Ex Parte Stehr et al

Patent Trial and Appeal Board

Oct 29, 2018

12664465 (P.T.A.B. Oct. 29, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/664,465 06/15/2010
15204 7590 10/29/2018
Harris Beach/Syracuse
333 West Washington Street
Suite 200
Syracuse, NY 13202
FIRST NAMED INVENTOR
Joachim A. Stehr
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.
1579 016 2444
EXAMINER
SISSON, BRADLEY L
ART UNIT PAPER NUMBER
1634
MAIL DATE DELIVERY MODE
10/29/2018 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 JOACHIM A. STEHR, THOMAS A. KLAR,
JOCHEN FELDMANN, CALIN HRELESCU,
WOLFGANG P ARAK, GUNNAR RASCHKE,
RALF SPERLING, MICHAEL WUNDERLICH,
KONRAD KURZINGER, DIETER HEINDL, and
ALFONS NICHTL 1
Appeal2017-000231
Application 12/664,465
Technology Center 1600
Before ERIC B. GRIMES, JOHN G. NEW, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants state that the real party-in-interest is GNA BIOSOLUTIONS
GMBH. App. Br. 3.
Appeal2017-000231
Application 12/664,465
SUMMARY
Appellants file this appeal under 35 U.S.C. § I34(a) from the
Examiner's Non-Final Rejection of claims 21, 23, 24, 26, 27, and 38--41.
Specifically, the claims stand rejected as unpatentable under 35 U.S.C.
§ 112, second paragraph as being indefinite.
Claims 21, 23, 24, 26, 27, and 38--41 also stand rejected as
unpatentable under 35 U.S.C. § 112, first paragraph, as: (1) failing to comply
with the enablement requirement; and (2) failing to comply with the written
description requirement.
Claims 21, 23, 24, 26, 27, and 38--41 also stand rejected as
unpatentable under 35 U.S.C. §§ 101 and 112, first paragraph, as lacking
specific and substantial utility.
Claims 21, 23, 24, 26, 27, and 38--41 stand further rejected as
unpatentable under 35 U.S.C. § I03(a) as being obvious over the admissions
of Appellants' Specification, specifically the Specification's citations to
Mirkin et al. (US 2004/0219520 Al, November 4, 2004) ("Mirkin"),
Jacobson et al. (US 2002/0061588 Al, May 23, 2002) ("Jacobson") and K.
Hamad-Schifferli et al., Remote Electronic Control of DNA Hybridization
through Inductive Coupling to an Attached Metal Nanocrystal Antenna, 415
NATURE 152 (2002) ("Hamad-Schifferli").
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
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NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to a process for detecting nucleic
acids in a sample by measuring the temperatures of hybridization and
dehybridization. Abstr.
REPRESENTATIVE CLAIM
Claim 21 is representative of the claims on appeal and recites:
21. A process for detecting one or several nucleic acids, if
present, in a sample, comprising the steps of:
a) providing a first fraction of one or a plurality of
functionalized nanoparticle (hereinafter "first
fraction"), wherein the first fraction is functionalized
with a first oligonucleotide that hybridizes with a first
segment of at least one of the one or several nucleic
acids to be detected,
b) bringing at least one nanoparticle of the first fraction
into contact with the sample,
c) measuring a degree of hybridization of the first
oligonucleotide with the first segment, at a
predetermined initial temperature,
d) heating the first fraction with electromagnetic radiation,
thereby heating a region of hybridization, if present,
between the first oligonucleotide and the first segment,
without the entire sample being heated,
e) renewed measuring of the degree of hybridization of the
first oligonucleotide with the first segment, and
f) ascertaining a change in the degree of hybridization
brought about by the heating, thereby detecting the one
or several nucleic acids, if present, in the sample.
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App. Br. 35-36.
ISSUES AND ANALYSES
We are persuaded by, and expressly adopt, the Examiner's findings,
reasoning, and conclusion that Appellants' claims are primafacie obvious
over the combined cited prior art. However, we do not agree with the
Examiner's findings and conclusions with respect to indefiniteness, lack of
enablement, lack of written descriptive support, and lack of specific and
substantial utility. We address the arguments raised by Appellants below.
A. Rejection under 35 U.S.C. § 112, second paragraph, as indefinite
Issue 1
Appellants argue the Examiner erred in concluding that the use of the
claim term "several" in the claims renders the claims indefinite. App. Br.
14.
Analysis
Appellants argue that the Examiner has not clearly explained why the
claim term "several" is a relative term that renders the claim indefinite.
App. Br. 14 (citing MPEP § 2173.02(III)(A)). Appellants argue that the
term "several," as used in Appellants' Specification, expressly delimits the
subject matter for which protection is sought. Id. According to Appellants,
the relevant context of claim 21 in which the term "several" occurs is in the
limitations reciting: "[ ... ] one or several nucleic acids[ ... ]." Id. Appellants
point to the relevant Oxford English Dictionary definition of "several,"
which, Appellants assert, states that the term "several" in legal usage means
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"more than one." Id. (citing definition of "several," Oxford English
Dictionary, section A.I.2.d; see App. Br., Ex. A). Therefore, contend
Appellants, "several" is synonymous with "one or more than one," but more
concise, and thus preferable for the language of the claims. Id. Appellants
further point out that an embodiment in their Specification expressly
discloses detecting two different nucleic acids with different melting
temperatures as an example of: "detect[ing] several different nucleic acids in
the same sample." Id. ( quoting Spec. 15).
Appellants also point to MPEP § 2173 .05(g), which, citing In re
Schreiber, 128 F.3d 1473 (Fed. Cir. 1997), notes that our reviewing court
found no fault in a claim that recited the term "several" in a claim directed to
"a conical spout ( the structure) that allow[ ed] several kernels of popped
popcorn to pass through at the same time." App. Br. 15 (quoting Schreiber,
128 F.3d at 1478). Consequently, Appellants assert, Schreiber counters the
Examiner's assertion that "several" is an inadmissible relative term. Id.
The Examiner responds that, whereas the claim term "several" implies
that there is "more than one," the term does not set forth what Appellants
contemplate as being the upper limit of the range. Ans. 32. The Examiner
finds, by way of example, that the term "several" is synonymous with "few,"
or "many," or "everything" or "an infinite number" or some other value
(e.g., 3). Id. The Examiner finds that, as presently worded, the language of
the claim is indefinite with respect to where the upper limit of the claimed
range ends and, therefore, the metes and bounds of the claim are not defined.
Id.
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In support of this conclusion, the Examiner points to the Federal
Circuit's holding in Teva Pharms. USA, Inc. v. Sandoz, Inc., 789 F.3d 1335
(Fed. Cir. 2015) that:
The Supreme Court articulated the standard to be applied: "[W]e
hold that a patent is invalid for indefiniteness if its claims, read
in light of the specification delineating the patent, and the
prosecution history, fail to inform, with reasonable certainty,
those skilled in the art about the scope of the invention." As we
explained on remand, "[t]he Court has accordingly modified the
standard by which lower courts examine allegedly ambiguous
claims; we may now steer by the bright star of "reasonable
certainty," rather than the unreliable compass of "insoluble
ambiguity."
Teva, 789 F.3d at 1340 (internal citations omitted).
We do not find the Examiner's reasoning persuasive. Appellants'
Specification discloses that:
With the invention it is also possible to detect several
different nucleic acids in the same sample. If, for example, the
first nucleic acid has a melting temperature that lies below the
melting temperature of the second nucleic acid to be detected, the
first nucleic acid can be detected by the presence of a melting
threshold at a temperature below its melting temperature, and the
second nucleic acid can be detected by detection of a melting
threshold at a temperature below the melting temperature of the
second nucleic acid but above the melting temperature of the first
nucleic acid. In one embodiment of the invention, steps a) to c)
are therefore run through at least one first and one second time,
the predetermined initial temperature being variable in the course
of the passes, and the melting signals of the passes being
compared.
