David Greenwood et al.

Patent Trials and Appeals Board

Jan 31, 2020

14307231 - (D) (P.T.A.B. Jan. 31, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/307,231 06/17/2014 David Greenwood 07588.0213-00000 5471
22852 7590 01/31/2020
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON, DC 20001-4413
EXAMINER
PIHONAK, SARAH
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
01/31/2020 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
regional-desk@finnegan.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DAVID GREENWOOD and WILFRIED DIMPFEL
Appeal 2018-004506
Application 14/307,231
Technology Center 1600
Before JEFFREY N. FREDMAN, TAWEN CHANG, and JAMIE T. WISZ,
Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 9, 10, and 15. We have jurisdiction
under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as BTG
International Limited. Appeal Br. 3.
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BACKGROUND
The Specification explains that “[i]t is known that both acute and
chronic neurodegenerative states in mammals . . . can be treated by inducing
ketosis.” Spec. 1:12–13. The Specification further explains that “ketosis
can be provided by restriction of diet . . . or by administration of ketogenic
materials, such as triglycerides, free fatty acids, alcohols (eg butan-1, 3-
diol), acetoacetate and [(R)]-3-hydroxybutyrate and their conjugates with
each other and further moieties, eg. esters and polymers of these.” Id. at
1:13–17.
According to the Specification, “[t]he present inventors . . . have now
found that . . . changes in brain electrical activity are induced by ketosis such
that . . . mood, cognition and tolerance of pain are each affected in a positive
fashion.” Id. at 1:24–29. Further according to the Specification, “[t]he
present invention relates to compounds and compositions that have the effect
of modulating mammalian central nervous system activity such as to have
anti-depressant effect, increase cognitive function and increase tolerance
with respect to pain stimuli.” Id. at 1:2–5.
CLAIMED SUBJECT MATTER
The claims are directed to a method of treating a subject in need of
therapy for depression and/or anxiety. Claim 9 is illustrative:
9. A method of treating a subject in need of therapy for
depression and/or anxiety, comprising orally administering to said
subject 5 to 5000mg/kg body weight per day of a material selected
from the group consisting of (R)-3-hydroxybutyrate, its salts, and
esters of (R)-3-hydroxybutyrate with glycerol or (R)-1,3-butandiol
sufficient to produce a ketosis in the subject sufficient to provide an
anti-depressant effect and/or an anxiolytic effect, wherein the total
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concentration of acetoacetate and (R)-3-hydroxybutyrate in the blood
is raised to between 1 and 10mM.
Appeal Br. 13 (Claims App.).
In response to the Examiner’s August 26, 2015 Requirement for
Restriction/Election, Appellant elected the ester of (R)-3-hydroxybutyrate
with (R)-1,3-butandiol for further substantive examination. Response to
Requirement for Restriction (Feb. 25, 2016); see also Ans. 3. We limit our
consideration on the merits to the elected species. See Ex parte Ohsaka, 2
USPQ2d 1460, 1461 (BPAI 1987).
REJECTION
Claims 9, 10, and 15 are rejected under pre-AIA U.S.C. § 103(a) as
being unpatentable over Likhodi2 and Veech.3

OPINION
A. Issue
The Examiner finds that Likhodi teaches a ketogenic diet may be used
to treat epilepsy because the diet is low in carbohydrates and protein, which
“forces the body to utilize fat as the main source of energy in a state known
as ketosis, resulting in the production of ketones, including beta-
hydroxybutyrate (3-hydroxybutyrate), acetoacetate, and acetone.” Ans. 3.
The Examiner finds that Likhodi also teaches treating neurological disorders
such as mood disorders, unipolar and bipolar depression, anxiety, and
affective disorders with a ketogenic diet. Id. at 3–4. The Examiner finds
Likhodi teaches that, because ketogentic diet has negative side effects, “it is

2 Likhodi et al., US 2004/0097598 A1, published May 20, 2004.
3 Veech et al., WO 2004/108740 A2, published Dec. 16, 2004.
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desirable to develop . . . treatments that can mimic the effect of a ketogenic
diet” for the previously mentioned neurological disorders. Id. at 4.
