Ex Parte Ramnarayan et al

Patent Trial and Appeal Board

Oct 25, 2012

10923620 (P.T.A.B. Oct. 25, 2012)

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.
10/923,620 08/19/2004 Kalyanaraman Ramnarayan 38355-1050 3220
7590 10/26/2012
Dr. Kal Ramnarayan
Sapient Discovery
10929 Technology Place, Suite B
San Diego, CA 92127
EXAMINER
BRUSCA, JOHN S
ART UNIT PAPER NUMBER
1631
MAIL DATE DELIVERY MODE
10/26/2012 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 KALYANARAMAN RAMNARAYAN
and
EDWARD T. MAGGIO
____________

Appeal 2011-009908
Application 10/923,620
Technology Center 1600
____________

Before TONI R. SCHEINER, DONALD E. ADAMS, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims 1-41, 50-66, and
68 (App. Br. 4; Reply Br. 2; Ans. 3). We have jurisdiction under 35 U.S.C.
§ 6(b).
STATEMENT OF THE CASE
The claims are directed to a computer-based method of drug design
based on genetic polymorphisms. Claim 1 is representative and is
reproduced in the Claims Appendix of Appellants‟ Brief.
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2

Claims 1-25, 27-41, 50-56, and 58-66 stand rejected under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Nair,
1
Chen,
2
Sali,
3

Shafer,
4
Pastor,
5
Matter,
6
and Dictionary.
7

Claims 1, 14, 25, 26, 55-57, and 68 stand rejected under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Nair, Chen, Sali, Shafer,
Pastor, Matter, Dictionary, and Mao.
8

We affirm.

1
Anil C. Nair, et al., A Computational Study of the Resistance of HIV-1
Aspartic Protease to the Inhibitors ABT-538 and VX-478 and Design of New
Analogues, 242 BIOCHEM. BIOPHYS. RES. COMM. 545-551 (1998).
2
Zhongguo Chen, et al., Three-dimensional Structure of a Mutant HIV-1
Protease Displaying Cross-resistance to All Protease Inhibitors in Clinical
Trials, 270(37) J. BIO. CHEM. 21433-21436 (1995).
3
Andrej Sali, 100,000 protein structures for the biologist, 5(12) NATURE
STRUCTURAL BIOLOGY 1029-1032 (1998).
4
Robert W. Shafer, et al., Human Immunodeficiency Virus Reverse
Transcriptase and Protease Sequence Database, 27(1) NUCLEIC ACIDS RES.
348-352 (1999).
5
Manuel Pastor and Gabriele Cruciani, A Novel Strategy for Improving
Ligand Selectivity in Receptor-Based Drug Design, 38 J. MED. CHEM. 4637-
4647 (1995).
6
Hans Matter and Wilfried Schwab, Affinity and Selectivity of Matrix
Metalloproteinase Inhibitors: A Chemometrical Study from the Perspective
of Ligands and Proteins, 42 J. MED. CHEM. 4506-4523 (1999).
7
Oxford English Dictionary, term “pharmacophore”,
http://dictionary.oed.com, accessed February 3, 2008.

8
Chen Mao, et al., RATIONAL DESIGN OF N-[2-(2,5-
DIMETHOXYPHENYLETHYL)]-N’-[2-(5-BROMOPYRIDYL)]-THIOUREA
(HI-236) AS A POTENT NON-NUCLEOSIDE INHIBITOR OF DRUG-
RESISTANT HUMAN IMMUNODEFICIENCY VIRUS, 9 BIOORGANIC &
MEDICINAL CHEMISTRY LETTERS 1593-1598 (1999).

