Trials@uspto.gov
`571.272.7822
`
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`
`
`
`
`
` Paper No. 11
`
` Entered: February 15, 2019
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`NEPTUNE GENERICS, LLC
`Petitioner,
`v.
`CORCEPT THERAPEUTICS, INC.
`Patent Owner.
`____________
`
`Case IPR2018-01494
`Patent 8,921,348 B2
`____________
`
`
`Before CHRISTOPHER G. PAULRAJ, ROBERT A. POLLOCK, and
`DAVID COTTA, Administrative Patent Judges.
`
`COTTA, Administrative Patent Judge.
`
`
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`
`

`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
` INTRODUCTION
`Neptune Generics, LLC (“Petitioner” or “Neptune”) filed a Petition
`requesting an inter partes review of claims 1–7 of U.S. Patent No. 8,921,348
`B2 (Ex. 1001, “the ’358 patent”).1 Paper 1 (“Pet.”). Corcept Therapeutics,
`Inc. (“Patent Owner” or “Corcept”) filed a Preliminary Response to the
`Petition. Paper 9 (Prelim. Resp.).2
`Institution of an inter partes review is authorized by statute only when
`“the information presented in the petition . . . and any response . . . shows
`that there is a reasonable likelihood that the petitioner would prevail with
`respect to at least 1 of the claims challenged in the petition.” 35 U.S.C.
`§ 314; see 37 C.F.R. §§ 42.4, 42.108. Upon considering the Petition, the
`Preliminary Response, and the cited evidence, we conclude that Petitioner
`has satisfied the burden under 35 U.S.C. § 314(a) to show that there is a
`reasonable likelihood that it would prevail with respect to at least one of the
`challenged claims.
`
`Related Proceedings
`A.
`Petitioner represents that it is unaware of any other matters related to
`the ’348 patent. Patent Owner identifies Corcept Therapeutics, Inc. v. Teva
`Pharmaceuticals USA, Inc., No. 18-cv-03632-SDW (D.N.J. Mar. 15, 2018)
`as relating to the ’348 patent. Paper 4, 1.
`The ’348 Patent (Ex. 1001)
`B.
`The ’348 patent issued December 30, 2014, identifying Joseph K.
`Belanoff as the inventor. Ex. 1001. The patent discloses “a method for
`
`
`1 Petitioner identifies Neptune Generics, LLC as the real party in interest.
`Pet. 1.
`2 Patent Owner identifies Corcept Therapeutics, Inc. as the real party in
`interest. Paper 4, 1.
`
`2
`
`

`

`IPR2018-01494
`Patent 8,921,348 B2
`
`optimizing levels of mifepristone in a patient suffering from a mental
`disorder amenable to treatment by mifepristone.” Id. at Abstract.
`
`The ’348 patent teaches that “[i]t has surprisingly been discovered that
`administration of the same dose of mifepristone can produce widely varying
`blood serum levels in different patients,” which can result in “some patients
`not receiving an efficacious dose of mifepristone.” Id. at 1:28–32. “[T]he
`blood serum levels can differ by as much as 800% from one patient to
`another. Thus a method for ensuring that blood serum levels of mifepristone
`remain in an efficacious and safe range is needed.” Id. at 1:33–36.
`
`According to the ’348 patent, the disclosed invention provides a
`method for optimizing mifepristone levels by treating the patient and then
`“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.”
`Id. at 1:40–49.
`
`Challenged Claims
`C.
`Petitioner challenges claims 1–7 of the ’348 patent. Claim 1 is
`representative and is reproduced below:
`
`A method for optimizing levels of mifepristone in a patient
`1.
`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.
`Ex. 1001, 16:26–35.
`
`3
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`IPR2018-01494
`Patent 8,921,348 B2
`
`
`D. The Prosecution History
`We provide a discussion of the prosecution history of the ’348 patent
`for context given that one of the prior art references asserted in this
`proceeding (Belanoff ‘9533) was cited by the Examiner during prosecution.
`The application that issued as the ’348 patent (Application
`No. 14/065,792), was filed on October 29, 2013 with 8 original claims.
`Ex. 1002, 142. During prosecution, the Examiner entered an obviousness-
`type double patenting rejection. Id. at 45–48. Patent Owner overcame this
`rejection by filing a terminal disclaimer. Id. at 20–32. No other rejections
`were entered.