The Examiner finds that Likhodi does not explicitly teach
administering the elected species, the (R)-1,3-butanediol ester of (R)-3-
hydroxybutyrate. Ans. 4. However, the Examiner finds that, like Likhodi,
Veech teaches that ketosis may be used to treat certain diseases such as
epilepsy. Id. The Examiner finds Veech further teaches that administering
(R)-3-hydroxybutyrate and acetoacetate or their sodium salts directly to a
subject are undesirable because of, respectively, acidosis and sodium
overload, and therefore teaches administering an (R)-3-hydroxybutyrate
derivative, including the elected species, in a dose ranging from about 70 mg
to about 5g per kg of body weight, in order to elevate blood concentrations
of ketone bodies to about 0.1 to about 20 mM and ameliorate symptoms of
neurological disorders. Id. at 4–5.
The Examiner concludes that it would have been prima facie obvious
to a skilled artisan to combine Likhodi and Veech to arrive at the claimed
invention, because Likhodi teaches that “neurological disorders such as
epilepsy, depression, and anxiety can be treated by mimicking the effects of
a ketogenic diet . . . , while Veech teaches derivatives of (R)-3-
hydroxybutyrate, including [the elected species], to provide therapeutic
blood concentrations of ketone bodies when administered.” Ans. 5–6.
Appellant contends Likhodi teaches that it is acetone, rather than beta-
hydroxybutyrate, that is “responsible for the neurological effects of the
ketogenic diet.” Appeal Br. 7–9. Appellant contends that Veech does not
suggest that the esters of its invention can treat depression or anxiety. Id. at
11. Appellant further contends Veech does not suggest that such esters can
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treat the same disorders as the acetone analogs taught in Likhodi and,
therefore, a skilled artisan would not have been motivated to combine
Likhodi and Veech. Id. at 10–11. Appellant contends that any combination
of Likhodi and Veech would be based on impermissible hindsight. Id. at 11.
Appellant does not separately argue the claims. We therefore limit
our analysis to claim 9 as representative. The issue with respect to this
rejection is whether a preponderance of the evidence of record supports the
Examiner’s conclusion that claim 9 is obvious over Likhodi and Veech.
B. Findings of Fact
1. Likhodi teaches that ketogenic diet, a non-drug therapy, “forces
the body to utilize fat as its major energy source,” which “leads to the
production of three ketones—acetoacetate, beta-hydroxybutyrate, and
acetone—and a state of ‘ketosis’ in the body.” Likhodi ¶ 11.
2. Likhodi teaches that “[t]here are several . . . reasons to believe
that ketogenic diet may have utility as a mood stabilizer.” Id. ¶ 15.
3. Likhodi teaches that disorders “for which a ketogenic diet has
shown beneficial effects” or the symptoms of which “the ketogenic diet can
alleviate” include “mood disorders and affective disorders (such as
depression, anxiety and unipolar and bipolar illnesses).” Id. ¶ 65.
4. Likhodi teaches that, “[a]lthough it has few side effects, the
ketogenic diet is not easy to maintain.” Id. ¶ 17.
5. Veech teaches that the body utilizes energy obtained from the
metabolism of fats during periods of carbohydrate deprivation and that,
during fat metabolism, large quantities of acetoacetate and 3-hydroxybutyric
acid accumulate in the blood in a condition known as ketosis. Veech 1:18–
22.
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6. Veech teaches that, “[m]ild ketosis, in which ketone bodies are
used by the body as an energy source, has been demonstrated to have
therapeutic effects in several disease states.” Id. at 1:25–26; see also id. at
2:11–20).
7. Veech likewise teaches that “[t]reatment of human tissues with
(R)-3-hydroxybutyrate results in several beneficial therapeutic and
nutritional effects,” including increase of cardiac efficiency and brain
metabolic efficiency and reduced effects of neurodegenerative disorders
such as Alzheimer’s and Parkinson’s diseases. Id. at 2:21–24, 2:29–31.
8. Veech teaches that a ketogenic diet, a high fat, low
carbohydrate diet, has been suggested for inducing ketosis and achieving the
beneficial effects of starvation for treating disease such as epilepsy. Id. at
1:28–30.
9. Veech teaches that “[t]he ketogenic diet has many drawbacks,
some of which include . . . elevated triglyceride levels, cholesterol levels, or
both caused by the high fact diet” as well as the fact that “the 4 to 1 ratio of
fat to protein [in the ketogenic diet] is unpalatable for many subjects.” Id. at
2:8–10.
