patient suffering from various mental disorders, such as a
`
`stress disorder, delirium, mild cognitive impairment (MCI), dementia, psychosis and
`
`psychotic major depression. (Ex. 1001 col 1:40-42 and 50-53)
`
`None of these methods have any novel or non-obvious elements. As will be
`
`seen in more detail below, at the time of the filing of the application that became the
`
`‘348 Patent, mifepristone had been extensively studied and characterized
`
`pharmacokinetically for decades, and was the subject of voluminous publications
`
`
`1 Mifepristone is 11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-
`propynyl)-estra-4, 9-dien-3-one, and is also known as RU-486. (Ex. 1001 col. 4:6-
`11).
`
`3
`
`

`

`U.S. Patent No. 8,921,348
`
`authored by Belanoff and others. Measuring the serum concentration of
`
`mifepristone – or most any other well-characterized drug – and then adjusting that
`
`concentration level was routine and very-well known at the time of filing.
`
`ii.
`
`The ‘348 Patent Claims
`
`The claims of the ‘348 Patent are directed to methods of maintaining certain
`
`levels of the drug mifepristone in blood. Claim 1 is the only independent claim
`
`and states:
`
`A method for optimizing levels of mifepristone in a
`patient suffering from a disorder amenable to treatment
`by mifepristone, the method comprising:
`treating the patient with seven or more daily doses of mifepristone
`over a period of seven or more days;
`testing the serum levels of the patient to determine whether the
`blood levels of mifepristone are greater than 1300 ng/mL; and
`adjusting the daily dose of the patient to achieve mifepristone
`blood levels greater than 1300 ng/mL.
`
`All of Claims 2-7 depend directly (Claims 2 and 4-7) or indirectly (Claim 3) from
`
`Claim 1: Claims 2 and 3 further define the disorders to which the method is directed;
`
`Claim 4 requires that the daily drug doses are administered orally; Claim 5 requires
`
`that the patient be treated with 28 or more daily doses over 28 or more days; Claim
`
`6 requires using a collection device suitable for detecting the drug; and Claim 7
`
`requires an adjustment that is an increase in dosage.
`
`iii.
`
`Prosecution History of the ‘348 Patent
`
`(a) Prior Art Considered and Reason for Allowance of
`the ‘348 Patent
`
`4
`
`

`

`U.S. Patent No. 8,921,348
`
`The application that issued as the ‘348 Patent (Application No. 14/065,792)
`
`was filed on October 29, 2013 with 8 original claims. It was a continuation of
`
`Application No. 12/199,144 (now issued US Patent 8,598,149) filed on August 27,
`
`2008, which claimed priority to a provisional application (60/969,027) filed on
`
`August 30, 2007.
`
`The entirety of the substantive examination of the ‘348 Patent involved the
`
`removal of the term “mental” from the phrase “mental disorder” in independent
`
`claim 1 and dependent claim 2.
`
`On January 21, 2014, Applicant requested amendment of the originally
`
`submitted claims to amend claims 1 and 2 and cancel claim 8. Claims 1 and 2 were
`
`originally directed to “A method for optimizing levels of mifepristone in a patient
`
`suffering from a mental disorder amenable to treatment by mifepristone…” but were
`
`broadened by deleting the term “mental” to read “A method for optimizing levels of
`
`mifepristone in a patient suffering from a mental disorder amenable to treatment by
`
`mifepristone…” (Ex. 1002 at 92 and 94)
`
`On April 24, 2014, a Non-Final Rejection for all claims 1-7 was issued based
`
`on nonstatutory double patenting “as being unpatentable over claims 1-7 of U.S.
`
`Patent No. 8,598,149 (‘149). Although the claims at issue are not identical, they are
`
`not patentably distinct from each other because the claims of ‘149 read on the instant
`
`claims. It is an anticipatory type of double patenting rejection.” (Ex. 1002 at 47) In
`
`5
`
`

