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Trials@uspto.gov Paper No.

11
571.272.7822 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.
A. Related Proceedings
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.
B. The ’348 Patent (Ex. 1001)
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.
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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.
C. Challenged Claims
Petitioner challenges claims 1–7 of the ’348 patent. Claim 1 is
representative and is reproduced below:

1. 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.
Ex. 1001, 16:26–35.

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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 ‘953 3) 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:
1. A method for optimizing levels of mifepristone in a patient
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).
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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”).
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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.

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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
1 Belanoff ’848 8 § 103(a) 1, 2, 4, 6, and 7
2 Belanoff 2002, Sitruk-Ware, 9 § 103(a) 1, 2, 4, 6, and 7
and Chu and Belanoff 10
3 Belanoff 2002, Sitruk-Ware, § 103(a) 3
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”).
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Ground References Basis Claims


Challenged
4 Belanoff 2002, Sitruk-Ware, § 103(a) 5
11
Chu and Belanoff, and Murphy
5 Belanoff ’848 and Belanoff ’953 § 103(a) 3
6 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
A. Person of Ordinary Skill in the Art
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”).
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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).
B. Claim Construction
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.
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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.
i. Disclosures of the Asserted Prior Art
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.

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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.

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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.

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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

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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

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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

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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[.]”)
4. “adjusting the daily dose of the patient to achieve
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 Sitruk-Ware
discloses this limitation. See Ex. 1008, 2 (disclosing that mifepristone “is
insoluble in water, but very rapidly dissolves in the gastric milieu when
ingested orally” and that mifepristone is “available in the form of tablets
containing 200 mg of active ingredient”).
Claim 6
Claim 6 depends from claim 1 and further requires that “testing is
performed by a plasma sampling collection device suitable for detecting
mifepristone serum levels.” Petitioner contends that Sitruk-Ware’s
disclosure of testing serum level using high performance liquid
chromatography satisfies this limitation. Pet. 39–40. 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 Sitruk-Ware discloses this limitation. See Ex. 1008, 6.

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Claim 7
Claim 7 depends from claim 1 and further requires that “the adjusting
step comprises increasing the daily dose of the patient to achieve
mifepristone blood levels greater than 1300 ng/mL.” Petitioner contends
that this limitation would have been obvious for essentially the same reasons
that the limitation in claim 1, “adjusting the daily dose of the patient to
achieve mifepristone blood levels greater than 1300 ng/ml,” would have
been obvious. Pet. 40–42. Patent Owner’s Preliminary Response does not
separately contest this limitation. We find that the current record tends to
support Petitioner’s position.
D. Ground 3: Obviousness of claim 3 over Belanoff 2002, Chu and
Belanoff, Sitruk-Ware and Belanoff ’953
Petitioner asserts that claim 3 would have been obvious over the
combination of Belanoff 2002, Chu and Belanoff, Sitruk-Ware, and
Belanoff ’953. We offer the following views on for the parties’
consideration, to the extent they wish to address them in any further briefing.
i. Disclosures of the Asserted Prior Art

Belanoff ’953
Belanoff ’953 discloses a “method of ameliorating the symptoms of a
stress disorder in a patient who has normal or decreased cortisol levels” by
administering “a therapeutically effective amount of a glucocorticoid
receptor antagonist to the patient.” Ex. 1010, 2:52–59. The stress disorders
identified include “Post-Traumatic Stress Disorder, Acute Stress Disorder,
or Brief Psychotic Disorder with Marked Stressor(s).” Id.

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ii. Analysis

Claim 3 depends from claim 1 and further requires that the stress
disorder is “a member selected from the group consisting of Acute Stress
Disorder, Post-Traumatic Stress Disorder and Brief Psychotic Disorder with
Marked Stressor(s).” Petitioner contends that it would have been obvious to
treat one of the stress disorders recited in claim 4 because “Belanoff ‘953
uses the same compound (mifepristone) to treat similar stress disorders as
does Belanoff 2002.” Pet. 43. Patent Owner’s Preliminary Response does
not separately contest this limitation. At this stage in the proceeding, and
absent evidence differentiating considerations for treating the stress
disorders recited in claim 4 from psychotic major depression, we find that
the current record tends to support Petitioner’s position.

E. Ground 4: Obviousness of claim 5 over Belanoff 2002, Chu and


Belanoff, Sitruk-Ware and Murphy
Petitioner asserts that claim 5 would have been obvious over the
combination of Belanoff 2002, Chu and Belanoff, Sitruk-Ware, and Murphy.
We offer the following views for the parties’ consideration, to the extent
they wish to address them in any further briefing.
i. Disclosures of the Asserted Prior Art

Murphy
Murphy discloses a study in which four patients with chronic severe
depression were treated with 200 mg/day of mifepristone for “periods up to
eight weeks.” Ex. 1006, Abstract. The results of the study “suggest that
glucocorticoid antagonists may be of use for treatment-resistant depression.”
Id. at 4.