10. Veech teaches that,
[i]n theory, (R)-3-hydroxybutyrate and acetoacetate could be
administered directly to achieve elevated levels of ketone
bodies in a subject. However, direct administration of these
compounds is impractical and dangerous. For example, direct
administration of either (R)-3-hydroxybutyrate or acetoacetate
in their acid form can result in significant acidosis following
rapid absorption from the gastrointestinal tract. Administration
of the sodium salt of these compounds is also unsuitable due to
a potentially dangerous sodium overload that would accompany
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administration of therapeutically relevant amounts of these
compounds.
Id. at 3:3–10.
11. Veech teaches “compounds and compositions containing (R)-3-
hydroxybutyrate derivatives effective for elevating blood concentrations of
ketone bodies and methods for using such compounds and compositions as
nutritional supplements or for treating medical conditions.” Id. at 1:12–15;
see also id. at Abstract, 4:22–5:4, 6:1–8, 6:16–19, 25:5–27:12.
12. Veech teaches that examples of its (R)-3-hydroxybutyrate
derivatives include esters of (R)-3-hydroxybutyrate and oligomers of (R)-3-
hydroxybutyrate and that “[d]isclosed ester compounds include esters
derived from . . . (R)-1,3-butanediol,” i.e., the elected species. Id. at 4:27–
5:2.
13. Veech teaches embodiments of (R)-3-hydroxybutyrate
derivatives according to Formulas 4 and 5, reproduced below:

Id. at 13:1–4. Veech teaches that “[p]roviding ketone bodies as (R)-3-
hydroxybutyrate esters offers several advantages over prior known
compositions,” for example because “the present esters are not contaminated
with significant amounts of a non-physiological stereoisomer” and thus “do
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not provoke undesired side effects or suffer from competitive inhibition by
the non-physiological stereoisomer.” Id. at 13:9–13. Veech further teaches
that, “[b]ecause (R)-3-hydroxybutyrate derivatives according to Formulas 4
and 5 release (R)-1,3-butanediol in vivo, which is oxidized to (R)-3-
hydroxybutyrate and acetoacetate in the liver, (R)-1,3-butanediol is a
particularly useful physiologically compatible alcohol for preparing (R)-3-
hydroxybutyrate derivatives.” Id. at 13:5–8.
14. Veech teaches that
[t]he blood concentration of ketone bodies can be
maintained at a therapeutically or nutritionally effective level
by administering the appropriate amount of the (R)-3-
hydroxybutyrate derivative based upon the disorder to be
treated and/or the weight and energy requirements of the
subject.
Using the (R)-3-hydroxybutyrate derivatives
disclosed herein, desired therapeutic and nutritional
effects can be sustained without resort to the ketogenic
diet. . . . Typically, therapeutic blood ketone
concentrations (measured as the sum of (R)-3-
hydroxybutyrate and acetoacetate) range from about 0.1
to about 20 mM, more typically from about 0.2 to about
10 mM, and[,] for some disorders, . . . from about 2 to
about 8 mM . . . . For example, it is currently believed
that ketone body concentrations greater than about 4 mM
yield a therapeutic response in refractory epilepsy. . . .
However, certain disorders benefit from relatively small
increases in the concentration of ketone bodies in the
blood. . . .
. . . .
. . . The amount [of (R)-3-hydroxybutyrate equivalents]
administered can be more conveniently expressed in terms of
grams . . . per day per kilogram of body weight, which typically
will range from about 70 milligrams to about 5 grams per
kilogram of body weight. More typically, the amount of
hydroxybutyrate equivalents per day will range from about 1
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gram to about 4 grams per kilogram of body weight, and most
typically from about 1.5 grams to about 3 grams per kilogram
of body weight.
Id. at 27:13–28:21.
15. Veech teaches that the compounds of its invention may be
administered orally. Id. at 6:3–8, 15:1–23, 19:4–6, 32:12–22.
C. Analysis
Likhodi and Veech both teach that a ketogenic diet, which leads to the
production of certain ketone bodies (acetoacetate, beta-hydroxybutyrate (i.e.,
3-hydroxybutyrate), and acetone) and a state of ketosis in the body, may be
useful in treating various medical conditions. FF1–3, FF5, FF6, and FF8.