`

`U.S. Patent No. 8,921,348
`
`response, Applicant filed a terminal disclaimer for all claims on August 19, 2014
`
`(Ex. 1002 at 23), and a Notice of Allowance issued on August 29, 2014. (Ex. 1002
`
`at 12)
`
`The Information Disclosure Statement filed on May 8, 2014 in support of the
`
`‘348 Patent application cited only a single U.S. patent (Belanoff’s prior art U.S.
`
`Patent No. 6,964,953) and only two non-patent literature documents, one of which
`
`was to a medical encyclopedia. (Ex. 1002 at 18) This is astounding, as there was a
`
`wealth of prior art and information available on the dosing, pharmacokinetics, and
`
`use of mifepristone as of the time of the filing of the ‘348 Patent application – many
`
`of which were authored or co-authored by Belanoff himself2, and none of which
`
`were disclosed to the PTO during prosecution of the ‘348 Patent.
`
`(b) Prior Art Considered and Reason for Allowance of
`Parent U.S. Patent No. 8,598,149
`
`
`2
`For example, Schatzberg and Belanoff US 6,150,349 (Ex. 1021) (issued
`2000-11-21); Chu and Belanoff (Ex. 1023) [“Successful Long-Term Treatment of
`Refractory Cushing’s Disease with High-Dose Mifepristone (RU 486)” (published
`2001)]; Schatzberg and Belanoff US 6,362,173 (Ex. 1026) (issued 2002-03-26);
`Belanoff 2002 (Ex. 1007) [“An Open Label Trial of C-1073 (Mifepristone) for
`Psychotic Major Depression” (published 2002)]; Belanoff US 8,450,379 (Ex.
`1027) (published 2004-07-08 as US 2004/013270); Belanoff US 7,361,646 (Ex.
`1028) (published 2004-08-26 as US 2004/0167110); Belanoff ‘848 (Ex. 1024)
`[U.S. Patent Application Pub. No. US 2004/0029848 (published 2004-02-12 and
`issued as US 7,163,934)]; Belanoff ‘953 (Ex. 1010) [U.S. Patent 6,964,953 (issued
`2005-11-15)]; DeBattista and Belanoff, “The use of mifepristone in the treatment
`of neuropsychiatric disorders” (Ex. 1029) (published 2006-03-10); DeBattista,
`Belanoff et al., “Mifepristone versus Placebo in the Treatment of Psychosis in
`Patients with Psychotic Major Depression” (Ex. 1030) (published 2006-08-04).
`
`6
`
`

`

`U.S. Patent No. 8,921,348
`
`Due to the paucity of substantive review of the ‘348 Patent application
`
`coupled with the lack of candor in the prior art disclosures by Applicant, it is
`
`necessary to look to the prosecution of parent U.S. No. 8,598,149 (U.S. Application
`
`12/199,114) for any useful or substantive analysis. (Ex. 1003)
`
`U.S. Patent No. 8,598,149 issued from U.S. Application 12/199,114,
`
`(hereafter “the ‘114 application”) filed on August 27, 2008 and claims priority to
`
`Provisional Application 60/969,027 filed on August 30, 2007. The ‘114 application
`
`was filed with 8 original claims. On March 31, 2011, the U.S. Patent and Trademark
`
`Office (the “PTO” or “Office”) requested restriction to either Group I (original
`
`claims 1-7) or Group II (original claim 8), and the Applicant then elected Group I
`
`with traverse. (Ex. 1003 at 170)
`
`On August 3, 2011, the Office issued a Non-Final Rejection of all claims as
`
`being unpatentable under 35 U.S.C. § 103(a) as obvious over the “Medical
`
`Encyclopedia of Medline” in view of U.S. 6,964,953 to Belanoff (“Belanoff ‘953”)
`
`and Sarkar, European Journal of Obstetrics and Gynecology and Reproductive
`
`Biology, 2002; 101:113-120 – these were the only three references cited during
`
`prosecution of either the ‘348 Patent or its parent, identified initially by the
`
`Examiner. The Examiner argued it was well known that “a certain level of drug is
`
`needed in the blood stream to obtain the desired therapeutic effect,” citing to the
`
`Medical Encyclopedia. The Examiner then correctly asserted that Belanoff ‘953
`
`7
`
`

`

`U.S. Patent No. 8,921,348
`
`teaches mifepristone as useful in treating stress disorders and that Sarkar teaches the
`
`serum concentrations of mifepristone at various dosage levels, including the claimed
`
`target level of 1300 ng/mL. The Examiner stated
`
`It would have been obvious to one of ordinary skill in the
`art at the time the invention was made to optimize the
`serum level of mifepristone in patients suffering from
`Acute Stress Disorder.
`
`One of ordinary skill in the art would have been motivated
`to optimize the serum level of mifepristone in patients
`suffering from Acute Stress Disorder. Adjusting the
`therapeutic serum levels to obtain a therapeutic effect is
`well-known in the art. Since both the serum concentration
`and the dosage of mifepristone useful in treating the Acute
`Stress Disorder are both well-known. [sic] Adjusting the
`serum level of mifepristone would be seen as equivalent
`to adjusting the dosage of mifepristone to effectively treat
`Acute Stress Disorder would be reasonably expected to be
`successful. [sic]
`
`
`(Ex. 1003 at 163-64 (emphasis added))
`
`In response, Applicant proffered two primary arguments to attempt to
`
`overcome
`
`the
`
`rejection: 1)
`
`that mifepristone exhibits “nonlinear serum
`
`pharmacokinetics” and 2) that it is “unpredictable what mifepristone serum
`
`concentrations would provide an effective treatment for a variety of mental
`
`disorders”. (Ex. 1003 at 145-47)
`
`Subsequently, the Office issued a Final Rejection reiterating that all claims,
`
`notwithstanding the arguments by Applicant, remained unpatentable over the
`
`Medical Encyclopedia in view of Belanoff ‘953 and Sarkar. The Examiner stated
`
`8
`
`