`The application that issued as the ’348 patent was a continuation of
`Application No. 12/199,144 (“the ’144 application”), which has now issued
`as US Patent 8,598,149. The claims at issue in this application are very
`similar to those in the issued ’348 patent.4 Accordingly, the ’144 patent is
`informative as to the reasons why the Examiner allowed the ’348 patent.
`
`
`3 Belanoff, US Patent No. 9,964,953, issued Nov. 15, 2005 (Ex. 1010,
`“Belanoff ’953”).
`4 Claim 1 of the ’144 application, as originally filed, reads as follows:
`A method for optimizing levels of mifepristone in a patient
`1.
`suffering from a mental 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.
`Ex. 1003, 233 (emphasis added to reflect differences as compared to claim 1
`of the ’348 patent).
`
`4
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`IPR2018-01494
`Patent 8,921,348 B2
`
`
`In an Office Action mailed August 3, 2011, the Examiner rejected the
`pending claims of the ’144 application as obvious under 35 U.S.C. § 103(a)
`over the combination of the Medical Encyclopedia of Medline,5 Sarkar,6 and
`Belanoff ’953. The Examiner found that the Medical Encyclopedia of
`Medline taught that “[t]herapeutic drug levels are usually performed to look
`for the presence and the amount of specific drug in the blood” and that
`“[w]ith most medications, a certain level of drug is needed in the blood
`stream to obtain the desired therapeutic effect.” Ex. 1003, 163. The
`Examiner found that Belanoff ’953 disclosed that mifepristone was useful
`for treating acute stress disorder and taught dosages of 1 to 10 mg/kg, which
`translates to 75–750 mg for an average adult weighing 75 kg. Id. The
`Examiner found that Sarkar taught that serum concentrations for a 100–200
`mg dose of mifepristone ranged from 1933.2–2276.88 ng/ml. Id.
`Based on the combination of the Medical Encyclopedia, Sarkar, and
`Belanoff ’953, the Examiner concluded that “[i]t 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 mefipristone [sic] in patients suffering from
`Acute Stress Disorder.” Id. The Examiner explained:
`One of ordinary skill in the art would have been motivated to
`optimize the serum level of mefipristone [sic] 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
`
`5 U.S. National Library of Medicine, Medical Encyclopedia: Therapeutic
`Drug Levels, http://www.nlm.nih.gov/medlineplus/ency/article/003430.htm,
`(“Medical Encyclopedia of Medline”).
`6 Sarkar, Mifepristone: Bioavailability, Pharmacokinetics, and Use-
`Effectiveness, 101(2) European Journal of Obstetrics and Gynecology and
`Reproductive Biology, 113-120 (2002) (“Sarkar”).
`5
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`both well-known. Adjusting the serum level of mifepristone
`would be seen as equivalent to adjusting the dosage of
`mifepristone to effectively treat Acute Stress Disorder [and]
`would be reasonably expected to be successful.
`Id. at 163–164.
`
`In response to the August 3, 2011 Office Action, Patent Owner argued
`that the claimed method was non-obvious because mifepristone exhibits
`nonlinear serum pharmacokinetics in humans and thus it was “unpredictable
`what mifepristone serum concentration would provide an effective treatment
`for mental disorders.” Id. at 146; see also generally id. at 145–148. In an
`April 4, 2012, Office Action, the Examiner rejected these arguments
`explaining that it was “well-known that mifepristone [dose] and the serum
`level are positively correlated, i.e., increasing the dose will increase the
`serum level.” Id. at 135–136.
`
`In response to the April 4, 2012, Office Action, Patent Owner argued
`that the data the Examiner relied upon to correlate mifepristone dosage with
`serum levels was unreliable because it “was obtained using a
`radioimmunoassay, which is unable to distinguish between mifepristone and
`mifepristone’s metabolites.” Id. at 64. According to Patent Owner, this
`contrasts with what was disclosed in the ’144 application, which was to
`measure mifepristone serum levels using “High Pressure Liquid
`Chromatography (HPLC) methods capable of separating mifepristone from
`its metabolites and accurately measuring mifepristone serum levels.” Id. at
`65. Patent Owner thus argued that “[i]n view of the inability of RIA and
`RRA detection methods to distinguish mifepristone from its 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.” Id. at 68.
