Ex Parte Afeyan et al

Patent Trial and Appeal Board

Oct 23, 2012

10922820 (P.T.A.B. Oct. 23, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte NOUBAR B. AFEYAN,
JAN VAN DER GREEF, FREDERICK E. REGNIER,
ARAM S. ADOURIAN, ERIC K. NEUMANN, MATEJ ORESIC,
and ELWIN ROBBERT VERHEIJ
__________

Appeal 2011-005471
Application 10/922,820
Technology Center 1600
__________

Before TONI R. SCHEINER, LORA M. GREEN, and
FRANCISCO C. PRATS, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to a process of
identifying biomarkers indicative of the biological state of a mammal. The
Examiner entered a rejection for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The Specification discloses that, “[r]ather than artificially simplifying
the inherent complexity of biological processes that underlie the biology of a
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complex organism, e.g., the biological processes involved in human diseases
or that govern drug responses, the methods and systems described herein
embrace the complexities and interdependencies contained within a
biological system” (Spec. 2). Thus, by “appropriately visualizing and
considering the complexity of a biological system, a skilled artisan can
undertake biological research at the systems level, developing a profile for a
state of a biological system which provides insight into the biological system
as a whole” (id.).
Claims 16, 17, 19, 21-23, 28, and 34-38 stand rejected and appealed
(see Ans. 4; App. Br. 6). Claims 16 and 23 are representative of the two
groups of claims argued by Appellants (see 37 C.F.R. § 41.37(c)(1)(vii))
and read as follows:
16. A method of identifying biomarkers indicative of a state of a
biological system in a mammal, the method comprising:
preprocessing a plurality of data sets comprising spectrometric
measurements of at least two different biomolecular component types
to generate a preprocessed data set, wherein the spectrometric
measurements are from a spectrometric measurement technique
comprising mass spectrometry, nuclear magnetic resonance
spectrometry, liquid chromatography, gas chromatography, high
performance liquid chromatography, or capillary electrophoresis;
evaluating using a suitably programmed computer the
preprocessed data set with statistical analysis and comparing features
of the evaluated data to develop a profile of one or more biomarkers;
and
displaying at least a portion of at least one of the plurality of
data sets comprising spectrometric measurements, the spectrometric
measurements, the preprocessed data set, and the evaluated data
relevant to the profile, which profile is indicative of the state of the
biological system in the mammal.

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23. The method of claim 16 wherein the plurality of data sets
comprise spectrometric measurements derived from more than one
type of spectrometric measurement technique.

The sole rejection before us for review is the Examiner‟s rejection of
claims 16, 17, 19, 21-23, 28, and 34-38 under 35 U.S.C. § 103(a) as obvious
over Sabry
1
and Aranibar
2
(Ans. 4-7).

DISCUSSION
The Examiner found that Sabry described a process of “using a
database system for predictive cellular bioinformatics by characterizing the
cell state based on feature measurements” (Ans. 4), the process substantially
including the steps required by claim 16 (see id. at 4-5). The Examiner
conceded, however, that Sabry did not “specifically describe spectrometric
measurements from a spectrometric technique comprising mass
spectrometry, nuclear magnetic resonance spectrometry, liquid
chromatography, gas chromatography, high performance liquid
chromatography, or capillary electrophoresis” as claim 16 require (id. at 5).
To address that deficiency, the Examiner cited Aranibar as describing
a similar process of “metabolome [or metabolite] profiling the state of a
biological system of an animal/mammal (title, abstract, 0011)” (id. at 6).
The Examiner found that, like Sabry, Aranibar‟s process included steps
substantially corresponding to those required by claim 16, as well as the use

1
U.S. Patent No. 6,615,141 B1 (filed November 21, 2000).
2
U.S. Patent App. Pub. No. 2003/0023386 A1 (filed January 18, 2002).
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in the profiling method of data generated using the spectrometric methods
recited in claim 16 (see id.).
Based on the references‟ combined teachings, the Examiner
concluded that an ordinary artisan would have considered it obvious to “use
spectrometric measurements from a spectrometric technique as taught by
Aranibar et al. in the method of Sabry” (id.). The Examiner reasoned that
an ordinary artisan would have been prompted to use those techniques to
evaluate mammalian samples as required by claim 16 so as to “rapidly assay
to assess the activity of compounds against drug targets, as stated by Sabry
et al. (Background of the Invention) and diagnose specific diseases and
allow for screening for unspecified changes upon treatment with unknown
compounds or genetic modification, as stated by Aranibar” (id. at 6-7).
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.