Likhodi specifically teaches that disorders “for which a ketogenic diet has
shown beneficial effects” or the symptoms of which “the ketogenic diet can
alleviate” include “mood disorders and affective disorders (such as
depression, anxiety and unipolar and bipolar illnesses).” FF3.
Both Likhodi and Veech also teach that the ketogenic diet has
drawbacks, including difficulty of maintenance, lack of palatability, and
elevated triglyceride and/or cholesterol levels. FF4, FF9. Veech then
teaches that administration of (R)-3-hydroxybutyrate derivatives, including
the elected species (i.e. the ester of (R)-3-hydroxybutyrate with (R)-1,3-
butandiol), can achieve the desired therapeutic and nutritional effects in a
subject without the need for ketogenic diet. FF11–FF14. Veech further
teaches that the compounds of its invention may be administered orally.
FF15.
We agree with the Examiner that, in light of the above teachings, a
skilled artisan would have had a reason to treat subjects in need of therapy
for depression and/or anxiety by orally administering the elected species, as
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recited in claim 9, because Likhodi teaches that a ketogenic diet is effective
in treating depression and anxiety and Veech teaches that orally
administering the elected species can achieve the therapeutic results of a
ketogenic diet.
Furthermore, Veech teaches that the compounds of its invention will
typically be administered in a range of from about 70 milligrams to about 5
grams per kilogram of body weight per day. FF14. This range falls entirely
within the range of 5 to 5000 mg/kg body weight per day recited in claim 9
and thus anticipates the claimed range. Similarly, Veech teaches that
therapeutic blood ketone concentrations (i.e., the sum of (R)-3-
hydroxybutyrate and acetoacetate) typically range from about 0.1 to about
20 mM. Id. This disclosed range overlaps with the range of total
concentration of acetoacetate and (R)-3-hydroxybutyrate recited in claim 9,
i.e., between 1 and 10mM, and renders this limitation prima facie obvious.
In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“In cases involving
overlapping ranges, we and our predecessor court have consistently held that
even a slight overlap in range establishes a prima facie case of
obviousness.”).
Finally, as to the limitation relating to administering an amount
“sufficient to produce a ketosis in the subject sufficient to provide an anti-
depressant effect and/or an anxiolytic effect,” we note that “discovery of an
optimum value of a result effective variable in a known process is ordinarily
within the skill of the art.” In re Boesch, 617 F.2d 272, 276 (CCPA 1980).
As Veech underscores, a skilled artisan would have been able to determine
“the appropriate amount of the (R)-3-hydroxybutyrate derivate [to be
administered] based upon the disorder to be treated.” FF14. Alternatively,
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we find that the Examiner has established that the prior art discloses a
method that is sufficiently similar to the claimed method such that the
burden is properly shifted to Appellant to show that the prior art method
does not meet this limitation. In re Best, 562 F.2d 1252, 1254–55, (CCPA
1977) (explaining that, “‘where the Patent Office has reason to believe that a
functional limitation asserted to be critical for establishing novelty in the
claimed subject matter may, in fact, be an inherent characteristic of the prior
art, it possesses the authority to require the applicant to prove that the
subject matter shown to be in the prior art does not possess the characteristic
relied on’”) (quoting In re Swinehart, 439 F.2d 210, 212–13 (CCPA 1971)).
Appellant contends that Likhodi “provides no disclosure of [(R)-1,3-
butandiol] ester of [(R)-3-hydroxybutyrate] and certainly no suggestion of
producing a total concentration of acetoacetate and [(R)]-3-
hydroxybutyrate in the blood of between 1 and 10mM.” Appeal Br. 9.
Appellant further contends that “none of [(R)-3-hydroxybutyrate], salts or a
glycerol or [(R)-1,3-butandiol ester of [(R)-3-hydroxybutyrate] have carbon
chains of 7 to 9 carbon length.” Id.