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ISSUE
Does the preponderance of evidence on this record support a
conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Nair suggests “a computer mediated method of docking molecules
and designing drugs that interact with mutant HIV proteases” (Ans. 6).
FF 2. Nair suggests the construction of mutant protease structures in silico
for use in the design of new antiviral drug candidates and “shows … [two]
mutations that are outside the drug interaction site of HIV protease” (id. and
id. at 11).
FF 3. Nair suggests the refinement of the protease structure “by relaxation
of the crystal structure” (id. at 6; see also id. at 7 (Chen suggests “that the
model of the protease was refined using the program CHAIN on a Silicon
Graphics system”)).
FF 4. Nair “does not show determination of structures of the target mutant
HIV proteases by X-ray crystallography, use of a pharmacophore of
common features of variants of a target protein or databases comprising
protein structure or relational databases, or analysis of target proteins that
are eukaryotic nonviral proteins” (id. at 6-7).
FF 5. Nair directs attention to Chen, which determines “mutant HIV
protease structures by X ray crystallography,” “as the source of the structural
data used by Nair” (id. at 7).
FF 6. Sali suggests “databases that store protein structures … for
performing new research with the data” (id.).
FF 7. Shafer suggests “a relational database of HIV protease sequence
data” that “allows researchers to help prioritize clinical investigations and
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further experimental work, … to retrieve a set of sequences meeting specific
criteria[, and] … can be expanded to include additional information relating
to drug susceptibility” (id.; see also id. at 11-12 (Shafer‟s “database shows
drugs, HIV protease variants, and the efficacy of drugs against different HIV
protease variants,” including the “resistance and susceptibility of a
polymorphism to a drug”)).
FF 8. Pastor suggests “a method of distinguishing features of target protein
variants that either favor or mitigate against selectivity in binding different
ligands” (id.; see also id. at 9 (Pastor suggests the “generation of shapes that
… highlight regions of target proteins that are involved in binding to
ligands” and “allows for determination of those regions of a plurality of
target proteins that are important in discriminating between different ligand
structures … [and] facilitate binding of the same ligand [to] each of the
target proteins”)).
FF 9. Pastor and Matter both suggest the “determination of contour maps
of” enzymes (id. at 7-8).
FF 10. Matter suggests that contour map “data is useful for designing
inhibitors for … proteases with a desired specificity” (id. at 8).
FF 11. Dictionary “defines the term „pharmacophore‟ as a part of a
molecule that is responsible for its characteristic pharmacological activity; a
pharmacologically active group” (id.).
FF 12. The combination of Nair, Chen, Sali, Shafer, Pastor, Matter, and
Dictionary fails to suggest “a method of designing drugs that interact with
HIV reverse transcriptases” (id. at 10).
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FF 13. Mao suggests “a computer-mediated method of designing drugs that
interact with HIV reverse transcriptases that are derived from patients
treated with anitival drugs that inhibit the HIV reverse transcriptase” (id.).
ANALYSIS
The claims have not been argued separately and therefore stand or fall
together. 37 C.F.R. § 41.37(c)(1)(iv). Claim 1 is representative. Appellants
address the merits of both rejections collectively. Therefore, the following
analysis will address both rejections collectively.
Based on the combination of Nair, Chen, Sali, Shafer, Pastor, Matter,
and Dictionary, Examiner concludes that, at the time Appellants‟ invention
was made, it would have been prima facie obvious to a person of ordinary
skill in this art “to modify the method of Nair … by determining the target
structures by X ray crystallography because Nair … used structures
determined by [X] ray crystallography as shown in Chen” (Ans. 8; FF 1, 2,
and 5).
Examiner relies on the combination of Sali and Shafer to suggest that
relational databases are useful to: (1) access structural data to perform
further research, such as that suggested by Nair to design effective anti-HIV
drugs, (2) allow for data to be extracted that meets specific criteria, and (3)
allow additional information relevant to HIV to be added to the database
(Ans. 8-9; FF 6-7). Therefore, Examiner concludes that it would have been
prima facie obvious to a person of ordinary skill in this art to combine Nair
and Chen with Sali and Shafer “to store the data analyzed by Nair …
together with data of other drugs and HIV proteases[] in a relational
database” (id.; see also FF 1, 2, and 5).
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Based on the combination of Dictionary, Pastor, and Matter, Examiner
finds that “the contour maps of both Pastor … and Matter … are
pharmacophores that show ligand binding activity” (Ans. 9; see, FF 8-11).
In this regard, Examiner relies on Pastor and Matter to suggest the use of
“eukaryotic human target proteins ... [to] develop[] drugs that target ...
[enzymes, such as proteases, to determine] those regions of a plurality of
target proteins that are important in discriminating between different ligand
structures … [and] facilitate binding of the same ligand [to] each of the
target proteins” (Ans. 9; see also FF 8-10). Therefore, Examiner concludes
that it would have been prima facie obvious to a person of ordinary skill in
this art to combine Nair, Chen, Sali, and Shafer with Pastor and Matter “to
use pharmacophore shapes of structural features shared by desired target
proteins such as the HIV protease … [to] design … inhibitors that are
effective on a plurality of HIV protease variants by consideration of the
structural differences in the variant proteases” (Ans. 9; FF 1, 2, and 5-11).
Based on the suggestion in Nair and Chen to refine the structure of
HIV protease “using in silico molecular dynamics programs,” Examiner
concludes that a person of ordinary skill in this art would have found it
prima facie obvious to utilize in silico molecular dynamics programs in the
method suggested by the combination of Nair, Chen, Sali, Shafer, Pastor,
Matter, and Dictionary to refine the structure of the protein (Ans. 9; FF 3).
While Examiner appreciates that the combination of Nair, Chen, Sali,
Shafer, Pastor, Matter, and Dictionary fails to suggest “a method of
designing drugs that interact with HIV reverse transcriptases,” Examiner
finds that Mao suggests “a computer-mediated method of designing drugs
that interact with HIV reverse transcriptases that are derived from patients
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treated with antiviral drugs that inhibit the HIV reverse transcriptase” (Ans.
10; FF 12-13). Therefore, Examiner concludes that, at the time Appellants‟
invention was made, it would have been prima facie obvious to a person of
ordinary skill in this art to modify the method suggested by the combination
of Nair, Chen, Sali, Shafer, Pastor, Matter, and Dictionary to “design[] drugs
that interact the HIV reverse transcriptase” as suggested by Mao (Ans. 10-
11).
Appellants contend that “Nair fails to mention the use of a database to
correlate effective drugs based on the mutation with each polymorphism in a
relational database” (App. Br. 14; Reply Br. 4). While this may be true (see
FF 4); Nair was not relied upon in isolation. Therefore, we are not
persuaded by Appellants‟ intimation that, when considered alone, Nair, fails
to support Examiner‟s prima facie case of obviousness.
The test for obviousness is not whether the features of a
secondary reference may be bodily incorporated into the
structure of the primary reference; nor is it that the claimed
invention must be expressly suggested in any one or all of the
references. Rather, the test is what the combined teachings of
the references would have suggested to those of ordinary skill
in the art.

In re Keller, 642 F.2d 413, 425 (CCPA 1981); see also In re Merck & Co.,
Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (“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.”).
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The same is true for Appellants‟ contentions relating to Sali, relied
upon by Examiner to establish a fact that Appellants‟ do not dispute;
specifically, that databases of protein structures were known in the prior art
at the time of Appellants‟ claimed invention (App. Br. 14; Ans. 12; Reply
Br. 5; FF 6). Further, we are not persuaded by Appellants‟ unsupported
contention that Nair‟s work has no practical application (Reply Br. 5).
Argument by counsel cannot take the place of evidence. In re Geisler, 116
F.3d 1465, 1471 (Fed. Cir. 1997).
Appellants contend that while Shafer suggests the storage of protein
structures of mutant forms of HIV together with the drugs that induced the
HIV mutation in a relational database, Shafer fails to suggest a relational
database that comprises “drugs that are effective in treating the disease based
on polymorphisms” (id.). According to Appellants, “Shafer discloses a
backwards looking database (what mutation were caused by the drug),
whereas this application proposes a forward looking database (what drugs
are effective based on the polymorphism)” (id. at 14-15). We are not
persuaded.
As Examiner explains, Shafer‟s “database shows drugs, HIV protease
variants, and the efficacy of drugs against different HIV protease variants,”
including the “resistance and susceptibility of a polymorphism to a drug”
(FF 7). Examiner relies on Shafer and Sali to suggest relational databases
and the use of such databases to: (1) access structural data to perform further
research, such as that suggested by Nair to design effective anti-HIV drugs,
(2) allow for data to be extracted that meets specific criteria, and (3) allow
additional information relevant to HIV to be added to the database (Ans. 8-9;
FF 6-7). Therefore, while Shafer may not anticipate Appellants‟ claimed
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invention, Appellants failed to provide persuasive evidence or reasoning as
to why the combination of Shafer with the other evidence relied upon by
Examiner would not have suggested, i.e. made obvious, Appellants‟ claimed
invention (Cf. App. Br. 14-15). KSR Int’l v. Teleflex Inc., 550 U.S. 398, 418
(2007) (A fact-finder “need not seek out precise teachings directed to the
specific subject matter of the challenged claim [in an analysis of
obviousness], for a court can take account of the inferences and creative
steps that a person of ordinary skill in the art would employ.”).
We recognize, but are not persuaded by, Appellants‟ contention that
Pastor and Matter “vary amino acids within a binding site to attempt to
elucidate the characteristics of the binding sites … [but,] are not primarily
concerned with polymorphisms” (App. Br. 15). As Examiner explains,
Pastor and Matter were relied upon to suggest the “identification of
pharmacophores and structural analysis of eukaryotic proteins” (Ans. 11; FF
8-11). In this regard, Pastor “is focused on using contour maps for in silico
modeling of protein structures and designing drugs that interact with
proteins” and “shows success in developing in silico protein structures of
different dihydrofolate reductases and determining their ligand interaction
sites” (id.; FF 8-9).
We recognize Appellants‟ contention that “polymorphisms are not
limited to changes to binding sites,” but find that Examiner has the better
argument on this point (App. Br. 15; Cf. Ans. 11). Specifically, Appellants‟
claimed invention “does not have a limitation that the polymorphism is
outside a binding site” and the evidence relied upon by Examiner
contemplates “mutations that are outside the drug interaction site of HIV
protease” (Ans. 11; FF 2).
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We recognize, but are not persuaded by, Appellants‟ “emphasized
argument, which is that the combination of Pastor, Matter, and Nair together
fail to guide an artisan in the creation of a relational database containing data
related to how polymorphisms affect binding of drugs on a drug design
level” (Reply Br. 5). Pastor, Matter, and Nair were not relied upon to
suggest relational databases, which is the subject matter suggested by Shafer
and Sali (see FF 1-5 and 8-11; Cf. FF 6 and 7).
We recognize Appellants‟ acknowledgement that Examiner “recited
facts that link one reference to the next” (App. Br. 20; see also id. at 23
(“The Office‟s attempted explanation found nexuses between the various
prior art references”)). We are not, however, persuaded by Appellants‟
contention that Examiner failed to explain “why a person of ordinary skill in
the art would have thought to look for such linkages in the first place” (id. at
20; Reply Br. 6-8; Cf. Ans. 8-10; see also Ans. 12 (“Sali and Shafer …
provide guidance to use their databases for conducting research on protein
structures. The rejection also shows that Matter … and Pastor … provide
guidance for using structural analysis of protein binding sites for research on
ligands such as inhibitors”)).
We recognize, but are not persuaded by, Appellants‟ contentions
relating to Shafer‟s use of published data (App. Br. 17-18; Reply Br. 8).
Instead, we agree with Examiner‟s reasoning that “one of ordinary skill in
the art would understand … that Shafer … describes a database that could
contain data from any available source that was determined after the
publication date of Shafer” (Ans. 12). In addition, notwithstanding
Appellants‟ contentions to the contrary, Shafer does not teach away from
Appellants‟ claimed invention simply because it does not suggest all the
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elements of Appellants‟ claimed invention (see App. Br. 18). “A reference
may be said to teach away when a person of ordinary skill, upon reading the
reference, would be discouraged from following the path set out in the
reference, or would be led in a direction divergent from the path that was
taken by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
On this record, Examiner “recited facts that link one reference to the
next” and provided an explanation as to why a person of ordinary skill in
this art, at the time of Appellants‟ claimed invention, would have combined
the references relied upon (Ans. 5-10; App. Br. 20). Accordingly, we are
not persuaded by Appellants‟ contention that “[a]n experimental design that
would have generated data useful in the instant claims does not, by itself,
rise to the level of a teaching, or suggestion, or motivation to combine …
[Nair] with any of the other references,” which fails to consider Nair in
combination with the other references relied upon by Examiner (App. Br.
21)). It is proper to “take account of the inferences and creative steps that a
person of ordinary skill in the art would employ.” KSR, 550 U.S. at 418.
See also id. at 421 (“A person of ordinary skill is also a person of ordinary
creativity, not an automaton.”). The “suggestion test is in actuality quite
flexible and not only permits, but requires, consideration of common
knowledge and common sense.” DyStar Textilfarben GmbH & Co.
Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1367 (Fed. Cir. 2006).
In sum, Examiner has made out a prima facie case of obviousness on this
record. Appellants, however, failed to provide persuasive evidence or
reasoning to rebut Examiner‟s prima facie case of obviousness.
We recognize, but are not persuaded by, Appellants‟ contentions
regarding the term “susceptibility” as utilized by Shafer (App. Br. 18; Reply
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Br. 8). In this context, Shafer suggests that “the database schema will be
expanded to include drug susceptibility data and the database will be
populated with drug susceptibility results from published articles” (Shafer
351: first column, ll. 18-20 (emphasis added); see also App. Br. 18).
According to Appellants, the term “susceptibility” is ambiguous and
provides “a person of ordinary skill in the art little guidance regarding how
this would be implemented,” with regard to populating a database with this
data from published articles (App. Br. 18; Reply Br. 8). As Examiner
explains, reading Shafer “as a whole … the term susceptibility … refer[s] to
drug susceptibility of an HIV protease” (Ans. 12). We find no error in
Examiner‟s interpretation of the term based on a reading of Shafer as a
whole. While, Appellants may disagree with Examiner‟s interpretation,
Appellants proffer no persuasive evidence or reasoning to rebut Examiner‟s
interpretation of the term (see Reply Br. 8).
Because, Shafer is not relied upon to suggest “„de novo‟ drug design,”
we are not persuaded by Appellants‟ contention that Examiner failed “to
address just where Shafer[] addresses the „de novo‟ drug design requirement
imposed by the claims” (id.; Cf. FF 7).
For the foregoing reasons, we are not persuaded by Appellants‟
contentions that the combination of prior art relied upon by Examiner fails to
provide a reasonable expectation of success or teaches away from
Appellants‟ claimed invention (App. Br. 16-24; Reply Br. 8-10).
CONCLUSION OF LAW
The preponderance of evidence on this record supports a conclusion
of obviousness.
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The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Nair, Chen, Sali, Shafer, Pastor, Matter, and
Dictionary is affirmed. Claims 2-25, 27-41, 50-56, and 58-66 are not
separately argued and fall together with claim 1. 37 C.F.R. §
41.37(c)(1)(iv).
The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Nair, Chen, Sali, Shafer, Pastor, Matter, Dictionary,
and Mao is affirmed. Claims 14, 25, 26, 55-57, and 68 are not separately
argued and fall together with claim 1. 37 C.F.R. § 41.37(c)(1)(iv).
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).

AFFIRMED

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