Mangala P. Bajpai

Patent Trials and Appeals Board

Oct 23, 2019

12054129 - (D) (P.T.A.B. Oct. 23, 2019)

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.
12/054,129 03/24/2008 Mangala P. Bajpai 5548
30621 7590 10/23/2019
JENSEN & PUNTIGAM, P.S.
2033 6th Ave
Suite 990
SEATTLE, WA 98121
EXAMINER
MARTIN, PAUL C
ART UNIT PAPER NUMBER
1653
MAIL DATE DELIVERY MODE
10/23/2019 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte MANGALA P. BAJPAI
__________

Appeal 2018-002926
Application 12/054,129
Technology Center 1600
__________

Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
RICHARD J. SMITH, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to a method for
identifying medicinally active chemical entities. The Examiner rejected the claims as
obvious. 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 Biological Life, Inc. (see App. Br. 3).
2 We have considered and refer to the Specification of Mar. 24, 2008 (“Spec.”); Final
Action of Dec. 20, 2016 (“Final Act.”); Appeal Brief of Oct. 18, 2017 (“App. Br.”);
Examiner’s Answer of Nov. 29, 2017 (“Ans.”); and Reply Brief of Jan. 26, 2018
(“Reply Br.”).
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Statement of the Case
Background
“This invention relates generally to methods of drug discovery and
development, and more specifically concerns such a method which is substantially
faster in identifying safe and effective drugs produced from ethnobotanical substances
than existing methods” (Spec. 1:8–11).
The Claims
Claims 1–8, 12–24 and 28–42 are on appeal. Independent claim 1 is
representative and reads as follows:
1. A method for identifying medicinally active chemical entities in
ethnobotanical substances, comprising the steps of:
(1) providing an ethnobotanical natural substance occurring
naturally in nature, the ethnobotanical substance comprising an
existing land or marine plant source identified as having an active
agent associated with a medicinal effect on humans, wherein the land
or marine plant source consists of roots or fruits or seeds or bark or
leaves;
(2) performing an in-vitro assay with the ethnobotanical
substance with one or more of the following: (a) human intestinal
preparations and (b) human liver preparations, thereby producing an
array of human chemical entities;
(3) performing an in-vitro assay of said ethnobotanical
substance using one or more of the following: (a) animal intestinal
preparations and (b) animal liver preparations from at least one
selected animal species to produce an array of animal chemical
entities;
(4) comparing the array of human chemical entities with the
array of animal chemical entities;
(5) determining any matches between the human chemical
entities in the array of human chemical entities and the animal
chemical entities in the array of animal chemical entities to identify a
matched animal species;
(6) performing an in-vivo dosing of the ethnobotanical
substance with the matched animal species;
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(7) obtaining a biological fluid sample from the matched animal
species following the in-vivo dosing;
(8) performing an analysis of the biological fluid sample from
the matched animal species to determine the presence of chemical
entities in the biological fluid sample; and
(9) comparing the chemical entities in the biological fluid
sample with the human chemical entities from the in-vitro assay and
determining any matches between the chemical entities in the
biological fluid sample with the human chemical entities from the in-
vitro assay, wherein the matched chemical entities are identified as
potentially medicinally active chemical entities.

The Issues
A. The Examiner rejected claims 1–7, 12, 13, 15, 17–23, 28, 29, 31, 33–39, and 41
under 35 U.S.C. § 103(a) as obvious over Ireson,3 Chattopadhyay,4 and Gilbert5 (Ans.
3–8).
B. The Examiner rejected claims 1–8, 12, 13–15, 17–24, 28–31, and 33–41 under
35 U.S.C. § 103(a) over Ireson, Chattopadhyay, Gilbert, and Lu6 (Ans. 8–9).
C. The Examiner rejected claims 1–7, 12, 13, 15–23, 28, 29, 31–39, 41, and 42
under 35 U.S.C. § 103(a) over Ireson, Chattopadhyay, Gilbert, and Barnes7 (Ans. 10–
11).

3 Ireson et al., Characterization of Metabolites of the Chemopreventive Agent
Curcumin in Human and Rat Hepatocytes and in the Rat in Vivo, and Evaluation of
Their Ability to Inhibit Phorbol Ester-induced Prostaglandin E2 Production, 61
CANCER RES. 1058–1064 (2001).
4 Chattopadhyay et al., Turmeric and curcumin: Biological actions and medicinal
applications, 87 CURRENT SCIENCE 44–53 (2004).
5 Gilbert et al., Synergy in Plant Medicines, 10 CURRENT MEDICINAL CHEMISTRY 13–
20 (2003).
6 Lu et al., Comparison of Intrinsic Clearance in Liver Microsomes and Hepatocytes
from Rats and Humans: Evaluation of Free Fraction and Uptake in Hepatocytes, 34
DRUG METABOLISM AND DISPOSITION 1600–05 (2006).
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A. 35 U.S.C. § 103(a) over Ireson, Chattopadhyay, and Gilbert
The Examiner states that Ireson teaches, inter alia, “a method comprising the
steps of: providing the naturally occurring ethnobotanical substance curcumin
associated with anti-inflammatory and cancer chemopreventative activities, which
reads on in part on” claim 1 along with the in vitro and in vivo assay steps and
comparisons required by claim 1 (Ans. 6).
The Examiner acknowledges that Ireson “does not teach a method wherein the
naturally occurring ethnobotanical substance comprising an existing land plant source
identified as having a medicinal effect on humans consists of roots, fruits, seeds, bark
or leaves” as required by claims 1, 17, and 33 or the use of “a plurality of animal
species” as required by claims 3, 19, and 35 (Ans. 5–6).
The Examiner finds Chattopadhyay teaches turmeric, a powdered rhizome
(root) “is an unrefined, unpurified medicinal plant which has an extensive history in
Traditional Indian and Chinese medicine and comprises many different compounds,
including curcumin and that both curcumin and turmeric have the potential for the
development of modern medicine for the treatment of various diseases” (Ans. 6). The
Examiner finds Gilbert teaches
plant derived medicines depend on active principles that in many cases
require adjuvant substances in the plant which enhance the activity of the
components responsible for the effect and in some cases the isolated
substance is often less active by itself than when retained in the mixture
present in the plant itself.
(Ans. 6).

7 Barnes et al., Applications of LC-MS in the study of the uptake,
distribution, metabolism and excretion of bioactive polyphenols from dietary
supplements, 78 LIFE SCIENCES 2054–59 (2006).
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The Examiner finds it obvious to use Chattopadhyay’s medicinal root turmeric
in the place of Ireson’s purified curcumin based on Gilbert’s teaching that “plant
derived medicines may be less active when in isolated (refined, purified) form due to
the loss of adjuvant enhancing substance” (Ans. 7). The Examiner finds it obvious to
“ascertain if the unrefined and unpurified ethnobotanical substance (turmeric) retained
the same active metabolites as the isolated active substance (curcumin)” (Ans. 7).
The issue with respect to this rejection is: Does the evidence of record support
the Examiner’s conclusion that Ireson, Chattopadhyay, and Gilbert render the claims
obvious?
Findings of fact
1. Ireson teaches that “[c]urcumin . . . is the major yellow pigment extracted
from turmeric, the powdered rhizome of the herb Curcuma longa” (Ireson 1058, col.
1).
2. Ireson “tested the hypothesis that curcumin is biotransformed similarly
by human and rat liver” (Ireson 1059, col. 1).
3. Ireson teaches
hepatocytes [liver cells] obtained from humans and rats were incubated
with curcumin, and their metabolites were identified. Curcumin was also
administered to rats via the i.v. and p.o. routes, and its plasma
metabolites were compared with those found in suspensions of liver cells.
Finally, to investigate whether the identified metabolites possess
pharmacological properties germane to chemoprevention, we compared
their ability with that of curcumin to inhibit phorbol ester-induced COX-
2 expression in human colon cells as reflected by PGE2 levels.
(Ireson 1059, col. 1).
4. Ireson teaches step (1) of providing a ethnobotanical substance,
specifically teaching the “following chemicals and reagents were purchased from the
suppliers listed: curcumin” (Ireson 1059, col. 1).
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5. Ireson teaches steps (2) and (3) of obtaining “hepatocytes from humans
or rats” and these “[f]reshly isolated hepatocytes . . . were suspended in liver
suspension medium (2 ml) and incubated in a slowly shaking incubator (37°C).
Curcumin dissolved in DMSO was added to furnish a final concentration of 100 µM”
(Ireson 1059, col. 2).
6. Ireson teaches steps (4) and (5) of comparison of the human and animal
chemical entities and identifying matches as shown in Figure 2, reproduced below:

Fig. 2. High-performance liquid chromatograms with detection at 280
nm of extracts of suspensions of hepatocytes from humans (A and B) or
rats (C and D) incubated for 2 h without (A and C) or with (B and D)
curcumin (100 µM). Chromatograms are representative of incubations
with six (rat) and four (human) separate hepatocyte preparations. Peaks
were identified by cochromatography and mass spectrometry (see text) as
curcumin (3), hexahydrocurcumin (2), and hexahydrocurcuminol (1).
(Ireson 1060, col. 2).
7. Ireson teaches step (6) of in vivo dosing where “[f]emale F344 rats
received curcumin either p.o. (gavage, 500 mg/kg; vehicle, DMSO; dosage volume,
2.0 ml/kg) or i.v. (40 mg/kg; vehicle, glycerol formal; dosage volume, 1.0 ml/kg)”
(Ireson 1059, col. 2).
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8. Ireson teaches step (7) where “blood was removed by cardiac puncture 30
min and 1, 2, 6, 12, and 24 h (p.o. administration) or 5 and 30 min and 1 and 6 h (i.v.
administration) after dosing” (Ireson 1059, col. 2).
9. Ireson teaches step (8) of analyzing the blood sample by separating
plasma where “[e]xtraction efficiencies from plasma using the ethyl acetate extraction
method for curcumin, hexahydrocurcumin, and curcumin sulfate were determined by
HPLC” (Ireson 1059, col. 2).
10. Ireson teaches step (9) of comparing the chemical entities to analyze their
medicinal activity, specifically teaching:
(a) human and rat liver reduces curcumin first to hexahydrocurcumin and
then to hexahydrocurcuminol, whereas conjugation of curcumin is only a
minor hepatic biotransformation route; (b) the biotransformation step
curcumin hexahydrocurcumin is rapid, and the overall rate of curcumin
reduction seems slower in human than in rat liver cells; (c) the
predominant metabolites of curcumin in rat plasma in vivo are curcumin
glucuronide and curcumin sulfate, whereas hexahydrocurcumin and
hexahydrocurcuminol, the major metabolites of curcumin in hepatocyte
suspensions, occur only in small amounts in rat plasma after curcumin
administration; (d) curcumin metabolites are markedly less able to inhibit
inducible COX-2 expression than their metabolic progenitor.
(Ireson 1062, col. 2).
11. Chattopadhyay teaches “Turmeric (Curcuma longa L.) is a medicinal
plant extensively used in Ayurveda, Unani and Siddha medicine as home remedy for
various diseases” (Chattopadhyay 44, col. 1).
12. Chattopadhyay teaches “[i]n old Hindu medicine, it is extensively used
for the treatment of sprains and swelling caused by injury” (Chattopadhyay 44, col. 1).
13. Chattopadhyay teaches “[t]urmeric powder, curcumin and its derivatives
and many other extracts from the rhizomes were found to be bioactive”
(Chattopadhyay 44, col. 2).
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14. Chattopadhyay teaches “[s]everal pharmacological activities and
medicinal applications of turmeric are known. Although curcumin has been isolated
in the 19th century, extracts of the rhizomes of C. longa have been in use from the
Vedic ages” (Chattopadhyay 45, col. 2).
15. Gilbert teaches
elucidating the actual mechanism of action of drugs at the cell or even at
the gene level have resulted in a rational explanation of the action of
some medicinal plants. The traditionally used crude extracts can thus be
compared for mode of action and effective dosage with their isolated or
synthetic counterparts. Somewhat surprisingly it turns out that the
isolated substance is often less active by itself than it is when retained in
the mixture present in the plant.
(Gilbert 13, col. 2).
16. Gilbert provides a mechanism explaining why a natural compound may
have lower activity after purification, teaching that “[p]lant tissues contain
phospholipids but these may be lost partially or wholly in the extraction process. . . . if
these lipophilicity promoting agents are conserved in the extract, then higher
absorption rates and lower excretion rates can be expected” (Gilbert 15, col. 1).
17. Gilbert teaches an example showing “a considerable enhancement of the
pharmacological activities of a standardised Ginkgo biloba extract when combined
with phosphatidylcholine” (Gilbert 15, col. 2).
18. Gilbert teaches therefore that
before discarding ancient traditional formulations incorporating several
plants, it would be wise to check whether some of the components,
apparently inactive in the particular use prescribed, may be contributing
to bioavailability of active principles of other plant components of the
formula. It has been noted above, for example, that curcumin appears as
a Phase I inhibitor and also as an MDR inhibitor. It is not surprising
therefore that Curcuma spp. which contain it are so often found in
Ayurveda and other traditional medicines.
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(Gilbert 18, col. 2 to 19, col. 1).
Principles of Law
“The combination of familiar elements according to known methods is likely to
be obvious when it does not more than yield predictable results” KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 416 (2007).
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the scope
and content of the prior art (Ans. 3–8; FF 1–18) and agree that the claims are obvious
over Ireson, Chattopadhyay, and Gilbert. We address Appellant’s arguments below.
Appellant contends that: “Ireson does not begin with or involve roots, fruits,
seeds, bark or leaves; rather it begins with a single, purified, refined compound
(curcumin) which has already been identified as having medicinal qualities and is thus
deemed worthy of further investigation”; that Chattopadhyay “is simply . . . historical
knowledge and nothing more, concerning use of a particular plant, namely turmeric,
for medicinal treatment”; and that “Gilbert is also simply historical information about
the possible medicinal effects of certain plants” (App. Br. 6–7).
We find these arguments unpersuasive because “[n]on-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).
In this case, Ireson teaches a method to investigate medicinally active chemical
entities in enthnobotanicals like curcumin (FF 3) using the steps of claim 1 (FF 4–10)
while Gilbert teaches to compare crude plant extracts with isolated components in
order to determine “whether some of the components, apparently inactive in the
particular use prescribed, may be contributing to bioavailability of active principles of
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other plant components of the formula” (FF 18). Thus, it is the combination of Ireson
and Gilbert, along with Chattopadhyay’s teaching that turmeric, the source of
curcumin, is well known as a medicinal plant (FF 1214), that provides reason for the
ordinary artisan to apply Ireson’s method to plant sources including turmeric rhizomes
(roots) (FF 1, 13, 18) in order to determine whether other turmeric components may
improve the efficacy of isolated curcumin (FF 16–18).
Appellant contends that “the examiner fails to provide a reference or any
reasoning that such a substitution would be obvious. In fact the lack of such a specific
teaching, given the ‘ancient history’ pointed out by the examiner of the secondary
references, is an indication that such a substitution in Ireson is in fact not obvious”
(App. Br. 8).
We find this argument unpersuasive because, as discussed above, Gilbert
provides a specific reason to investigate entire ethnobotanical sources for activity
using methods such as the screening method of Ireson, because “traditionally used
crude extracts can thus be compared for mode of action and effective dosage with
their isolated or synthetic counterparts. Somewhat surprisingly it turns out that the
isolated substance is often less active by itself than it is when retained in the mixture
present in the plant” (FF 15). Ireson expressly teaches methods for comparing activity
of different components to determine medicinal efficacy (FF 2, 3, 10) and the ordinary
artisan, interested in analyzing whether crude extracts provide superior efficacy to
isolated compounds would have reasonably selected Ireson’s method, already shown
effective on metabolites of the isolated ethnobotanical substance curcumin (FF 10).
Appellant contends that
Gilbert simply teaches a plant per se as an alternative to an isolated
compound thereof. There is no reason why one of ordinary skill would
be motivated to make the substitution asserted by the examiner in the
Ireson drug discovery process. The reasonable conclusion from Gilbert
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would be to consider using the plant (turmeric) per se as an alternative to
purified curcumin only after purified curcumin was determined worthy of
further investigation for possible human drug use, rather than in the
Ireson process.
(Reply Br. 3).
We find this argument unpersuasive because claim 1 expressly states an interest
in screening an “ethnobotanical substance comprising an existing land or marine plant
source identified as having an active agent associated with a medicinal effect on
humans.” Thus, consistent with claim 1, the ordinary artisan, informed by Ireson that
isolated curcumin, derived from turmeric rhizomes, functions as a medicinal
compound that inhibits COX-2 (FF 1, 10), would have had reason based on Gilbert to
test the original starting material for improved activity because Gilbert teaches that “it
would be wise to check whether some of the components, apparently inactive in the
particular use prescribed, may be contributing to bioavailability of active principles of
other plant components of the formula” (FF 18).
That is, the arrangement of steps in the Examiner’s reasoning (see, e.g., Ans.
16–17) is substantially the same as the arrangement of steps recited by claim 1, where
after a plant having an active medicinal effect is identified, the plant is subjected to
screening to identify active chemical entities within the plant, just as Gilbert suggests
in order to identify whether other components contribute to the activity of the already
known chemical entity (FF 15, 18).
Appellant contends “[a]pplying the human-system based steps in the
independent claims thus has the surprising benefit of identifying a broad array of
active agents in ethnobotanical substances not otherwise discovered by the use of
traditional chemical (non-human system based) fractionation methods” (App. Br. 8).
We find this argument unpersuasive because Appellant does not provide any
evidence to support this argument. “[I]t is well settled that unexpected results must be
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established by factual evidence. ‘Mere argument or conclusory statements in the
specification does not suffice.’” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997).
We further note that Appellant fails to provide any comparison showing such a result
with the closest prior art of Ireson, nor does Appellant provide a showing that any
such advantage is commensurate in scope with a claim open to any ethnobotanical
substance whatsoever. See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir.
1991) (“[W]hen unexpected results are used as evidence of nonobviousness, the
results must be shown to be unexpected compared with the closest prior art.”). Also,
unexpected results must be “commensurate in scope with the degree of protection
sought by the claimed subject matter.” In re Harris, 409 F.3d 1339, 1344 (Fed. Cir.
2005).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that Ireson,
Chattopadhyay, and Gilbert render the claims obvious.

B-C. 35 U.S.C. § 103(a)
Appellant does not separately argue the rejections including Lu and Barnes (see
App. Br. 9–10). Having affirmed the obviousness rejection of claim 1 over Ireson,
Chattopadhyay, and Gilbert for the reasons given above, we also find that the further
combination with Lu or Barnes renders the dependent claims obvious for the reasons
given by the Examiner (see Ans. 8–11).
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CONCLUSION
In summary:

No time period for taking any subsequent action in connection with this appeal
may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED
Claim(s)
Rejected
35
U.S.C. §
Basis Affirmed Reversed
1–7, 12, 13, 15,
17–23, 28, 29,
31, 33–39, 41
§ 103(a) Ireson,
Chattopadhyay,
Gilbert
1–7, 12, 13, 15,
17–23, 28, 29,
31, 33–39, 41

1–8, 12, 13–15,
17–24, 28–31,
33–41
§ 103(a) Ireson,
Chattopadhyay,
Gilbert, Lu
1–8, 12, 13–15,
17–24, 28–31,
33–41

1–7, 12, 13, 15–
23, 28, 29, 31–
39, 41, 42
§ 103(a) Ireson,
Chattopadhyay,
Gilbert, Barnes
1–7, 12, 13,
15–23, 28, 29,
31–39, 41, 42

Overall
Outcome
1–8, 12–24,
28–42