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ii. Analysis

Claim 5 depends from claim 1 and further requires that “the patient is
treated with 28 or more daily doses over a period of 28 or more days.”
Petitioner contends that it would have been obvious to have treated patients
for a period of at least 28 days with 28 or more daily doses because Murphy
teaches “the usefulness and efficacy of dosing for periods up to 56 days.”
Pet 44. Patent Owner’s Preliminary Response does not separately contest
this limitation. At this stage in the proceeding, and absent evidence to the
contrary, we find that the current record tends to support Petitioner’s
position. See, Ex. 1006, 4 (“While the results are not dramatic, they suggest
that glucocorticoid antagonists may be of use for treatment-resistant
depression.”).

F. Ground 1: Obviousness of claims 1, 2, 4, 6, and 7 over Belanoff ’848


Petitioner asserts that claims 1, 2, 4, 6, and 7 would have been
obvious over Belanoff ’848. We offer the following views for the parties’
consideration, to the extent they wish to address them in any further briefing.
i. Disclosures of the Asserted Prior Art
Belanoff ’848

Belanoff ’848 discloses administering mifepristone in dosages of 600–


1200 mg daily for one week to treat delirium. Ex. 1024, ¶¶ 94–96. Dosages
may be “adjusted if necessary.” Id. ¶ 96. “The dosage regimen . . . takes
into consideration pharmacokinetics parameters well known in the art, i.e.,
the GR antagonists’ rate of absorption, bioavailability, metabolism,
clearance, and the like.” Id. ¶ 88. According to Belanoff ’848, it was known
in the art to “determine the dosage regimen for each individual patient, GR

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antagonist and disease or condition treated.” Id. Belanoff ’848 discloses


that “it may be necessary to measure blood and urine levels of GR
antagonist” and that “[m]eans for such monitoring are well described in the
scientific and patent literature.” Id. ¶ 41.

ii. Analysis

Claim 1
Petitioner contends that Belanoff ’848 discloses all of the elements of
claim 1 with the exception that it does not disclose the serum level of 1300
ng/ml. Pet. 29. With respect to this limitation, Petitioner asserts:
[A]dministration of mifepristone at the dosage levels taught by
Belanoff ‘848 would necessarily and inevitably result in a range
of blood serum concentrations that achieve mifepristone blood
levels greater than 1300 ng/mL as claimed. (Ex. 1004 at ¶20).
It would have been readily obvious to one of ordinary skill in
the art with a very high expectation of success that the daily
dosing of the patient could be adjusted to optimize mifepristone
blood level, whatever level that might be. (Id.)
Id. at 30.
Patent Owner argues that Petitioner’s position is “unsupported by any
reasoned rationale and is based purely on hindsight.” Prelim. Resp. 37.
Patent Owner contends that Petitioner and Dr. Heikinheimo failed to
explain, inter alia, “why a POSA would understand, and how they would
determine, that the 1300 ng/mL serum level was the minimum required for
efficacy.” Id. at 38.
As an initial matter, Petitioner repeatedly invokes the language of
inherency in connection with this ground. Pet. 29–30 (“These dosage levels
inherently translate directly into mifepristone serum levels.”). However, the
current record does not tend to show that, in every case, administration of

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mifepristone at the levels disclosed in Belanoff ‘848 would necessarily


result in the serum levels that satisfy the claim. Id. at 30 (asserting that the
‘348 Patent teaches that administration of 300 and 600 mg/day resulted in
serum levels exceeding 1357 ng/mL in 269 of 443 patients); see also, Ex.
1004, Heikinheimo Decl. ¶ 25 (“It is in no way surprising that administration
of the same dose of mifepristone can produce widely varying blood serum
levels in different patients.”); Pet. 48 (“administration of the same dose of
mifepristone can produce widely varying blood serum levels in different
patients.”); Ex. 1001 1:33–34 (“For the same dose of mifepristone, the blood
serum levels can differ by as much as 800% from one patient to another.”).
Accordingly, to the extent Petitioner relies on inherency to establish the
claimed serum level, we are unpersuaded based on the present record. In re
Oelrich, 666 F.2d 578, 581-82, (CCPA 1981) (“The mere fact that a certain
thing may result from a given set of circumstances is not sufficient [to
establish inherency]”) (emphasis added).
Moreover, while we tend to agree with Petitioner that the ordinary
artisan would have understood that “the daily dosing of the patient could be
adjusted to optimize mifepristone blood level,” and that Belanoff ’848
discloses adjusting dosage based on pharmacokinetic parameters like
absorption, bioavailability, metabolism and clearance (see Ex. 1024, ¶¶ 87,
88, and 96), Petitioner does not clearly articulate why an optimization
rationale would have led the skilled artisan to “adjust[] the daily dose of the
patient to achieve mifepristone blood levels greater than 1300 ng/mL”. See
Pet. 29–30.
Under the current guidance, “if the PTAB institutes a trial, the PTAB
will institute on all challenges raised in the petition.” See SAS Guidance.