We are not persuaded. “Non-obviousness cannot be established by
attacking references individually where the rejection is based upon the
teachings of a combination of references. . . . [The reference] must be read,
not in isolation, but for what it fairly teaches in combination with the prior
art as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
As discussed above, in this case Veech suggests that administration of the
elected species may mimic the therapeutic and nutritional effects of the
ketogenic diet and further teaches a therapeutic concentration of acetoacetate
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and (R)-3-hydroxybutyrate that overlaps the claimed concentration. FF12–
FF14.
Appellant contends that Veech does not teach that the esters of its
invention can treat depression or anxiety. Appeal Br. 11. Appellant also
contends that a skilled artisan would not have had reason to combine
Likhodi and Veech because “there is no disclosure or suggestion in Veech
that such esters can treat the same disorders that long chain acetone analogs
are claimed to treat in Likhodi,” because “the compounds of Veech do not
meet Likhodi’s requirement of a carbon chain of 7 to 9 continuous carbons,”
and because Veech does not suggest that administration of its compounds
elevate the blood levels of acetone. Id. at 10–11.
We are not persuaded. Once again, Appellant fails to take into
account the combination of references. While Veech does not explicitly
teach that the esters of its invention can treat depression or anxiety, it
suggests that administration of such esters may mimic the therapeutic effects
of the ketogenic diet, and Likhodi teaches that a ketogenic diet can alleviate
symptoms of mood and affective disorders such as depression and anxiety.
FF2, FF3, and FF14.
We are likewise unpersuaded by Appellant’s argument that a skilled
artisan would have had no reason to combine the teachings of Likhodi and
Veech. As discussed above, Likhodi teaches, among other things, the
therapeutic effects of a ketogenic diet, and Veech teaches that its compounds
can mimic such therapeutic effects. Our reviewing court has explained that,
“in a section 103 inquiry, ‘. . . all disclosures of the prior art . . . must be
considered.’” Merck & Co. Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807
(Fed. Cir. 1989) (quoting In re Lamberti, 545 F.2d 747, 750, 192 USPQ 278,
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280 (CCPA 1976).) Thus, the fact that Likhodi and Veech focus on the
effects of different compounds (acetone derivative in Likhodi and (R)-3-
hydroxybutyrate derivatives in Veech) do not obviate the reason a skilled
artisan would have had in combining the teachings of these references.
Appellant contends that Likhodi discloses that “ketones, particularly
acetone, are responsible for the neurological effects of the ketogenic diet”
and that, “whereas acetone has proven to be anticonvulsant, acetoacetate and
beta-hydroxybutyrate have not.” Appeal Br. 7–9, 10, 11.
We are not persuaded. Likhodi does suggest that acetone and certain
of its derivatives show anticonvulsant activity and that in certain
experimental models beta-hydroxybutyrate was not anticonvulsant. Likhodi
Abstract, ¶¶ 21, 25, 27, and 28. However, while Likhodi teaches that its
compounds may be used to treat depression and/or anxiety and “are useful in
replicating therapeutic and anticonvulsant effects . . . of the ketogenic diet,”
id. ¶¶ 41–42 and 65, we do not find Likhodi teaches that all of the
therapeutic effects of the ketogenic diet result from the production of
acetone, or that the therapeutic effect of ketognic diet on anxiety and
depression is solely the result of the production of acetone and its
anticonvulsant effect during such diet.
Finally, we note that “[w]here the prior art contains ‘apparently
conflicting’ teachings (i.e., where some references teach the combination
and others teach away from it) each reference must be considered ‘for its
power to suggest solutions to an artisan of ordinary skill. . . . consider[ing]
the degree to which one reference might accurately discredit another.’”
Medichem S.A. v. Rolabo S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006)
(quoting In re Young, 927 F2d 588, 591 (Fed. Cir. 1991)). In this case,
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Likhodi teaches there is also evidence “support[ing] a direct relationship
between the level of beta-hydroxybutyrate and seizure resistance.” Likhodi
¶ 22. Given this and Veech’s teaching that its (R)-3-hydroxybutyrate may
mimic the therapeutic and nutritional effects of the ketogenic diet, and given
that Likhodi does not suggest that acetone is responsible for all of the
therapeutic effects of the ketogenic diet, we agree with the Examiner that a
skilled artisan would find the invention of claim 9 obvious over the
combination of Likhodi and Veech.

CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
9, 10, 15 103(a) Likhodi, Veech

9, 10, 15
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED