PHYTON HOLDINGS, LLC

Patent Trials and Appeals Board

Jul 29, 2020

2020000019 (P.T.A.B. Jul. 29, 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.
15/100,780 06/01/2016 Gilbert Gorr P0850.70008US01 9995
23628 7590 07/29/2020
WOLF GREENFIELD & SACKS, P.C.
600 ATLANTIC AVENUE
BOSTON, MA 02210-2206
EXAMINER
STANKOVIC, BRATISLAV
ART UNIT PAPER NUMBER
1663
NOTIFICATION DATE DELIVERY MODE
07/29/2020 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):
Patents_eOfficeAction@WolfGreenfield.com
WGS_eOfficeAction@WolfGreenfield.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte GILBERT GORR, HARALD HECKENMULLER,
DAVID ALEXANDER ULLISCH, JENS STEFAN WILKE, and
YANTREE DEVI SANKAR-THOMAS

Appeal 2020-000019
Application 15/100,780
Technology Center 1600
____________

Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 files this appeal from
Examiner’s decision to reject claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.

1 Appellant identifies the real party in interest as Phyton Holdings LLC.
Appeal Br. 3. We use the word “Appellant” to refer to “applicant” as defined
in 37 C.F.R. § 1.42(a).
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STATEMENT OF THE CASE
According to the Specification, “the thapsigargin family of
sesquiterpene lactones act as apoptosis inducers in a proliferation
independent manner. . . . [Thapsigargin] is a specific inhibitor of the sarco-
endoplasmic reticulum calcium transport ATPase (SERCA) family, thus
suggesting a possible use in the fight against cancer.” Spec. ¶ 4. The most
prominent compound of the thapsigargin family is thapsigargin. Id. ¶ 5. “At
present Thapsia garganica plants are the only commercially reasonable
source for the compound thapsigargin because due to the complex chemical
structure of this compound, it cannot be chemically synthesized at an
economically reasonable price.” Id. ¶ 6. The molecular structure of
thapsigargin is shown below.

Fig. 2, reproduced above show, shows the chemical structure of
thapsigargin. Id. ¶ 17. The Specification lists 13 members belonging to the
hexaoxygenated thapsigargin family. Id. ¶ 21.
Claims 1, 3, 5, 7, 8, 10, and 11 are on appeal, and can be found in the
Claims Appendix of the Appeal Brief. Claim 1 is representative of the
claims on appeal, and reads as follows:
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1. A method of producing sesquiterpene lactones of the
thapsigargin family, the method comprising the steps of:
(a) culturing non-embryogenic plant cells of the genus
Thapsia in a nutrient medium in a suspension cell culture,
wherein the cells produce one or more sesquiterpene lactones of
the thapsigargin family, and wherein the nutrient medium is
free of 2,4-Dichlorophenoxyacetic acid; and
(b) recovering the one or more sesquiterpene lactone( s)
of the thapsigargin family produced in (a);
wherein the one or more of the sesquiterpene lactones of
the thapsigargin family comprises a 2β,3α,7β,8α,10β,11α-
hexaoxygenated-6β,12-guaianolide nucleus.
Appeal Br. 19 (Claims Appendix).
REJECTION
Appellant requests review of the rejection of claims 1, 3, 5, 7, 8, 10,
and 11 under 35 U.S.C. ¶ 103 over Smitt2 in view of Smetanska,3 Steward,4
and Gantet.5
ANALYSIS
Examiner finds that Smitt teaches the production of thapsigargins in
Thapsia garganica. Ans. 5. Examiner finds that Smitt teaches suspension
cultures of Thapsia gargancia. Id. at 6. Examiner finds that “[w]hen callus
cultures were transferred to media deprived of 2,4-D, the Thapsia garganica

2 Smitt et al., XXIV Thapsia garganica L.: In Vitro Culture, Somatic
Embryogenesis, and the Production of Thapsigargins, 37 Biotechnology in
Agriculture and Forestry, 402–9 (1996) (“Smitt”).
3 Smetanska, Production of Secondary Metabolites Using Plant Cell
Cultures, 111 Adv. Biochem. Engin./Biotechnol. 187–228 (2008).
4 Steward et al., US 2012/0225936 A1, published Sept. 6, 2012 (“Steward”).
5 Gantet et al., Necessity of a Functional Octadecanoic Pathway for Indole
Alkaloid Synthesis by Catharanthus roseus Cell Suspensions Cultured in an
Auxin Starved Medium, 39 Plant Cell Physiol. 220–25 (1998) (“Gantet”).
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in vitro cultures produced the thapsigargins nortrilobolid and trilobolid. Id.
(citing Smitt 406, table 2). Examiner acknowledges that Smitt “does not
explicitly teach the production of thapsigargin sesquiterpene lactones
[comprising a 2β,3α,7β,8α,10β,11α-hexaoxygenated-6β,12-guaianolide
nucleus] using Thapsia suspension cells cultured in a nutrient medium that is
free of 2,4-D.” Id. Examiner nevertheless concludes that production of these
secondary metabolites would have been obvious, citing Smetanska, Steward,
and Gantet in support. See id. at 7–10. Examiner relies on Smetanska for
teaching that “the growth regulator 2,4-D has been shown to inhibit the
production of secondary metabolites” at least in some circumstances. Id. at 8
(emphasis removed). Examiner relies on Steward for teaching that removing
2,4-D enhances secondary metabolite production. Id. at 9. Examiner relies
on Gantet for teaching that auxin-depleted medium induces alkaloid
biosynthesis. Id. at 10. Examiner concludes that based on the combination of
references one of ordinary skill in the art would have been motivated to
grow Thapsia species in auxin-depleted media “for the purpose of producing
secondary metabolites such as the terpenoids sesquithapsigargins.” Id.
Appellant contends that the proembryonic callus cultures of Smitt
“were grown in the presence of 2,4-D but then transferred to four solid
media free of 2,4-D [and] did not produce any thapsigargins. It was only
after the embryos had developed a little further into the cotyledonary stage
that any thapsigargins were synthesized.” Reply Br. 2; Appeal Br. 5. Most
notable, however, is that the thapsigargins that were produced were not
hexaoxygenated thapsigargins as claimed. Reply Br. 2; Appeal Br. 8.
Appellant contends that “[a]t best, Smetanska taught that 2,4-D can either
stimulate or inhibit the production of secondary metabolites.” Reply Br. 5;
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see also Appeal Br. 11 (“it even teaches that 2,4-D can be both inhibitory
and stimulatory in the same plant cell depending on the desired
compounds”). Appellant contends that Steward does not provide any further
insight because “using 2,4-D free medium is not sufficient for induction of
the production of triptolide in Tripterygium sp, suspension cultures” a
different plant species than presently claimed. Appeal Br. 12. Finally,
Appellant contends that Gantet teaches using auxin-starved medium to
produce indole alkaloid secondary metabolite in a different type of plant.
Based on these disclosures, Appellant contends that there is neither
motivation nor expectation of success in the combination. See Appeal Br.
14–15.
The issue is whether the preponderance of evidence of record supports
Examiner’s conclusion that the combination of references teaches the
claimed method of thapsigargin production, specifically, those having a
hexaoxygenated nucleus.
“[E]xaminer bears the initial burden, on review of the prior art or on
any other ground, of presenting a prima facie case of unpatentability.” In re
Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). To establish obviousness,
there must be “an apparent reason to combine the known elements in the
fashion” recited in the claims. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
418 (2007). “To differentiate between proper and improper applications of
‘obvious to try,’ [the U.S. Court of Appeals for the Federal Circuit] outlined
two classes of situations where ‘obvious to try’ is erroneously equated with
obviousness under § 103.” In re Kubin, 561 F.3d 1351, 1359 (Fed. Cir.
2009), citing In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988).
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Smitt discloses using six different media for the initiation of calli from
Thapsia species:
(A)(1) = Murashige and Skoog minimal medium with 0.2 mg/l
kinetin and 2 mg/l indole-3-acetic acid (IAA);
(A)(2) = Murashige and Skoog minimal medium with 1 mg/l 2,4-
dichlorophenoxy acetic acid (2,4-D), l mg/l 1-naphthalene
acetic acid (NAA), and l mg/l benzylaminopurine (BAP);
(B)(1) = Murashige and Skoog medium with 0.2 mg/l kinetin and
2 mg/l IAA);
(B)(2) = Murashige and Skoog medium with 1 mg/l 2,4-D, l mg/l
1- NAA, and l mg/l BAP;
(C)(1) = B5 medium with 0.2 mg/l kinetin and 2 mg/l IAA;
(C)(2) = B5 medium with 1 mg/l 2,4-D, l mg/l NAA, and l mg/l
BAP.
Smitt 405. According to Smitt, the best growth medium proved to be (C)(2)
containing 2,4-D and was used for all maintenance cultures. Id. Smitt
teaches that “[t]hapsigargins were not produced spontaneously in either calli
or suspension cultures from any of the plants.” Id., see also id. at 408.
Table 2 of Smitt lists the results of secondary metabolite production
from cultures after transfer to media deprived of 2,4-D:

The table shows that the callus culture did not produce thapsigargin. Id. at
407. Only when the cell cultures transition to embryos or “a little further into
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the cotyledonary stage and became green did the synthesis of two
thapsigargins, nortrilobolid Ill, and trilobolid IV start.” Id. at 408. Thus,
thapsigargin production in Smitt did not occur until the cultures entered the
embryonic stage, and the thapsigargins that were produced contained a
pentaoxygenated nucleus. Id. at 405 (see Fig. 2).
Smetanska teaches that many physical or chemical factors can
influence the production of secondary metabolites. Smetanska 198. For
example, “[t]he growth regulator 2,4-D has been shown to inhibit the
production of secondary metabolites in a large number of cases.” Id. at 208.
Smetanska at the same time teaches that in some plant cells 2,4-D does the
opposite and works to enhance secondary metabolite production. Id.
Steward discloses a method for producing triptolide from a suspension
cell culture of Tripterygium sp. Steward ¶ 57. Steward suggests using a
hormonal elimination medium containing no 2,4-D and NAA for the
synchronization of cells, i.e. depression of the terpene biosynthesis pathway
and activation of the defense pathways for the production of triptolide, a
precursor of the terpene biosynthesis pathway. Id. ¶¶ 65, 66, 75.
Gantet also discloses using auxin-starved medium. See Gantet, Title
and Abstract. “Alkaloid biosynthesis was induced by transferring
C[atharanthus] roseus cells from a medium containing an auxin, 2,4-
dichlorophenoxyacetic acid (2,4-D), to a 2,4-D-depleted medium.” Id. at
220. “Cells cultured in the presence of auxin (m-cells) did not accumulate
alkaloids. The addition of exogenous [methyl jasmonate (mJA)] to m-cells
restored the ability to produce alkaloids. In cells cultured in a 2,4-D-starved
medium (p-cells), exogenous mJA greatly increased alkaloid production.”
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Id. at Abstract. This implies that cells cultured in 2,4-D-starved medium (p-
cells) showed alkaloid production.
The teachings of Smetanska, Steward, and Gantet suggest that in some
circumstances culturing plant cells in auxin-starved medium may support
secondary metabolite production. On the other hand, Smetanska also teaches
that in some circumstances auxin starvation does not increase secondary
metabolite production. Therefore, the combined teachings of the references
suggest that the person of ordinary skill in the art would not know at the
outset whether auxin starvation would reasonably produce a secondary
metabolite, let alone a thapsigargin having a hexaoxygenated nucleus as
claimed.
An impermissible “obvious to try” situation occurs when the art
provides only a general approach that seemed promising and only provides
general guidance as to how to achieve the invention. Kubin, 561 F.3d at
1359 (citing O’Farrell, 853 F.2d at 903). We recognize that a finding of
obviousness does not require absolute predictability but there should be at
least a reasonable expectation of success. O’Farrell, 853 F.2d at 904–905.
As discussed above, Smitt teaches that “[n]either callus nor
suspension cultures of T. garganica produced thapsigargins.” Smitt 408, see
also 405 (“Thapsigargins were not produced spontaneously in either calli or
suspension cultures from any of the plants”). Both T. garganica callus and
suspension cultures instead produced an unknown compound that is neither
present in the mother plant nor in other Thapsia species. Id. This unknown
compound does not appear to be a thapsigargin because it behaves
differently on thin layer chromatography or in HPLC systems. Id.
Furthermore, the thapsigargins that are produced in Smitt have a
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pentaoxygenated nucleus and not the hexaoxygenated nucleus as claimed.
See Appeal Br. 8. The disclosure of Smitt therefore weighs against finding a
reasonable expectation of success, a necessary condition in order to fall
within a permissible class of “obvious to try” rationale under KSR and
O’Farrell. This lack of reasonable expectation is further buttressed by
Smetanska teaching that 2,4-D depletion does not always support secondary
metabolite production. See Smetanska 208. Thus, based on the combined
teachings we find there is no reasonable expectation that growing pre-
embryonic cultures in 2,4-D deprived medium will produce thapsigargins
having a hexaoxygenated nucleus.
The preponderance of evidence of record does not support Examiner’s
conclusion that the combination of Smitt, Smetanska, Steward, and Gantet
renders the claims obvious. Accordingly, we reverse the rejection of claims
1, 3, 5, 7, 8, 10, 11 under 35. U.S.C. 103.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 3, 5, 7, 8,
10, 11
103 Smitt, Smetanska,
Steward, Gantet
1, 3, 5, 7, 8,
10, 11

REVERSED