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Because we are instituting a trial as to whether claim 1 is unpatentable over


the combination of Belanoff 2002, Chu and Belanoff, and Sitruk-Ware, we
also institute trial as to whether claim 1 would have been obvious over
Belanoff ’848.
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
depression.” Petitioner contends that Belanoff ’848 discloses this limitation.
Pet. 30–31. Patent Owner’s Preliminary Response does not contest that
Belanoff ’848 discloses this limitation. We find that the current record tends
to support Petitioner’s contention that Belanoff ’848 discloses this
limitation. See Ex. 1024, ¶ 91.
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 Belanoff ’848 discloses that mifepristone is
administered orally. Pet. 31. Patent Owner’s Preliminary Response does
not contest that Belanoff ’848 discloses this limitation. We find that the
current record tends to support Petitioner’s contention that Belanoff ’848
discloses this limitation. See Ex. 1024, ¶¶ 96, 97.
Claim 6
Claim 6 depends from claim 1 and further requires that “testing is
performed by a plasma sampling collection device suitable for detecting
mifepristone serum levels.” Petitioner contends that Belanoff ’848’s
disclosure of testing serum level using thin layer chromatography satisfies

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this limitation. Pet. 31–32. Patent Owner’s Preliminary Response does not
contest that Belanoff ’848 discloses this limitation. We find that the current
record tends to support Petitioner’s contention that Belanoff ’848 discloses
this limitation. See Ex. 1024, ¶ 44.
Claim 7
Claim 7 depends from claim 1 and further requires that “the adjusting
step comprises increasing the daily dose of the patient to achieve
mifepristone blood levels greater than 1300 ng/mL.” Petitioner contends
that this limitation would have been obvious for essentially the same reasons
that the limitation in claim 1, “adjusting the daily dose of the patient to
achieve mifepristone blood levels greater than 1300 ng/ml,” would have
been obvious. Pet. 32. Patent Owner’s Preliminary Response does not
separately contest this limitation. We find that the current record tends to
support Petitioner’s position.

G. Ground 5: Obviousness of claim 3 over Belanoff ’848


and Belanoff ’953
As with Ground 3, Petitioner relies upon Belanoff ’953 as supplying
the limitation requiring that the stress disorder is “a member selected from
the group consisting of Acute Stress Disorder, Post-Traumatic Stress
Disorder and Brief Psychotic Disorder with Marked Stressor(s).” Pet. 45.
Our views with respect to the application of Belanoff ’953 to this limitation
are discussed in connection with Ground 3.

H. Ground 6: Obviousness of claim 3 over Belanoff ’848 and Murphy


As with Ground 4, Petitioner relies upon Murphy as supplying the
limitation requiring that “the patient is treated with 28 or more daily doses

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over a period of 28 or more days.” Pet. 46. Our views with respect to
Murphy’s application to this limitation are discussed in connection with
Ground 4.

I. 35 U.S.C. 325(d)
We have discretion to deny review when “the same or substantially
the same prior art or arguments previously were presented to the Office.”
35 C.F.R. § 325(d). When evaluating whether the same or substantially the
same prior art or arguments were previously presented to the Office under
§ 325(d), the Board has considered a number of non-exclusive factors,
including, for example: (1) the similarity of the asserted art and the prior art
involved during the examination; (2) the extent to which the asserted art was
considered during examination, including whether the prior art was the basis
for rejection; (3) the cumulative nature of the asserted art and the prior art
considered during examination; (4) whether Petitioner has pointed out
sufficiently how the Examiner erred in its consideration of the asserted prior
art; (5) the extent of the overlap between the arguments made during
examination, and the manner in which Petitioner relies on the prior art or the
applicant’s arguments during examination; and (6) the extent to which
additional evidence and facts presented in the Petition warrant
reconsideration of the asserted prior art. Becton, Dickinson & Co. v. B.
Braun Melsungen AG, Case IPR2017-01586, slip op. at 17–28 (PTAB
Dec. 15, 2017) (Paper 8) (informative).
Patent Owner invites us to enter a discretionary denial under
35 C.F.R. § 325(d) because “Grounds 1-6 present substantially the same art
and arguments that were overcome during prosecution, and Petitioner fails to

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provide a compelling reason to readjudicate them.” Prelim. Resp. 21. After


considering the factors outlined in Becton, Dickinson & Co., we are
persuaded that additional prior art provided in the Petition warrants
reconsideration of the patentability of the claimed method.
We acknowledge that the arguments presented by Petitioner are
similar to the arguments considered by the Examiner during prosecution of
the ’144 application. However, in allowing the method claimed in the
’144 application – and by extension, the similar method claimed in the
’348 patent – the Examiner was evidently persuaded by Patent Owner’s
argument 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.” Ex. 1003, 68 (discussed
supra p. 6–7). Sitruk-Ware, which is relied upon in connection with
Grounds 2–4, discloses testing mifepristone serum levels using HPLC
chromatography (Ex. 1008, 6)—the same methodology that Patent Owner
highlighted during prosecution as being capable of separating mifepristone
from its metabolites and accurately measuring mifepristone serum levels—
and thus belies Patent Owner’s argument that the ordinary artisan would
have been unable to identify 1300 ng/ml as the serum level of mifepristone
necessary for treatment of disorders. Sitruk-Ware was not considered during
prosecution; nor did the Examiner appear to consider any other prior art
reference discussing the measurement of serum mifepristone levels using the
more accurate HPLC method. Accordingly, we agree with the Petitioner
that “[t]he Examiner either overlooked or was not aware [that] . . .

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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.” Pet.
11.
Applying the factors identified in Becton, Dickinson & Co., to the
case at hand, we find that the circumstances favor institution. We recognize
that the arguments presented in the Petition are somewhat similar to the
arguments considered by the Examiner. We also recognize that the Belanoff
references relied upon by the Petitioner appear to be identical or cumulative
to the prior art considered by the Examiner. But, as noted above, the
Examiner did not appear to consider Sitruk-Ware or any other prior art
discussing the measurement of serum mifepristone levels using HPLC.
Furthermore, we find Becton-Dickinson factor 4 strongly favors institution
of inter partes review. Petitioner has convincingly explained that the
Examiner erred by failing to appreciate the full scope of what was known in
the art. In particular, contrary to Examiner’s conclusion, the evidence
presented with the Petition tends to show that “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.” Pet. 11. Accordingly, we decline
to exercise our discretion to deny review under 35 U.S.C. § 325(d).

CONCLUSION
For the foregoing reasons, we conclude that the information presented
in the Petition establishes a reasonable likelihood that Petitioner will prevail
in showing that at least claim 1 of the ’348 patent is unpatentable.
Accordingly, we institute an inter partes review of all challenged claims and
all ground presented in the Peition. SAS Inst., Inc. v. Iancu, 2018 WL
1914661, at *10 (U.S. Apr. 24, 2018).

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ORDER
In consideration of the foregoing, it is hereby:
ORDERED that pursuant to 35 U.S.C. § 314(a), an inter partes
review is instituted as to claims 1, 2, 4, 6, and 7 of the ‘348 Patent under
35 U.S.C. § 103 as obvious over Belanoff ‘848.
ORDERED that pursuant to 35 U.S.C. § 314(a), an inter partes
review is instituted as to claims 1, 2, 4, 6, and 7 of the ‘348 Patent
under 35 U.S.C. § 103 as obvious over the combination of Belanoff 2002,
Sitruk-Ware, and Chu and Belanoff.
ORDERED that pursuant to 35 U.S.C. § 314(a), an inter partes
review is instituted as to claims claim 3 of the ‘348 Patent under 35
U.S.C. § 103 as obvious over the combination of Belanoff 2002, Sitruk-
Ware, Chu and Belanoff, and Belanoff ‘953.
ORDERED that pursuant to 35 U.S.C. § 314(a), an inter partes
review is instituted as to claim 5 of the ‘348 Patent under 35 U.S.C. § 103 as
obvious over the combination of Belanoff 2002, Sitruk-Ware, Chu and
Belanoff, and Murphy.
ORDERED that pursuant to 35 U.S.C. § 314(a), an inter partes
review is instituted as to claim 3 of the ‘348 Patent under 35 U.S.C. § 103 as
obvious over the combination of Belanoff ‘848 and Belanoff ‘953.
ORDERED that pursuant to 35 U.S.C. § 314(a), an inter partes
review is instituted as to claim 5 of the ‘348 Patent under 35 U.S.C. § 103 as
obvious over the combination of Belanoff ’848 and Murphy.

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For PETITIONER:

Kenneth Goldman
MASSEY & GAIL LLP
Ken.Goldman98@gmail.com

For PATENT OWNER:

Bob Steinberg
David Frazier
LATHAM & WATKINS LLP
Bob.Steinberg@lw.com
David.Frazier@lw.com

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