We have carefully considered all of Appellants‟ arguments.
Appellants‟ arguments do not persuade us, however, that a preponderance of
the evidence fails to support the Examiner‟s conclusion that claim 16 would
have been obvious to an ordinary artisan.
Aranibar discloses processes which “apply neural network technology
to recognize small metabolic changes in microorganisms, plants or animals
to detect changes induced by pesticide (herbicide, insecticide, fungicide)
treatment, genetic modification, environmental stress, and other external or
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internal factors that have influence on metabolite concentrations” (Aranibar,
abstract). As Aranibar explains, the artificial neural network, or ANN (id. at
[0005]), is essentially an automated pattern recognition system that uses
spectrometric or chromatographic data generated from biological samples to
determine, based on metabolites detected in the samples, the metabolic state
of the source organism as compared to other organisms (see id. at [0050]).
In Aranibar‟s process, which focuses largely on analyzing the
response of plants to herbicide treatments (see id. at [0071]), spectra or
chromatograms are generated from samples of plants grown under different
conditions, and suitable mathematical models are then used to compare the
spectra/chromatograms and thereby assess the metabolic state of the
particular plant being evaluated (id. at [0075]-[0082]; see also [0116]-[0120]
(neural network as suitable mathematical model)). Aranibar discloses that,
before the ultimate computerized comparative analysis is performed, the
data is processed into a suitable format (see id. at [0105] (“The data acquired
and processed on the analytical instrument is exported and converted into a
format suitable for the ANN program used.”); see also id. at [0114]
(preferred embodiment “involves the generation of a database of information
that contains, for specific defined treatments, the metabolic profiles in a
suitable format”)).
Given Aranibar‟s disclosure of processing the spectral/
chromatographic data into a format suitable for the ultimate computer-based
analysis, we are not persuaded that the Examiner erred in finding that the
cited references teach the preprocessing step of claim 16. We are also not
persuaded that the Examiner erred in finding that the cited references teach
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that the preprocessed data includes data regarding “two different
biomolecular component types” as claim 16 also requires.
Specifically, as Aranibar explains, optimal preparation of tissue
samples allows analysis of data regarding “the widest range of primary
metabolites (amino acids, sugar, sugar-alcohols, organic acids, etc.). Due to
the relative low sensitivity of NMR spectroscopy, it is important to choose
as many of the metabolites present in the highest concentrations as probes
for the total metabolic profile” (id. at [0271]).
In addition to these different types of compounds for which Aranibar
generates data, as the Examiner pointed out, Aranibar further discloses that
the “methods of this invention can be used to compare the profile of protein
expression with the protein product in genetically modified
plants/microorganisms. The profile of protein expression can be correlated
with the metabolic responses to stress factors” (id. at [0188]).
Thus, given Aranibar‟s disclosure that NMR analysis of biological
samples generates data regarding a wide range of different types of
compounds, including amino acids, sugars, sugar-alcohols, and organic
acids, and further given Aranibar‟s teaching of using the “methods of this
invention” (id.) to compare protein expression profiles with the metabolite
data, we are not persuaded that the cited references fail to teach or suggest
preprocessing data regarding at least two different biomolecular component
types, wherein the data is generated from one of the techniques recited in
claim 16.
Appellants urge that metabolites are a single type of “biomolecular
component” (App. Br. 18), despite the fact that a number of significantly
different types of compounds can be considered metabolites (see Aranibar
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[0271]). Appellants do not, however, point to a definition of “biomolecular
component type” in either the art or the Specification suggesting an ordinary
artisan would have considered amino acids, sugars, sugar-alcohols, and
organic acids to be a single type of biomolecular component.
The Specification does not positively define “biomolecular
component type” (see Spec. 11). Rather, although the Specification does list
a number of different biomolecular component types, including metabolites
and proteins, there appears to be significant overlap among the different
types, as evidenced by the fact that peptides can be included with either
proteins or metabolites (see id.). Moreover, Appellants point to no clear or
specific evidence suggesting that the techniques preferred by Aranibar,
NMR and mass spectroscopy (Aranibar [0052]), both of which are recited in
claim 16, would fail to detect or measure proteins or peptides present in a
mammalian sample.
Thus, in the absence of a positive, clear, definition of “biomolecular
component type,” and in light of Aranibar‟s teaching that NMR and mass
spectroscopy analysis of a biological sample were useful for evaluating the
presence of a number of distinct types of compounds in the sample, we are
not persuaded that Aranibar‟s data preprocessing step fails to include data
from measurements of at least two different biomolecular component types,
as claim 16 requires. Accordingly, we are not persuaded that the cited
references fail to suggest claim 16‟s preprocessing step.
We are also not persuaded that Aranibar fails to use statistical analysis
to compare features of the preprocessed data, as required in the evaluating
step of Appellants‟ claim 16. As noted above, Aranibar uses a neural
network to analyze the preprocessed NMR/mass spectroscopy data, and to
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compare data between different biological samples (see Aranibar [0050]).
As Aranibar explains, a neural network is “an automated pattern recognition
system” (id.; see also, id. at [0063]). As disclosed in Appellants‟
Specification, statistical analysis includes “pattern recognition techniques”
(Spec. 14).
Thus, for the reasons discussed, Appellants‟ arguments do not
persuade us that the cited references fail to teach or suggest claim 16‟s
preprocessing and evaluating steps. As to claim 16‟s final displaying step,
Appellants do not clearly or specifically dispute the Examiner‟s finding that
Aranibar‟s process includes a step of “displaying relevant information”
(Ans. 6), and we discern no error in that respect.
While Aranibar describes all of the manipulative steps of claim 16,
Aranibar focuses its methods on plant tissue, rather than the mammal
required by claim 16. Appellants‟ arguments nonetheless do not persuade us
that the Examiner erred in finding that an ordinary artisan would have been
motivated to apply Aranibar‟s spectrometric techniques, or the attendant
computational analysis, to Sabry‟s mammalian cell samples.
Specifically, Aranibar includes a number of teachings suggesting that
combining NMR measurements of mammalian samples with neural
network/pattern recognition analysis, analogous to the methods described by
Aranibar for analyzing plants, would be useful for evaluating a mammal‟s
response to diseases and drug treatments (see Aranibar [0003]-[0004],
[0010]-[0011], [0027]). Thus, while we note that Sabry‟s analysis focuses
on morphological and structural attributes of mammalian cells (see Sabry,
col. 6, ll. 47-61), given Aranibar‟s suggestion that combining NMR with
pattern recognition analytical techniques would be useful for evaluating
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mammalian samples, we are not persuaded than an ordinary artisan lacked
motivation, or a reasonable expectation of success, for applying Aranibar‟s
analytical methods to evaluate mammalian samples.
In sum, because we are not persuaded that the cited references would
have failed to suggest a process having all of the steps recited in claim 16,
we conclude that the Examiner has made out a prima facie case of
obviousness as to that claim. We are also unconvinced that a preponderance
of the evidence fails to support the Examiner‟s prima facie case as to the
other representative claim, claim 23.
Claim 23 recites “[t]he method of claim 16 wherein the plurality of
data sets comprise spectrometric measurements derived from more than one
type of spectrometric measurement technique” (App. Br. 40). As the
Examiner pointed out, Aranibar discloses that its process can use data from
more than one type of spectrometric measurement technique: “[I]n certain
embodiments, the chromatographic technique for obtaining data is gas
chromatography. In certain embodiments, the spectroscopic technique is
nuclear magnetic resonance spectroscopy or mass spectroscopy. In other
embodiments, the technique for obtaining data is some combination of any
chromatographic or spectroscopic technique.” (Aranibar [0052] (emphasis
added).)
Given the plain teaching of using a “combination of any
chromatographic or spectroscopic technique” (id.), we are not persuaded that
Aranibar fails to suggest incorporating into the analysis data from more than
one type of spectrometric technique, as claim 23 requires. Accordingly,
Appellants‟ arguments do not persuade us that a preponderance of the
evidence fails to support the Examiner‟s prima facie case as to claim 23.
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We are also not persuaded that Appellants have advanced evidence of
secondary considerations sufficient to overcome the prima facie case of
obviousness as to either claim 16 or claim 23.
As evidence of commercial success, Appellants advance the Adourian
Declaration,
3
in which Dr. Adourian, a co-inventor of the subject matter
claimed herein and vice president of BG Medicine (Adourian Dec. ¶¶ 1, 3),
states that “BG Medicine entered into a multi-year commercial research and
development contract in 2004 with the global pharmaceutical company
GlaxoSmithKline, Research Triangle Park, North Carolina („GSK‟)” (id. at ¶
9; see also App. Br., Evidence App‟x, Exhibit 4 (BG Medicine Press
Release
4
(GSK to pay upfront fee and fund research program for full term))).
As Dr. Adourian explains, the GSK collaboration yielded, in part,
International Application PCT/US2008/007304 (published December 24,
2008 as WO 2008/156617 A2) which describes using BG Medicine‟s
“technology platform,” which includes data preprocessing and evaluations
steps, “to identify biomarker profiles that are indicative of the biological
state of a human patient diagnosed with type 2 diabetes mellitus, and that
predict successfully the response of human patients diagnosed with type 2
diabetes mellitus to treatment with certain pharmacological agents”
(Adourian Dec. ¶ 9).

3
Declaration of Dr. Aram S. Adourian under 37 C.F.R. § 1.132 (executed
June 3, 2009).
4
http://www.bg-medicine.com/content/news-center/news/q/id/54.
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Dr. Adourian also cites the Clish,
5
Oresic,
6
and Davidov
7
articles as
supporting “the commercial utility, scientific and commercial significance,
and scientific and commercial success of the pending claims. In particular,
the scientific subject matter of these three scientific journal publications is
described in the examples of the specification of the present application” (id.
at ¶ 12).
Dr. Adourian explains that the articles “were used by BG Medicine to
demonstrate a fundamental part of its technology platform, including the
subject matter of the pending claims, to commercial partners and
collaborators” and also “played a significant role in BG Medicine being able
to attract and secure commercial business for the Company” (id. at ¶ 17).
Dr. Adourian concludes:
[I]t is my opinion that the subject matter of the pending
claims in the present application forms a fundamental part of
BG Medicine‟s technology platform and has been a significant
factor in the Company‟s ability to attract and secure
commercial business for the Company, as exemplified above,
as well as to promote beneficial research and development
toward improving health care.

5
Clary B. Clish et al., Integrative Biological Analysis of the APOE*3-Leiden
Transgenic Mouse, 8 OMICS 3-12 (2004).
6
Matej Orešič et al., Phenotype Characterisation Using Integrated Gene
Transcript, Protein, and Metabolite Profiling, 3 APPL. BIOINFORMATICS 1-13
(2004). Note that, while the title, journal, and volume number of the Oresic
article in the Evidence Appendix to the Appeal Brief are the same as cited in
the Adourian Declaration, the Declaration appears to incorrectly cite the
article as appearing at pages 205 of the journal (see Adourian Dec. ¶ 13).
7
Eugene Davidov et al., Methods for the Differential Integrative Omic
Analysis of Plasma from a Transgenic Disease Animal Model, 8 OMICS
267-288 (2004).
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(Id. at ¶ 18.)
Based on this evidence, Appellants urge that “BG Medicine‟s
collaboration with a world-leading biopharmaceutical company, which
collaboration successfully used the claimed invention to generate profiles of
biomarkers, evidence the commercial success of the claimed invention”
(App. Br. 31). While Appellants concede that the “monetary value of the
collaboration is confidential and unknown publicly,” Appellants argue that
“such a world-leading biopharmaceutical company would not invest time
and financial resources to enter into an agreement absent an expectation of
successfully achieving the goal of the collaboration as well as backing up its
expectations with an appropriate monetary incentive and reward” (id.).
It might be true, despite Appellants‟ reluctance to advance specific
sales figures with respect to the technology platform of BG Medicine, that
certain embodiments encompassed by representative claims 16 and 23 have
achieved a level of commercial success.
As the Federal Circuit has pointed out, however, “evidence of
commercial success alone is not sufficient to demonstrate nonobviousness of
a claimed invention.” In re DBC, 545 F.3d 1373, 1384 (Fed. Cir. 2008).
Instead, “the proponent must offer proof „that the sales were a direct result
of the unique characteristics of the claimed invention-as opposed to other
economic and commercial factors unrelated to the quality of the patented
subject matter.‟” Id. (quoting In re Huang, 100 F.3d 135, 140 (Fed. Cir.
1996)).
Thus, “the applicant must submit some factual evidence that
demonstrates the nexus between the sales and the claimed invention-for
example, an affidavit from the purchaser explaining that the product was
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purchased due to the claimed features.” Huang, 100 F. 3d at 140 (holding
that an inventor‟s affidavit stating an opinion as to purchaser‟s reasons for
buying claimed product was insufficient to outweigh prima facie
obviousness).
In the instant case, while Appellants have advanced Dr. Adourian‟s
opinion that the collaboration with GSK was due to the features of claims 16
and 23, Appellants provide no specific evidence, other than the existence of
the collaboration itself, that provides a factual basis for that opinion.
Moreover, other than Dr. Adourian‟s opinion, Appellants advance no
specific evidence directly tying GSK‟s investment to the claimed features, as
opposed to economic or commercial factors unrelated to the claims.
Compare, In re Huang, 100 F.3d at 140.
Also, as the Examiner points out (Ans. 15), it is well settled that
“[e]vidence of secondary considerations must be reasonably commensurate
with the scope of the claims.” In re Kao, 639 F.3d 1057, 1068 (Fed. Cir.
2011).
Thus, the Adourian Declaration repeatedly refers to evaluating
samples “by multiple types of spectrometric techniques” (Adourian Dec. ¶ 7;
see also id. at 9, 11, 15, 16). In contrast, however, representative claim 16
encompasses the use of a single spectrometric technique.
While representative claim 23 recites the use of more than one
spectrometric technique, neither claim 23 nor claim 16 is limited to
assessing any particular disorder, or using any particular type of statistical
analysis. In contrast, the „304 PCT application is limited to providing
diagnostic analysis regarding type II diabetes (see Adourian Dec. ¶ 9), and
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uses specific types of multivariate analysis (see „304 PCT App. at p. 17),
none of which is required by either claim 16 or 23.
Similarly, the Clish, Oresic, and Davidov articles are limited to the
evaluation of a mouse model for atherosclerosis (see Clish 3, Oresic 1,
Davidov 267), and use specific methods of statistical analysis (see Clish 7,
Oresic 4-11, Davidov 270), none of which are required by either claim 16 or
23. Thus, to the extent Appellants urge that the „304 PCT Application and
the Clish, Oresic, and Davidov articles provide evidence that underlies and
substantiates the commercial success Appellants allege, claims 16 and 23
recite much subject matter that is significantly broader than any showing
those publications might support.
In sum, for the reasons discussed, we are not persuaded that the
evidence of secondary considerations advanced by Appellants is sufficient to
outweigh the evidence advanced by the Examiner to support the prima facie
case of obviousness. Accordingly, as we conclude that a preponderance of
the evidence supports the Examiner‟s decision to maintain the obviousness
rejection of claims 16 and 23, we affirm the Examiner‟s rejection of those
claims over Sabry and Aranibar. The remaining claims fall with claims 16
and 23. See 37 C.F.R. § 41.37(c)(1)(vii).

SUMMARY
We affirm the Examiner‟s obviousness rejection of claims 16, 17, 19,
21-23, 28, and 34-38 over Sabry and Aranibar.

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TIME PERIOD
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

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