Ex Parte Wilson et al

Patent Trial and Appeal Board

Dec 3, 2012

11833580 (P.T.A.B. Dec. 3, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte MIKE WILSON, IVAN P. PARKIN,
SEAN NAIR, and JESUS J. GIL-TOMAS
__________

Appeal 2011-012713
Application 11/833,580
Technology Center 1600
__________

Before ERIC GRIMES, JEFFREY N. FREDMAN, and
STEPHEN WALSH, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to a method of
killing bacteria with a metallic nanoparticle-ligand-photosensitiser
conjugate. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.
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Statement of the Case
Background
“The present invention relates to mixtures comprising charge-
stabilized metallic nanoparticles and a photosensitiser, and their use as light
activated antimicrobials” (Spec. 1 ¶ 0002).
The Claims
1

Claims 1-13, 15-21, 24, 28, 30, 31, and 38 are on appeal. Claims 2-
13, 15-21, 24, 28, 30, 31, and 38 have not been argued separately and
therefore stand or fall with claim 1. 37 C.F.R. § 41.37(c)(1)(vii). Claim 1
reads as follows:
1. A method of killing bacteria comprising:
applying a metallic nanoparticle-ligand-
photosensitiser conjugate to a desired treatment site,
wherein: ligand of the conjugate is a water-solubilising
ligand; metallic nanoparticle and photosensitizer of the
conjugate are chosen such that the conjugate generates
singlet oxygen and/or free radicals; and the conjugate acts as
a light-activated antimicrobial.

The Issue
The Examiner rejected claims 1-13, 15-21, 24, 28, 30, 31, and 38
under 35 U.S.C. § 103(a) as obvious over Chen,
2
Embleton,
3
and Templeton
4

(Ans. 4-9).

1
The Examiner issued a restriction and series of species elections
requirement Jul. 24, 2009, to which Appellants elected the species of gold,
tiopronin, methylene blue, S. aureus, and skin wounds on Oct. 23, 2009.
2
Chen, J., US 2002/0127224 A1, published Sep. 12, 2002.
3
Embleton et al., Selective lethal photosensitization of methicillin-resistant
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The Examiner finds that “Chen et al. appreciate the use of
photodynamic therapy to combat bacterial or viral infections” (Ans. 5). The
Examiner finds that “Chen teaches targeting conjugate photoluminescent
nanoparticles” (id.). The Examiner finds that the “treatment site treated by
Chen et al. are skin wounds and lesions” (id.). The Examiner finds that
“Templeton et al. teach a water-soluble, tiopronin-monolayer-protected gold
cluster” (id.). The Examiner finds that “Embleton et al. teach activating a
conjugate of photoluminescent particles with an HeNe laser to inhibit
methicillin-resistant Staphylococcus aureus (MRSA)” (id. at 6).
The Examiner finds it obvious to “use the tiopronin-MPC of
Templeton et al. as the metallic nanoparticle platform in the conjugate of
Chen et al. because of its stability, isolability in dried forms that can be
redissolved without aggregation and easy functionalization” (id. at 5-6). The
Examiner finds it obvious “to inhibit MRSA with a nanometer-sized
tiopronin-MPC of Templeton et al. conjugated to IgG to target MRSA . . .
and a photosensitizing agent, such as methylene blue and toluidine blue,
taught by Chen et al. to specifically target the antibacterial effect to the
infected area and avoid development of bacterial resistance” (id. at 6).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner‟s conclusion
that Chen, Embleton, and Templeton render Claim 1 obvious?

Staphylococcus aureus using an IgG-tin (IV) chlorin e6 conjugate, 50 J.
ANTIMICROBIAL CHEMOTHERAPY 857-864 (2002).
4
Templeton et al., Redox and Fluorophore Functionalization of Water-
Soluble, Tiopronin-Protected Gold Clusters, 121 J. AM. CHEM. SOC. 7081-
7089 (1999).
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(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. Chen teaches that photodynamic therapy:
is a form of energy-activated therapy for destroying
abnormal or diseased tissue. The procedure for this
treatment includes administration of a photosensitive
compounds (a PDT drug) to a patent, followed by
illumination with light having a wavelength or waveband
corresponding to a characteristic absorption wavelength of
the photosensitive compound. Upon illumination, the
photosensitive compound absorbs photons from the light
source and transfers this energy to surrounding oxygen
molecules. This in turn induces formation of singlet oxygen
and other highly-reactive free radical species . . . and often
ultimately results in cell death.

(Chen 1 ¶ 0003.)
2. Chen teaches
a photodynamic therapy in which light-emitting
nanoparticles are administered to a patient in addition to a
PDT drug in order to activate the drug. The light-emitting
nanoparticles absorb light from the light source and re-emit
light at a different wavelength, one which is suitable to
activate the PDT drug in the vicinity of the light emitting
nanoparticles. The PDT drug near the light-emitting
nanoparticles is activated, thus treating the disease anyplace
that the PDT drug and nanoparticles are located and that
light . . . from the light source can reach.

(Chen 1 ¶ 0007.)
3. Chen teaches that a “light-emitting nanoparticle may be
attached to a delivery moiety, which delivers the nanoparticle to a specific
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target site within the patient. A delivery moiety may be . . . an antibody”
(Chen 5 ¶ 0059).
4. Chen teaches that “[l]ight-emitting nanoparticles may be linked
to a reactive group on a PDT drug by any of the methods described
previously. Consequently, light-emitting nanoparticles may be covalently
bound or may be complexed with the drug through a delivery moiety” (Chen
6 ¶ 0067).
5. Chen teaches that a “PDT drug thus destroys . . . bodies
responsible for bacterial or viral infections” (Chen 8 ¶ 0090).
6. Chen teaches that “[p]hotosensitive compounds include, but are
not limited to: . . . methylene blue; toluidine blue” (Chen 8 ¶ 0093).
7. Chen teaches that “[t]opical carriers include ointments, creams,
or gels that may be applied to the skin” (Chen 6 ¶ 0073).
8. Chen teaches that there “are a number of light-emitting
nanoparticles that my [sic may] be used, alone or in combination with one
another, in photodynamic therapy. These include quantum dots” (Chen 3 ¶
0032).
9. Chen teaches that “[q]uantum dots have a size in the regime of
about 1 nm to about 20 nm and are typically only a few nanometers in size”
(Chen 3 ¶ 0034).
10. Chen teaches that a “quantum dot is typically composed of . . .
metal(s), or metal oxides exhibiting a certain bandgap energy. . . . A variety
of materials may be utilized for construction of nanoparticles, including but
not limited to TiO2, Al2O3, AgBr, CdSe, CdS, CdSxSe1-x, CuCl” (Chen 3 ¶
0035).
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11. Templeton teaches “the synthesis and characterization of a
water-soluble, monolayer-protected gold cluster (MPC) molecule, in which
the monolayer is composed of the simple compound „tiopronin‟ (N-2-
mercaptopropionyl-glycine)” (Templeton 7081, col. 1).
12. Templeton teaches that “[a]lkanethiolate-MPCs have received
considerable attention for their advantages of stability, isolability in dried
forms that can be redissolved without aggregation, and facile
characterization and functionalization. Tiopronin-protected clusters have the
same exceptional features, plus water solubility” (Templeton 7081, col. 2).
13. Templeton teaches that “the fluorescence spectrum of a
solution of monomer is unchanged . . . by the addition of (unlabeled)
tiopronin-MPC at the same cluster” (Templeton 7088, col. 2).
14. Templeton teaches that “[g]iven the absence of any quenching
in a fluorescein + tiopronin - MPC solution, the intensity difference must
reflect effects associated with the attachment of the fluorescein to the MPC”
(Templeton 7089, col. 1).
15. Embleton teaches that the “growing resistance of methicillin-
resistant Staphylococcus aureus (MRSA) to conventional antimicrobial
agents necessitates the development of alternative approaches to preventing
and treating infections. One such approach is photodynamic therapy,
whereby target cells are treated with light-activated drugs (photosensitizers)”
(Embleton, abstract).
16. Embleton teaches that “[w]hen S. aureus NCTC 6571 was
treated with 25 µg/mL SnCe6 and exposed to 8.4 J/cm
2
of red light from the
HeNe laser . . . a 2.5 log10 reduction in the viable count was achieved when
compared with a control sample” (Embleton 859, col. 1).
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17. Embleton teaches that the “antibody-targeting approach has
been used successfully to target specifically different photosensitizers to a
variety of bacteria: . . . toluidine blue O (TBO) to Porphyromonas
gingivalis” (Embleton 858, col. 1).
18. Embleton teaches that “we aimed to direct a suitable
photosensitizer to S. aureus, including MRSA, while retaining the
photodynamic activity of the molecule. Previous studies have shown that S.
aureus is sensitive to lethal photosensitization using a variety of
photosensitizers, e.g. porphyrins, thiazin dyes” (Embleton 858, col. 1).
19. Embleton teaches that the “effectiveness of this IgG-SnCe6
conjugate against the clinically important EMRSA-16 strain may make it a
good candidate for treatment of topical EMRSA-16 infections, e.g. wounds
and burns, ulcers, pressure sores and prosthetic or catheter biofilm-
associated infections” (Embleton 862, col. 2 to 863, col. 1).
Principles of Law
“In proceedings before the Patent and Trademark Office, the
Examiner bears the burden of establishing a prima facie case of obviousness
based upon the prior art.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir.
1992).
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of
ordinary skill can implement a predictable variation, § 103 likely bars its
patentability.” Id. at 417.
Moreover, an “[e]xpress suggestion to substitute one equivalent for
