Ex Parte West et al

Patent Trials and Appeals Board

Apr 12, 2019

14257299 - (D) (P.T.A.B. Apr. 12, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/257,299 04/21/2014
21710 7590 04/16/2019
BROWN RUDNICK LLP
ONE FINANCIAL CENTER
BOSTON, MA 02111
FIRST NAMED INVENTOR
PaulR. West
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
STEM-001/03US 33600/6 8927
EXAMINER
TON, THAIAN N
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
04/16/2019 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):
ip@brownrudnick.com
usactions@brownrudnick.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PAUL R. WEST, APRIL M. WEIR-HAUPTMAN,
ALAN M. SMITH, ELIZABETH L.R. DONLEY,
and GABRIELA G. CEZAR
Appeal 2017-011411
Application 14/257 ,299 1
Technology Center 1600
Before DONALD E. ADAMS, RY ANH. FLAX, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of predicting human developmental toxicity of a test compound, which have
been rejected as anticipated and obvious. We have jurisdiction under 35
U.S.C. § 6(b ).
We reverse.
1 Appellants identify the real party in interest as Stemina Biomarker
Discovery, Inc. (Appeal Br. 3.)
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Application 14/257 ,299
STATEMENT OF THE CASE
The Specification states that, "the art has lacked a robust and efficient
model for testing developmental toxicity for the more than 80,000 chemicals
in the market, plus the new 2,000 compounds introduced annually." (Spec.
2.) "[S]ome attempts have been made to use animal model systems to assess
toxicity ... [but] differences in the sensitivity of humans in utero have
limited the predictive usefulness of such models." (Id.) An in vitro model
that uses "mouse embryonic stem cells as a screening system for predictive
developmental toxicology ... is limited in part because toxicological
endpoints are defined only for compounds that impair cardiac differentiation
... [ and because it ] fails to account for interspecies developmental
differences between mice and humans."
Metabolomics, assessing "functional changes in biochemical
pathways by detecting changes to the dynamic set of small molecules that
comprise the metabolome" in conjunction with human embryonic stem cells
has been used in biomarker discovery. (Id. at 2-3.) "The invention provides
human-specific in vitro methods for reliably determining toxicity,
particularly developmental toxicity and teratogenicity of pharmaceuticals
and other chemical compounds" using human stem-like cells ("hSLCs") and
metabolomics. (Id. at 3.)
Claims 1, 2, 5, 14, 18, and 32-35 are on appeal. Claim 1 is
representative and reads as follows:
1. A method of predicting human developmental toxicity of a
test compound, the method comprising the steps of:
(a) culturing human stem-cell like cells (hSLCs):
(i) in the presence of a first known developmental
toxicant; and
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Application 14/257 ,299
(ii) in the absence of the first known
developmental toxicant;
(b) detecting a plurality of metabolites having a
molecular weight of less than about 3000 Daltons
associated with hSLCs exposed to the first known
developmental toxicant in comparison with hSLCs not
exposed to the first known developmental toxicant in
order to identify a difference in metabolic response of
hSLCs exposed to the first known developmental
toxicant in comparison with hSLCs not exposed to the
first known developmental toxicant;
wherein the plurality of metabolites is detected by mass
spectrometry;
( c) generating a set of mass features associated with
exposure of hSLCs to the first developmental toxicant by
analyzing the difference in metabolic response;
( d) repeating steps a)-c) multiple times, each time with a
different known developmental toxicant;
( e) grouping mass features generated from each exposure
to a developmental toxicant to obtain a reference profile
of mass features correlating with developmental toxicity;
(f) culturing hSLCs;
(i) in the presence of a test compound; and
(ii) in the absence of the test compound;
(g) detecting a plurality of metabolites having a
molecular weight of less than about 3000 Daltons
associated with hSLCs exposed to the test compound in
comparison with hSLCs not exposed to the test
compound in order to identify a difference in metabolic
response of hSLCs exposed to the test compound in
comparison with hSLCs not exposed to the test
compound;
wherein the plurality of metabolites is detected by mass
spectrometry; and
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(h) generating a set of mass features associated with
exposure ofuSLCs to the test compound by analyzing the
difference in metabolic response;
(i) comparing the set of mass features associated with
exposure ofuSLCs to the test compound of step (h) to the
reference profile of mass features correlating with
developmental toxicity of step ( e) to predict the human
developmental toxicity of the test compound.
(Appeal Br. Claims Appendix Al-A2.)
The following grounds of rejection by the Examiner are before us on
review:
Claims 1, 5, 14, 18, 44--46, and 52 under 35 U.S.C. § 102 as
anticipated over Cezar. 2
Claims 1, 2, 52, and 53 under 35 U.S.C. § 103 as unpatentable
over Cezar.
Claims 37--40 under 35 U.S.C. § 103 as unpatentable over
Cezar and Sigma-Aldrich. 3
Claims 1 and 41--43 under 35 U.S.C. § 103 as unpatentable
over Cezar and Schrattenholz. 4
DISCUSSION
Anticipation
The Examiner finds that Cezar teaches screening human embryonic
stem cell (hESC) derived lineage specific cells by exposing the cells to
known teratogens and comparing the metabolic response between the tested
2 US 2007/0248947 Al, published Oct. 25, 2007.
3 Sigma-Aldrich, Metabolomics, 4(8) Life Science BioFiles 1-32 (2009).
4 US 2011/0143366 Al, published June 16, 2011.
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Application 14/257 ,299
and untested cells. (Final Action 4 ( citing Cezar ,r,r 11, 14, 3 7, and 4 7--49).)
The Examiner finds that Cezar teaches that "alterations in cells or cell
activity are measured by determining a profile of changes in cellular
metabolites having a molecular weight of less than 3000 Daltons." (Id. at 4--
5.) Cezar teaches using mass spectrometry to identify the metabolites. (Id.
at 5 (citing Cezar ,r,r 22, 23, 25, and 39).) The Examiner further finds that
"Cezar teaches performing the same steps with known and unknown
compounds." (Id.)
The Examiner explains further that "Cezar teaches [the] cellular
metabolite profiles that are obtained [ after exposing a cell to a teratogen] can
be used to compose a library of biomarker portfolios which can be used as a
reference for toxicological analysis of known compounds." (Id.) The
Examiner notes that Cezar states: "'This approach can reveal functional
markers of toxic response, which serve as screening molecules that are
shared at least in part as a consequence of exposure to various different toxic
and teratogenic compounds.' Seep. 6, ,r 47 and 53." (Id.; see also id.
(quoting Cezar ,r 14) ("Cezar teaches that their invention provides methods
for identifying predicative markers of toxic responses to toxic compounds,
including teratogens, by identification of a plurality of cellular
metabolites.").)
The Examiner particularly notes that the teaching in Cezar that its
"method can be applied to other known teratogens to establish metabolite
profiles (p. 8, ,r 65)" meets step ( d) of claim 1. Id. The Examiner also
particularly notes that Cezar's teaching that "cellular metabolite profiles can
be used to compose a library of biomarker profiles, as a reference for
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toxicological analysis of unknown compounds" meets step ( e) of claim 1.
(Id.)
The Examiner bears the burden of establishing a prima facie case of
unpatentability. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). On the
record before us, the Examiner has not established that Cezar teaches step e
of claim 1. 5 While it is true, as the Examiner notes (Ans. 3), that Cezar
teaches that the metabolic profiles of novel compounds can be compared to
identify common mechanisms of toxic response, and that the profiles are
collected into a library of biomarker portfolios (Cezar ,r 53), the Examiner
fails to explain how those two facts demonstrate that Cezar groups mass
features that were generated from each exposure into "a reference profile."
Cezar's biomarker portfolio is simply a collection of profiles for each
teratogen tested where each separate profile is a record of all the detected
metabolites after the hESC was exposed to a toxicant. While it may be true
that one of ordinary skill can look through each one of the profiles of the
library to determine a common metabolite or a set of common metabolites
and thus find a functional marker of toxic response, such does not teach the
creation of "a" reference profile as claimed. An example of creating such a
reference profile is described in Appellants' Specification. (See, e.g., Spec.
141-144 ( determining metabolites based on mass spectrometry through
identifiable mass features), id. at 144--150 (predicting teratogenicity using
subset of mass features determined across multiple data files.) The
Examiner has not pointed us to any similar disclosure in Cezar, nor do we
discern any. Moreover, we do not discern Cezar's teachings with respect to
5 This is also a step of independent claim 52.
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using mass spectrometry to teach a grouping of mass features determined
across teratogen exposures to obtain a profile that correlates with
developmental toxicity. (Cezar ,r,r 60-64 (identifying small molecules with
mass spectrometry after VPA treatment), id. ,r,r 76-80 (metabolite profile
after exposure to valproate ), id. ,r,r 91-92 (metabolite profile in response to
ethanol).)
Thus, for the foregoing reasons, we do not sustain the Examiner's
anticipation rejection of claims 1, 5, 14, 18, 44--46, and 52 over Cezar.
The Examiner's obviousness rejections rely on the position that Cezar
teaches step e of claim 1. (See, e.g., Final Action 7 (noting that step a is not
explicitly taught to be accomplished "in the presence of a known non-
developmental toxicant ( claim 2) or a non-teratogenic compound ( claim 20)"
but that such would have been obvious); id. at 8 ("Cezar is described above.
They do not explicitly teach that the set of metabolites comprises 1 or
more/5 or more/IO or more/15 or more small molecule metabolites shown in
table 8 ( claims 37--40)."); id. at 9 ("Cezar is summarized and relied upon as
detailed above. They do not explicitly teach that the mass spectrometry
comprises MALDI and/or SELDI (claims 41--43).)"; id. at 10 ("Cezar is
summarized and relied upon as detailed above. Cezar does not explicitly
teach the specific developmental toxicants in claims 47 and 49; the mass
features correlating with the toxicants of claim 48.").) For the reasons
discussed above, we disagree. Therefore, we do not sustain any of the
Examiner's obviousness rejection of claims 1, 2, 37--43, 52, and 53.
SUMMARY
We reverse the rejection of claims 1, 5, 14, 18, 44--46, and 52 under
35 U.S.C. § 102 as anticipated over Cezar.
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We reverse the rejection of claims 1, 2, 52, and 53 under 35 U.S.C.
§ 103 as unpatentable over Cezar.
We reverse the rejection of claims 37--40 under 35 U.S.C. § 103 as
unpatentable over Cezar and Sigma-Aldrich.
We reverse the rejection of claims 1 and 41--43 under 35 U.S.C. § 103
as unpatentable over Cezar and Schrattenholz.
REVERSED
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