`
`6
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`IPR2018-01494
`Patent 8,921,348 B2
`
`In a May 24, 2013 Office Action, the Examiner indicated that Patent
`
`Owner’s arguments were persuasive. The Examiner stated:
`The method of using the mifepristone level for adjusting the
`treatment of mental disorder is not taught or fairly suggested by
`the prior art. Although the effective dosages of mifepristone for
`treating mental disorders are known, the correlation of the level
`of mifepristone to the therapeutic effectiveness of mifepristone
`is not known.
`Id. at 52; see also id. at 34 (Notice of Allowability).
`D. The Asserted Ground of Unpatentability
`Petitioner challenges the patentability of claims 1‒7 of the ’348 patent
`on the following grounds:7
`Ground References
`
`Basis
`
`Claims
`Challenged
`§ 103(a) 1, 2, 4, 6, and 7
`§ 103(a) 1, 2, 4, 6, and 7
`
`1
`2
`
`3
`
`§ 103(a) 3
`
`Belanoff ’8488
`Belanoff 2002, Sitruk-Ware,9
`and Chu and Belanoff10
`Belanoff 2002, Sitruk-Ware,
`Chu and Belanoff, and Belanoff
`’953
`
`7 Petitioner numbers the grounds differently in different parts of the Petition.
`Compare Pet. 25 with Pet. 42, 43, 45, and 46. We have numbered the
`grounds in a manner consistent with the headings used in the Petition. See,
`Pet. 42, 43, 45, and 46. For convenience and consistency, the parties are
`encouraged to use this numbering going forward when referencing the
`grounds.
`8 Belanoff, US Patent Publication No. 2004/0029848 A1, published
`Feb. 12, 2004 (Ex. 1024, “Belanoff ’848”).
`9 Sitruk-Ware et al., Pharmacological Properties of Mifepristone:
`Toxicology and Safety in Animal and Human Studies, 68 Contraception 409–
`420 (2003) (Ex. 1008, “Sitruk-Ware”).
`10 Chu et al., Successful Long-Term Treatment of Refractory Cushing’s
`Disease with High-Dose Mifepristone (RU 486), 86(8) Journal of Clinical
`Endocrinology & Metabolism 3568–3573 (2001) (Ex. 1023, “Chu and
`Belanoff”).
`
`7
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`Ground References
`
`Basis
`
`Claims
`Challenged
`§ 103(a) 5
`
`4
`
`5
`6
`
`Belanoff 2002, Sitruk-Ware,
`Chu and Belanoff, and Murphy11
`Belanoff ’848 and Belanoff ’953 § 103(a) 3
`Belanoff ’848 and Murphy
`§ 103(a) 5
`
`Petitioner submits the Declaration of Dr. Mikko A. Oskari
`Heikinheimo (Ex. 1004) in support of institution of inter partes review.
`
` ANALYSIS
`Person of Ordinary Skill in the Art
`A.
`Factual indicators of the level of ordinary skill in the art include “the
`various prior art approaches employed, the types of problems encountered in
`the art, the rapidity with which innovations are made, the sophistication of
`the technology involved, and the educational background of those actively
`working in the field.” Jacobson Bros., Inc. v. U.S., 512 F.2d 1065, 1071 (Ct.
`Cl. 1975); see also Orthopedic Equip. Co., v. U.S., 702 F.2d 1005, 1011
`(Fed. Cir. 1983) (quoting with approval Jacobson Bros.).
`Petitioner contends that the person of ordinary skill 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.” Pet. 12.
`
`
`11 Murphy et al., Possible Use of Glucocorticoid Receptor Agonists in the
`Treatment of Major Depression: Preliminary Results Using RU 486, 18(5)
`J. Psychiatr. Neurosci. 209–213 (1993) (Ex. 1006, “Murphy”).
`8
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`

`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`At this stage in the proceeding, Patent Owner does not challenge
`Petitioner’s definition. Prelim. Resp. 18 (“Patent Owner does not believe it
`is necessary to address at this time Petitioner’s proffered level of ordinary
`skill in the art for the limited purpose of this Preliminary Response.”).
`Accordingly, for purposes of this Decision and based on the present record,
`we accept Petitioner’s definition, which is consistent with the level of skill
`reflected in the asserted prior art references. See Okajima v. Bourdeau, 261
`F.3d 1350, 1355 (Fed. Cir. 2001) (the prior art itself can reflect the
`appropriate level of ordinary skill in the art).
`Claim Construction
`B.
`We interpret claims of an unexpired patent using the “broadest
`reasonable construction in light of the specification of the patent in which
`[they] appear[].” 37 C.F.R. § 42.100(b); see also Cuozzo Speed Techs., LLC
`v. Lee, 136 S. Ct. 2131, 2144–46 (2016).12 Under the broadest reasonable
`construction standard, claim terms are generally given their ordinary and
`customary meaning as would be understood by one of ordinary skill in the
`art at the time of the invention. In re Translogic Tech., Inc., 504 F.3d 1249,
`1257 (Fed. Cir. 2007). “Absent claim language carrying a narrow meaning,
`the PTO should only limit the claim based on the specification . . . when [it]
`expressly disclaim[s] the broader definition.” In re Bigio, 381 F.3d 1320,
`1325 (Fed. Cir. 2004).
`
`
`12 The broadest reasonable interpretation (“BRI”) construction standard
`applies to inter partes reviews filed before November 13, 2018. 77 Fed.
`Reg. 48727 (Aug. 14, 2012) (codified at 37 C.F.R. § 42.100(b)), as amended
`at 81 Fed. Reg. 18766 (Apr. 1, 2016); see also 83 Fed. Reg. 51340 (Oct. 11,
`2018) (changing the standard for interpreting claims in inter partes reviews
`filed on or after November 13, 2018). Because the Petition was filed prior to
`this date, on August 2, 2018, the BRI construction standard applies.
`9
`
`

`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`Although Petitioner offers several claim constructions (Pet. 12–15), at
`this stage of the proceeding, we determine that no explicit construction of
`any claim term is necessary to determine whether to institute a trial in this
`case. See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd.,
`868 F.3d 1013, 1017 (Fed. Cir. 2017) (“[W]e need only construe terms ‘that
`are in controversy, and only to the extent necessary to resolve the
`controversy’” (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d
`795, 803 (Fed. Cir. 1999))); Wellman, Inc. v. Eastman Chem. Co., 642 F.3d
`1355, 1361 (Fed. Cir. 2011) (“[C]laim terms need only be construed ‘to the
`extent necessary to resolve the controversy’”).
`C. Ground 2: Obviousness of claims 1, 2, 4, 6, and 7 over Belanoff 2002,
`Chu and Belanoff, and Sitruk-Ware
`
`
`
`Petitioner asserts that claims 1, 2, 4, 6, and 7 are rendered obvious by
`the combination of Belanoff 2002, Chu and Belanoff, and Sitruk-Ware.
`Pet. 32–42. We have reviewed Petitioner’s and Patent Owner’s assertions,
`as well as the evidence of record, and, for the reasons discussed below, we
`conclude that Petitioner has demonstrated a reasonable likelihood of
`prevailing in showing that claims 1, 2, 4, 6, and 7 would have been obvious
`over the combination of Belanoff 2002, Chu and Belanoff, and Sitruk-Ware.
`Disclosures of the Asserted Prior Art
`i.
`
`Belanoff 2002
`
`Belanoff 2002 discloses an open label trial of mifepristone in which
`thirty patients with psychotic major depression (“PMD”) received 50 mg,
`600 mg or 1200 mg of mifepristone administered once daily for 7 days.
`Ex. 1007, 1, 3. Belanoff 2002 reports that “nearly two thirds of the subjects
`showed significant reductions in the psychosis in a week or less.” Id. at 4–5.
`
`10
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`Chu and Belanoff
`
`Chu and Belanoff disclose the treatment of a patient with Cushing’s
`syndrome (“CS”) with high-dose long-term mifepristone therapy. Ex. 1023,
`2. Chu and Belanoff teach that the dosage of the patient was adjusted over
`the course of treatment. Id. at 4. Thus, the patient “was initiated on
`mifepristone at 400 mg/d ( ̴ 6 mg/kg•d).” Id. “During the initial 8 months
`of mifepristone treatment, the dose was gradually increased to a maximum
`of 2000 mg/d ( ̴ 25 mg/kg•d) in response to continued signs of
`hypercortisolism.” Id. “[C]linical findings attributable to CS slowly
`improved, and the mifepristone dosage was titrated downward over the
`following 10 months.” Id.
`Sitruk-Ware
`Sitruk-Ware discloses:
`Following single-dose administration of mifepristone (600 mg),
`to healthy female volunteers, mean maximum plasma
`concentrations were about 2.0 mg/L 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 [radioimmunoassay] or HPLC
`[high-performance liquid chromatography], tmax is similar
`within the dose range of 200–600 mg. Peak drug plasma
`concentration (Cmax) rises according to the dose of mifepristone
`within the dose range of 2–25 mg.
`Ex.1008, 6–7.
`
`
`
`
`11
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`ii. Analysis
`
`Claim 1
`
`1.
`
`“A method for optimizing levels of mifepristone in a
`patient suffering from a disorder amenable to treatment by
`mifepristone”
`The preamble to claim 1 recites a “method for optimizing levels of
`mifepristone in a patient suffering from a disorder amenable to treatment by
`mifepristone.” Neither Petitioner nor Patent Owner presents argument as to
`whether the preamble limits claim 1. Instead, Petitioner argues that the
`optimization recited in the preamble is “a direct result of the performance of
`the three steps included in claim 1.” Pet. 34. Petitioner asserts that Belanoff
`2002 discloses treatment of a “disorder amenable to treatment by
`mifepristone” – i.e., PMD – and that “optimizing levels of a drug to treat a
`patient” was “standard practice” and “routine.” Id. at 33–34.
`Other than identifying the patient population to which the subsequent
`method steps are applied (i.e., “a patient suffering from a disorder amenable
`to treatment by mifepristone”), we determine that the preamble does not add
`any material limitations to the claim. We find, based on the present record,
`that Belanoff 2002 teaches the required patient population. We further agree
`with Petitioner that the optimization recited in the preamble merely requires
`performance of the three steps recited in the body of claim 1. Accordingly,
`for purposes of institution, we do not conduct a separate analysis to
`determine whether the optimization recited in the preamble is satisfied by
`the prior art, and instead confine our analysis to the subsequent claim steps.
`
`
`
`12
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`2.
`
`“treating the patient with seven or more daily doses of
`mifepristone over a period of seven or more days”
`The first step of claim 1 requires “treating the patient with seven or
`more daily doses of mifepristone over a period of seven or more days.”
`Petitioner asserts that this limitation is disclosed in Belanoff 2002’s teaching
`that 30 patients with PMD were treated with once daily doses of 50 mg, 600
`mg, or 1200 mg of mifepristone for seven days. Pet. 34. Patent Owner’s
`Preliminary Response does not contest that Belanoff 2002 discloses this
`limitation. We find that, for purposes of institution, the current record tends
`to support Petitioner’s contention that Belanoff 2002 discloses this
`limitation. See Ex. 1007, 3 and Abstract.
`
`3.
`
`“testing the serum levels of the patient to determine
`whether the blood levels of mifepristone are greater than
`1300 ng/mL”
`The second step of claim 1 requires “testing the serum levels of the
`
`patient to determine whether the blood levels of mifepristone are greater
`than 1300 ng/mL.” Petitioner concedes that Belanoff 2002 does not disclose
`this element, but contends that testing of patient serum levels was “routine”
`and that it would have been obvious to measure serum levels “in order to
`correlate those levels to an effective does of the drug as a standard drug
`development protocol.” Pet. 35 (citing Ex. 1004, ¶ 14).
`Patent Owner contends that Petitioner relies on the Declaration of
`Dr. Heikinheimo to support this proposition and that Dr. Heikinheimo’s
`Declaration is “devoid of factual support” and thus “should be accorded no
`weight.” Prelim. Resp. 35–36.
`Notwithstanding Patent Owner’s concern that Dr. Heikinheimo does
`not identify any evidentiary basis for his opinion, we find that the record
`
`13
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`IPR2018-01494
`Patent 8,921,348 B2
`
`includes evidence consistent with Dr. Heikinheimo’s testimony that it would
`have been obvious to measure blood serum levels of mifepristone in order to
`determine optimal dosing. See Ex. 1004 (¶¶ 16–18) (identifying evidentiary
`support for opinion that skilled artisan would have monitored serum
`mifestrone levels); see also Ex. 1008, 6 (describing testing of blood serum
`levels following administration of mifepristone); Ex, 1024, ¶ 41 (“Because a
`patient’s metabolism, clearance rate, toxicity levels, etc. differs with
`variations in underlying primary or secondary disease conditions, drug
`history, age, general medical condition and the like, it may be necessary to
`measure blood and urine levels of GR antagonist. Means for such
`monitoring are well described in the scientific and patent literature.”);
`Ex. 1003, 134 (Office Action in parent application in which the Examiner
`noted that the Medical Encyclopedia of Medline teaches that “[t]herapeutic
`drug levels are usually performed to look for the presence and the amount of
`specific drug in the blood. With most medications, a certain level of drug is
`needed in the blood stream to obtain the desired therapeutic effect.”). Thus,
`at this stage in the proceeding, we find that the current record tends to
`support Petitioner’s contention that it would have been obvious to determine
`blood levels of mifepristone.
`
`With respect to the “greater than 1300 ng/mL” threshold recited in
`claim 1, Petitioner contends that Belanoff 2002 teaches that a daily dose of
`600 mg/day is efficacious and that Sitruk-Ware teaches that a single dose of
`600 mg rapidly results in serum levels of 2000 ng/mL. Pet. 36. Petitioner
`asserts that in view of this knowledge, it would have been obvious “to
`determine if blood levels of mifepristone were greater than 1300 ng/mL
`
`14
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`Patent 8,921,348 B2
`
`since it was known that such dosages were efficacious in the treatment of
`stress disorders.” Id. at 36–37, citing Ex. 1004, ¶ 19.
`Patent Owner argues that “none of the references teach or disclose the
`efficacious 1300 ng/mL serum level.” Prelim. Resp. 33. We are not
`persuaded. Patent Owner cannot demonstrate the non-obviousness of the
`claimed method by attacking the prior art references individually. See, In re
`Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (“Non-obviousness
`cannot be established by attacking references individually where the
`rejection is based upon the teachings of a combination of references.”).
`Here, the doses that Belanoff 2002 teaches are efficacious for treating
`patients with PMD (600 and 1200 mg/day) are described in Sitruk-Ware as
`producing a mean serum concentration of “greater than 1300 ng/mL.”
`Ex. 1007, 4–5 (“In the higher dose groups (600 mg and 1200 mg), nearly
`two thirds of the subjects showed significant reductions in their psychosis in
`a week or less”); Ex. 1008, 6 (“Following single-dose administration of
`mifepristone (600 mg), to healthy female volunteers, mean maximum
`plasma concentrations were about 2.0 mg/L at 1.35 h (tmax).”). We find that,
`for purposes of institution, the current record tends to support Petitioner’s
`contention that the combination of Belanoff 2002 and Sitruk-Ware discloses
`1300 ng/mL as an efficacious serum level.
`
`Patent Owner argues that Petitioner fails to provide a reasoned
`explanation “why a POSA would understand a dosage range of 600–1200
`mg or any of the various dosages within that range to correlate with a
`specific serum level, particularly in view of the nonlinear relationship
`between dose and serum level, and the unpredictability in the art as further
`discussed in Section IX.” Prelim. Resp. 37–38. With respect to the alleged
`
`15
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`IPR2018-01494
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`unpredictability in the art discussed in Section IX of the Preliminary
`Response, Patent Owner asserts that “mifepristone exhibits non-linear
`pharmacokinetics such that the same dose of mifepristone can produce
`widely varying blood serum levels in different patients—differing by as
`much as 800% from one patient to another.” Id. at 42–43; see also id. at 44–
`45. Patent Owner also points to articles written by Petitioner’s Expert,
`Dr. Heikinheimo, which teach that “because ‘[t]he pharmacokinetics of RU
`486 were not linear,’ ‘[n]o clear dose-response correlation with clinical
`performance has been found.’” Id. at 45 (citing Ex. 1013 at 1); see also id.
`at 45–46 (citing Exc. 2007) (“Dr. Heikinheimo specifically reported on the
`vast uncertainty infiltrating and impeding clinical application for
`mifepristone: ‘[a]fter the first clinical studies with RU 486 it soon became
`apparent that the clinical outcome was not correlated with doses of RU 486
`administered.’”). We are not persuaded.
`At this stage in the proceeding we find that the current record tends to
`support the existence of a correlation between a mifepristone dosage range
`of 600-1200 mg and a mean serum level in excess of 1300 ng/mL. We
`acknowledge that the pharmacokinetics of mifepristone are non-linear, but
`this does not change the fact that Sitruk-Ware discloses a mean serum level
`of 2 mg/L at 1.35 h after single-dose administration. Ex. 1008, 6. That this
`serum level was achieved by non-linear absorption does not change that a
`mean serum level in excess of the claimed threshold was obtained by
`administration of 600 ng/mL. We also acknowledge the evidence of serum
`level unpredictability highlighted by Patent Owner. See Prelim. Resp. 44–48
`However, at this stage in the proceeding, we find this evidence of
`unpredictability in mifepristone serum levels for any individual patient tends
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`to further support obviousness because the skilled artisan would have had all
`the more reason to measure the serum levels to ensure proper dosage for
`each patient. See, e.g., Ex. 2007, 8 (“([t]he similar serum levels of RU 486
`[mifepristone] measured following various doses seems to explain the
`observation that there is no correlation between the regimen of RU 486 and
`the clinical outcome[.]”)
`“adjusting the daily dose of the patient to achieve
`4.
`mifepristone blood levels greater than 1300 ng/ml”
`The third step of claim 1 requires “adjusting the daily dose of the
`patient to achieve mifepristone blood levels greater than 1300 ng/ml.”
`Petitioner contends that Chu and Belanoff teaches “adjusting the daily dose
`of the patient to achieve effective or functional mifepristone dosing.” Pet.
`37. In view of this teaching, Petitioner, asserts that it would have been
`obvious to adjust the patient dose meet the claimed threshold. Petitioner
`explains:
`Knowing 600 mg was efficacious in treating a patient in need of
`mifepristone treatment as described by Belanoff 2002 and
`knowing that 600 mg daily should be reasonably expected to
`give blood serum levels higher than 1300 ng/mL as disclosed
`by Sitruk-Ware, it would have been readily obvious to one of
`ordinary skill in the art to adjust the daily dosing of the patient
`as described by Chu and Belanoff for treating psychotic major
`depression with dosages in the range of those described by both
`Belanoff 2002 and Sitruk-Ware in order to achieve mifepristone
`blood levels greater than 1300 ng/mL so that efficacy could be
`maintained.
`Id. at 38 (citing Ex. 1004, Heikinheimo Decl. ¶ 19).
`
`Patent Owner’s arguments with respect to the “testing” limitation
`discussed above also apply to this limitation. We are not persuaded by these
`arguments for the reasons already discussed.
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`Based on our review of the current record, we find that evidence tends
`to support the obviousness of the “adjusting” limitation for the reasons
`provided by the Petitioner. We note that Chu and Belanoff discloses
`adjusting dose based on how the patient responds to treatment rather than
`based on the detected serum level of mifepristone. Based on the current
`record, we do not find this to be fatal to Petitioner’s case because Chu and
`Belanoff provides support for the general proposition to adjust mifepristone
`dosage during treatment. Ex. 1023, 4. At this point in the proceeding, we
`find that the evidence tends to support Petitioner’s position that it would
`have been obvious to adjust the dosage of mifepristone during a course of
`treatment if serum levels were found to fall below the level that the
`combination of Belanoff 2002 and Sitruk-Ware suggests is efficacious. See,
`e.g., Ex. 1004, ¶ 19.
`Having determined that Petitioner has demonstrated a reasonable
`likelihood of success in proving that at least one claim of the ’368 patent is
`unpatentable, we institute a review as to all of challenged claims and all
`grounds contained in the Petition. See SAS Inst., Inc. v. Iancu, 138 S. Ct.
`1348, 1359–60 (2018); USPTO, Guidance on the Impact of SAS on AIA
`Trial Proceedings (April 26, 2018).
`We offer the following views on the remaining claims and grounds for
`the parties’ consideration, to the extent they wish to address them in any
`further briefing.
`Claim 2
`Claim 2 depends from claim 1 and further requires that “the disorder
`is a member selected from the group consisting of a stress disorder, delirium,
`mild cognitive impairment (MCI), dementia, psychosis and psychotic major
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`depression.” Petitioner contends that Belanoff discloses this limitation.
`Patent Owner’s Preliminary Response does not contest that Belanoff 2002
`discloses this limitation. We find that the current record tends to support
`Petitioner’s contention that Belanoff 2002 discloses this limitation. See Ex.
`1007, Abstract.
`Claim 4
`Claim 4 depends from claim 1 and further requires that “each of the
`seven or more daily doses of mifepristone are administered orally.”
`Petitioner contends that Sitruk-Ware discloses that mifepristone is
`administered orally. Pet. 39. Patent Owner’s Preliminary Response does
`not contest that Sitruk-Ware discloses this limitation. We find that the
`current record tends to support Petitioner’s contention that