another need not be present to render such substitution obvious.” In re Fout,
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675 F.2d 297, 301 (CCPA 1982). As noted by the Court in KSR, “[a] person
of ordinary skill is also a person of ordinary creativity, not an automaton.”
550 U.S. at 421.
Analysis
Chen teaches that a “PDT [photodynamic therapy] drug thus destroys
. . . bodies responsible for bacterial or viral infections” (Chen 8 ¶ 0090; FF
5). Chen teaches quantum dot metallic nanoparticles (FF 8-10) conjugated to
a PDT drug such as toluidine blue (FF 6) as well as to a delivery moiety
such as an antibody, specifically teaching that “[l]ight-emitting nanoparticles
may be linked to a reactive group on a PDT drug . . . Consequently, light-
emitting nanoparticles may be covalently bound or may be complexed with
the drug through a delivery moiety” (Chen 6 ¶ 0067; FF 4). Chen also
teaches “a delivery moiety, which delivers the nanoparticle to a specific
target site within the patient. A delivery moiety may be . . . an antibody”
(Chen 5 ¶ 0059; FF 3). Chen teaches that after delivery of the conjugated
particles to a treatment site (FF 3), “[u]pon illumination, the photosensitive
compound absorbs photons from the light source and transfers this energy to
surrounding oxygen molecules. This in turn induces formation of singlet
oxygen and other highly-reactive free radical species . . . and often
ultimately results in cell death” (Chen 1 ¶ 0003; FF 1). Templeton teaches
the use of gold linked to tiopronin (FF 11-14).
Embleton teaches treatment of bacteria including S. aureus with
photodynamic therapy (FF 15-16). Embleton teaches that the “antibody-
targeting approach has been used successfully to target specifically different
photosensitizers to a variety of bacteria: . . . toluidine blue O (TBO) to
Porphyromonas gingivalis” (Embleton 858, col. 1; FF 17).
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Applying the KSR standard of obviousness to the findings of fact, we
conclude that the person of ordinary skill and creativity would have
predictably used photodynamic therapy to kill bacteria (FF 5, 15) using a
metallic nanoparticle – ligand – photosensitizer conjugate since Chen
teaches conjugation of quantum dots (FF 8-10) and antibody ligands (FF 3)
to photosensitizer drugs (FF 4-6) and since Embleton teaches conjugation of
antibodies and photosensitizer drugs (FF 15-17). The ordinary artisan would
have incorporated the quantum dot of Chen into the conjugated antibody and
photosensitizer drug of Embleton since Chen teaches providing “a
sufficiently high concentration of nanoparticles around the PDT drug to
assure the drug receives the intensity of light needed to activate the drug”
(Chen 6 ¶ 0067). Such a combination is merely a “predictable use of prior
art elements according to their established functions.” KSR, 550 U.S. at 417.
Appellants contend that “there is nothing in either Embleton or Chen
which suggests in any way that someone skilled in the art would conjugate a
metallic nanoparticle with a photosensitiser [sic] via a ligand in order to
enhance the light-activated killing of bacteria” (App. Br. 18-19).
We are not persuaded. Chen teaches that “[l]ight-emitting
nanoparticles may be linked to a reactive group on a PDT drug by any of the
methods described previously. Consequently, light-emitting nanoparticles
may be covalently bound or may be complexed with the drug through a
delivery moiety” (Chen 6 ¶ 0067; FF 4). This is an express teaching to link
the metallic nanoparticle to the PDT drug and further complex these
components with a delivery moiety which is a ligand, such as an antibody
(FF 3). Chen expressly teaches light activated killing of bacteria, and
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Embleton also teaches that ligands linked to PDT drugs can be used for light
activated killing of bacteria (FF 5, 15-19).
Appellants contend that “nothing in the cited prior art would have
provided any motivation for a skilled person in the art to combine the known
species as in the present invention in order to improve the light activated
antimicrobial effect of a photosensitiser” (App. Br. 19).
We are not persuaded. There is no requirement in obviousness law
that the combination is formed to improve an effect, only that the
combination is prima facie obvious. Each of Appellants‟ species were
disclosed in the prior art, whether gold-tiopronin synthesis by Templeton
(FF 11-14), the use of methylene blue by Chen and Embleton (FF 6, 17), or
the treatment of S. aureus and skin wounds by Embleton (FF 16, 18, 19).
The fundamental concept of the invention is taught by both Chen and
Embleton (FF 1-10 and 15-19). The Examiner provides specific motivations
to combine the prior art, and we agree that the ordinary artisan would have
reasonably desired to use the light activated antibacterial therapy of Chen
and Embleton to treat S. aureus and skin wounds using a quantum
dot/nanoparticle linked to a ligand linked to a PDT drug for the reasons
given above.
Appellants also rely on the Wilson Declaration,
5
where Dr. Wilson
states that “The documents read together do not suggest to me that there
could be any advantage in conjugating a known photosensitiser to a metallic
nanoparticle. In my view, the results on which the present invention is based
would not have been predictable from Embleton, Chen and/or Templeton”
(Wilson Dec. 34 ¶ 14).

5
Declaration of Dr. Michael Wilson, filed Nov. 12, 2010.
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We are not persuaded. We agree with the Examiner that the Wilson
Declaration, lacking factual evidence to support the offered opinion, lacks
substantial probative value. Conspicuously absent in the declaration are
specific reasons why the proposed combination of Chen, Templeton, and
Embleton proposed by the Examiner would have been unobvious to one of
ordinary skill in the art. General assertions by the Declarant fall short of
outweighing the specific analysis presented by the Examiner.
Appellants contend that “tiopronin-MPC would frustrate Chen‟s
purpose of using a light emitting nanoparticle for conjugation with a known
photosensitiser . . . Chen actually teaches away from using tiopronin-MPC
as a conjugate” (App. Br. 20). Appellants also contend that a “metallic
nanoparticle as used in the present invention is not a quantum dot, and
moreover would not be suitable for Chen because it is not light-emitting”
(Reply Br. 4).
We are not persuaded. Appellants‟ Specification defines nanoparticle
as “particles having a diameter of from about 1 to about 100 nm” (Spec. 4 ¶
0018). The Specification states that “[n]anoparticles typically, but not
exclusively comprise metals” (Spec 4 ¶ 0019). The Specification teaches
that the “term „metallic‟. . . is intended to encompass all such structures
having a metallic outer surface” (Spec 4 ¶ 0019). Chen teaches metal
containing quantum dots, where the quantum dot particles have a diameter
between 1 nm and 20 nm in size (FF 9), where the particles are composed of
metals and alloys (Chen 3 ¶ 0035; FF 10). Thus, the evidence of record
shows that the Specification‟s definition of metallic nanoparticle
encompasses quantum dots and Appellants provide no rebuttal evidence.
That Templeton teaches an alternative type of gold nanoparticle does not
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teach away from the use of gold quantum dots in the combined method of
Chen, Templeton and Embleton. See In re Fulton, 391 F.3d 1195, 1201
(Fed. Cir. 2004) (“The prior art‟s mere disclosure of more than one
alternative does not constitute a teaching away from any of these alternatives
because such disclosure does not criticize, discredit, or otherwise discourage
the solution claimed”).
Unexpected Results
Appellants contend that the “examples of the present application
provide this comparison and clearly show that the conjugated photosensitiser
provides an enhanced light-activated antimicrobial effect when compared to
the same photosensitiser in a non-conjugated form, See Examples 10, 14-15”
(App. Br. 22).
We are not persuaded. As the Examiner finds “it is already
appreciated in the prior art that combining photoluminescent conjugate
particles with light kills a comparable amount of bacteria, i.e., at least 99%,
and no unexpected result is demonstrated” (Ans. 17). Additionally, the
comparisons shown in Examples 10, 14 and 15 are not as close as either
Chen, Templeton, or Embleton. Examples 10, 14, and 15 compare the three
part TBO-tiopronin-gold conjugate to TBO alone, but not conjugated to
either gold or tiopronin. By contrast, each of the other references use at least
two of the required components, where Chen expressly teaches PDT drugs
covalently linked to nanoparticles, Templeton teaches gold linked to
tiopronin, and Embleton teaches an example where the ligand IgG linked to
the sensitizer SnCe6 killed 99.9% of cells (see Embleton 860, Figure 4).
Therefore, Examples 10, 14, and 15 do not show a comparison with the
closest prior art. See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed.
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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.”). Appellants have provided no comparison with either
Chen or Embleton.
Conclusion of Law
(i) The evidence of record supports the Examiner‟s conclusion that
Chen, Templeton, and Embleton render Claim 1 obvious.
(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
103(a) as obvious over Chen, Templeton, and Embleton. Pursuant to 37
C.F.R. § 41.37(c)(1), we also affirm the rejection of claims 2-13, 15-21, 24,
28, 30, 31, and 38, as these claims were not argued separately.

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

cdc