`

`U.S. Patent No. 8,921,348
`
`it is well-known that mifepristone and the serum level are
`positively correlated, i.e., increasing the dose will increase
`the serum level. Therefore, one of ordinary skill in the art
`would readily see that adjusting the serum level is
`essentially
`the same as adjusting
`the dosage of
`mifepristone. Since the dosages of mifepristone for
`treating various disorders are known and the common
`dosage are corresponding to the serum level of more than
`1300ng/ml,
`regardless of
`the pharmacokinetics of
`mifepristone, one of ordinary skill in the art would have
`been motivated to employ the herein claimed dosages of
`mifepristone, and thereby achieve the serum levels of
`mifepristone to be more than 1300ng/ml. No claims are
`allowed.
`
`(Ex. 1003 at 135-136)
`
`In response, Applicant argued 1) “Historical mifepristone serum levels are not
`
`comparable to the claimed mifepristone serum level because radioimmunoassay
`
`detection methods cannot distinguish mifepristone from its metabolites” (Ex. 1003
`
`at 63-64 (emphasis added)) In other words, Applicant argued that the inherent
`
`mifepristone pharmacokinetics were not known in the prior art because of poor
`
`instrumentation, hence Applicant should be allowed to lay claim to those properties
`
`in the application that eventually became the ‘149 patent. In essence, Applicant
`
`argued that monitoring the claimed levels of mifepristone was not possible at the
`
`time of filing because the prior art relied upon by the Examiner used a methodology
`
`of detecting mifepristone that was imprecise. (Id.)
`
`Applicant argued the
`
`9
`
`

`

`U.S. Patent No. 8,921,348
`
`Office points to [Belanoff ‘953] describing use of mifepristone for the
`treatment of acute stress disorder where mifepristone can be
`administered at 1 to 10 mg/kg, corresponding to 75 to 750 mg for an
`adult of 75 kg, for 30 days. The Office then relies on the teachings of
`Sarkar to allege that the doses used in [Belanoff ‘953] would produce
`serum concentrations of at least the claimed 1300 ng/ml.
`
`
`(Id.)
`
`However, Applicant continued, “the method for detecting mifepristone would
`
`be unable to distinguish between mifepristone and its metabolites, thus providing
`
`serum levels that overestimate the mifepristone serum level.”3 (Ex. 1003 at 68)
`
`Applicant concluded by saying
`
`In view of the inability of RIA and RRA detection
`methods to distinguish mifepristone from its metabolites,
`especially in view of the rapid mifepristone metabolism
`and high serum levels of mifepristone metabolites, there is
`no reasonable expectation of success for identifying 1300
`ng/ml as the serum level of mifepristone only necessary to
`treat a patient suffering from a mental disorder amenable
`to treatment by mifepristone.
`
`(Ex. 1003 at 68)
`
`This is not true. The arguments that Applicant proffered to rebut the assertions
`
`of the Examiner for the ‘114 application were based on partial and incomplete
`
`information of what was known in the prior art at the time of the invention. (Ex.
`
`
`The Examiner had stated “For medium dose (100-200 mg of mifepristone),
`3
`the serum concentration can reach to 4.5 and 5.4 umol/1 (1933.2 ng/ml to 2276.88
`ng/ml). For a higher dose (400-600 mg), the serum concentration gets even
`higher.” (Ex. 1003 at 135)
`
`10
`
`

`

`U.S. Patent No. 8,921,348
`
`1004 at ¶6) The Examiner either overlooked or was not aware of prior art that would
`
`have supported the Examiner’s original contentions that the method for monitoring
`
`mifepristone serum levels would have been readily obvious to one of ordinary skill
`
`in the art since techniques to “distinguish mifepristone from its metabolites” were,
`
`in fact, very well known in the art and widely used at the time of the filing. (Id.)
`
`(See Section VIII, infra, discussing the state of the art.)
`
`Moreover, Applicant’s arguments to the Examiner concerning methods for
`
`detecting mifepristone were directly contrary to the disclosure of the ‘348 Patent,
`
`namely “Mifepristone levels can be determined by any method known in the art.
`
`Methods for detecting mifepristone levels include, but are not limited to, radio-
`
`immuno assay and mass spectrometry….” (Ex. 1001 at col. 11:62-66)
`
`On August 2, 2013, the Office issued a Notice of Allowance for all of
`
`remaining claims 1-7. In the reason for allowance, the Examiner stated:
`
`The method of using mifepristone level for adjusting the
`treatment of mental disorder is not taught or fairly
`suggested by the prior art. Although effective dosages of
`mifepristone for treating mental disorders are known, the
`correlation of the level of mifepristone to the therapeutic
`effectiveness of mifepristone in treating such disorders is
`not known.
`
`(Ex. 1003 at 34)
`
`Notwithstanding the fact that Applicant furnished six non-patent documents
`
`to support the rebuttal for rejection of all the claims, the same anemic number of
`
`11
`
`

`

`U.S. Patent No. 8,921,348
`
`prior art documents were disclosed during the prosecution of the ‘114 application as
`
`in the ‘348 Patent application. There was a plethora of prior art and information
`
`available on the dosing and pharmacokinetics of mifepristone as of the time of the
`
`filing of the ‘348 Patent application, only a miniscule fraction of which was
`
`disclosed with candor to the USPTO during examination.
`
`VI. Level of Skill in the Art
`The level of skill in the art is apparent from the cited art. Further, a person
`
`having ordinary skill in the art (“POSA”) would have either a Pharm. D. or a Ph.D.
`
`in organic chemistry, pharmacy, pharmacology, or a related discipline; or a
`
`Bachelor’s or Master’s degree in organic chemistry or a related field with at least
`
`four years of experience relating to the study of pharmacokinetics or dosing of drugs,
`
`their detection and quantification, or their metabolism. A POSA may have
`
`collaborated with others having expertise in, for example, methods of treating
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`diseases and administering medicines. (Ex. 1004 at ¶5)
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`VII. Claim Construction
`In inter partes review, a claim term is given its “broadest reasonable
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`construction in light of the specification.” See 37 C.F.R. § 42.100(b); see also
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`Cuozzo Speed Technologies, LLC v. Lee, 579 U. S. ____ (2016). Unless otherwise
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`specified, all terms are to be given their broadest reasonable interpretation as well as
`
`their normal and customary meaning.
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`12
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`U.S. Patent No. 8,921,348
`
`a. “mifepristone”
`
`Mifepristone
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`is
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`11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-
`
`propynyl)-estra-4, 9-dien-3-one and is also known at least as RU-486. (Ex. 1001
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`col. 4:6-11; Ex. 1004 at ¶4; see also U.S. Patent No. 6,150,349 to Schatzberg and
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`Belanoff (Ex. 1021 col 5:13-36) and National Center for Biotechnology Information.
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`PubChem Entry: Compound Summary for CID 55245 (Ex. 1022) for other generally
`
`accepted names and terms.) Mifepristone is the active ingredient in Corcept’s
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`Korlym product (previously referred to as Corlux). (Ex. 1004 at ¶4; Ex. 1032)
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`b. “optimizing levels of mifepristone”
`The ‘348 Patent describes the term “optimizing” as referring “to the process
`
`of testing mifepristone blood levels and adjusting the dosage … in order to achieve”
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`a stated mifepristone level. (Ex. 1001 col 5:53-56) The term “optimizing levels of
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`mifepristone” should mean, in the broadest reasonable interpretation, “a method or
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`process of making the level of mifepristone in blood as functional or effective as
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`possible”. (Ex. 1004 at ¶13)
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`c. “adjusting the daily dose of the patient”
`The ‘348 specifications describe “adjusting” as “increasing the daily dose
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`of the patient to achieve mifepristone blood levels greater than 1300 ng/mL.” (Ex.
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`1001 col 1:65-67). Under the broadest reasonable interpretation of the claim, the
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`term “adjusting the daily dose of the patient” should be construed to mean
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`13
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`U.S. Patent No. 8,921,348
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`“changing the daily dose of the patient.”4 (Ex. 1004 at ¶10)
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`d. “a plasma sampling collection device suitable
`mifepristone serum levels”
`
`for detecting
`
`The ‘348 specification does not define this term, nor does it describe “a
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`plasma sampling collection device”. It does describe “plasma collection devices” as
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`those well known in clinical labs, such as “vacutainers” (Ex. 1004 at ¶11): “Patient
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`plasma can be collected by any known plasma collection device. Some plasma
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`collection devices useful in the present invention include, but are not limited to,
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`vacutainers.” (Ex. 1001 col. 12:32-35; underline added) The specification goes on
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`to list additives that help in blood collection that may be further comprised in the
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`vacutainers (e.g. heparin, sodium citrate, etc.). (Id. col. 12: 35-40)
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`However, “vacutainers” are not “suitable for detecting mifepristone serum
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`levels.” 5 (Ex. 1004 at ¶12 emphasis added) Such a “suitable” device “for detecting
`
`
`4 It will be noted that Claim 7 of the ‘348 patent is directed to the “method of claim
`1, wherein the adjusting step comprises increasing the daily dose . . .” By comparing
`claim 7 to claim 1 using the well-established doctrine of claim differentiation,
`Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005), it is clear that claim 1
`encompasses methods wherein the adjustment step does not necessarily comprise
`“increasing” the dose alone, and may therefore also comprise “decreasing” the dose
`for purposes of “optimizing levels of mifepristone”. The term “adjusting the daily
`dose”, as used in the ‘348 specification, may mean either increasing or decreasing
`the daily dose to achieve mifepristone blood levels greater than 1300 ng/mL. (Ex.
`1004 at 10)
`5
`In every example in the ‘348 specification, the device that is used to collect
`the plasma (e.g., vacutainer) is different than the device used to detect the
`mifepristone level. (Ex. 1004 at 11)
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`14
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`U.S. Patent No. 8,921,348
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`mifepristone” is one that is capable of actually sensing or identifying mifepristone
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`in a serum sample. (Ex. 1001 at cols. 10:63-12:10; Ex. 1004 at ¶12) A “vacutainer”
`
`is only a blood collection device, not a device for sensing or detecting components
`
`in blood. (Ex. 1004 at ¶12) Accordingly “a plasma sampling collection device
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`suitable for detecting mifepristone serum levels” must be a device capable of
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`identifying or revealing mifepristone in a blood serum sample. Such devices include
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`instruments like mass spectrometers and those useful in thin layer chromatography
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`or column chromatography such as high pressure liquid chromatography (HPLC).
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`(Id.) The ‘348 specification explains mifepristone levels “can be determined by any
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`method known in the art. Methods for detecting mifepristone levels include, but are
`
`not limited to, radio-immuno assay and mass spectrometry.” (Ex. 1001 at col. 11:62-
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`66)
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`VIII. State of the Art at the Time of Filing of the ‘348 Patent
`The ‘348 Patent claims a method of adjusting the dosage of mifepristone in
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`order to achieve a target blood serum concentration of the drug. Mifepristone is also
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`known as RU-486 and is active ingredient in the so-called “early option” birth
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`control pill marketed as Mifeprex. (Ex. 1004 at ¶4) Mifepristone was first
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`synthesized in April 1980 by the French pharmaceutical company Roussel-Uclaf and
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`discovered to be a progesterone receptor antagonist. In October of 1981, it was first
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`tested for use as a medical abortifacient. Clinical trials were undertaken in over
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`15
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`

`U.S. Patent No. 8,921,348
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`20,000 test subjects and the drug was approved for such use in France on September
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`23, 1988. In the United States, clinical trials were later undertaken and approval as
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`an abortifacient was granted by the FDA in September 2000. In 2012, the drug
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`received FDA approval to treat the orphan malady of Cushing’s disease, which
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`affects about 20,000 patients in the United States. (Id.)
`
`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. (Ex. 1004 at ¶8) Dosing
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`from ranges of less than a milligram to 1200 mg daily or more had been investigated
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`and studied in both single dose administrations and prolonged administrations for
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`years prior to the filing of the ‘348 Patent application. (Id.)
`
`For example, Sitruk-Ware discloses that
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`[f]ollowing single-dose administration of mifepristone
`(600 mg), to healthy female volunteers, mean maximum
`plasma concentrations were about 2.0 mg/L [2000 ng/mL]
`at 1.35 h (tmax). After oral ingestion, mifepristone is rapidly
`absorbed, and the time to peak serum concentration (tmax)
`is approximately 1–2 h (Table 1). When analyzed by
`specific RIA or HPLC, tmax is similar within the dose range
`of 200–600 mg.
`
`(Ex. 1008 at p. 413)
`
`Because the mean plasma concentration discussed in Sitruk-Ware of 2.0 mg/mL
`
`[2000 ng/mL] follows a single 600 mg dose of mifepristone, this demonstrates that
`
`the ‘348 Patent’s target leve