App. Br. 14--15 (quoting Spec. 15). The Specification thus discloses that
"several different nucleic acids" can mean at least two, as long as they have
different melting temperatures. The Specification discloses that several
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different nucleic acids can be detected using multiple passes at different
temperatures, as long as the nucleic acids have sufficiently different melting
temperatures. However, a person of ordinary skill in the art would realize
that there must be an upper boundary to the number of nucleic acids sampled
via this method, because the range of temperatures at which the invention
can be practiced must necessarily be within the range in which the nucleic
acids can be dehybridized ( as claimed) and not degraded. We agree with
Appellants that a person of ordinary skill in the art would understand the
boundaries of this range and would be able to determine how many nucleic
acids could be practicably detected by Appellants' methods, by knowing the
range of the melting temperatures of the nucleic acids sought to be detected.
Issue 2
Appellants argue that the Examiner erred in finding that the claim
term "degree of hybridization" is indefinite. App. Br. 16.
Analysis
Appellants contend that the claim term "degree" means the amount,
level, or extent, to which something happens or is present. App. Br. 16.
According to Appellants, the context in which the expression "degree of
hybridization" is used in claim 21 reads: "c) measuring a degree of
hybridization of the first oligonucleotide with the first segment", i.e., the
degree of hybridization indicates how much hybridization has taken place.
Id. Appellants assert that it is an important aspect of the method of claim 21
that it does not require an absolute measure obtained by any particular
method, but merely a comparison of a measure before (step c) and after (step
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e) the local heating step (step d), and an assessment as to whether a change
has occurred. Id. Appellants therefore argue that any measure can be used,
as long as it allows such a comparison, and that that is what "degree of
hybridization" in the context of claim 21 means. Id.
Appellants respond to the Examiner's inquiry as to how the "degree of
hybridization" is to be measured, by arguing that, although it is irrelevant
which particular method is employed for measuring the "degree of
hybridization," recited in claim 21, Appellants' Specification provides a
number of examples of suitable methods. App. Br. 16-17 ( citing Spec. 9-
10, Figs 1-3 and corresponding descriptions on pages 18 and 20-21).
Appellants therefore assert that a person of ordinary skill in the art could
realistically practice the method of claim 21. Nevertheless, Appellants
argue, limiting the claim to any particular method would be unduly limiting,
because the method of claim 21 and the kit of claim 40 can be practiced
regardless of which particular method of measuring the degree of
hybridization is employed. Id. at 16-17.
The Examiner responds that the metes and bounds of the claim term
"degree of hybridization" is not defined by Appellants' claims and
Specification. Ans. 33. The Examiner finds that, without knowing the
values to be ascribed to "a degree of hybridization," it is unclear as to what
type and level of comparison one is being required to perform in step c) of
claim 21. Id. The Examiner concludes that, as presently worded, a person
of ordinary skill in the art would not have known what constitutes the metes
and bounds of "a degree of hybridization" without defining the units of
measure by which such a "degree" is to be measured. Id. at 17.
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We are not persuaded by the Examiner's reasoning. It is undoubtedly
well known in the art that the claim term "hybridization" refers to the
binding of one nucleic acid sequence to another by the interactions of
complementary base pairs. Thus, and as is common knowledge in the art,
when the two nucleic acid sequences have entirely complementary base
pairs, complete hybridization occurs. Conversely, when there are no
complementary base pairs, no hybridization takes place. These two
situations define the logical endpoints of hybridization - either complete or
none.
However, some hybridization of nucleic acid sequences is possible
when some, but not all, of the base pairs in the two sequences are
complementary. As such, the two nucleic acid sequences are bound less
tightly to each other than when the base pair sequences are entirely
complementary.
Appellants' Specification discloses that:
Many processes for detecting nucleic acids are based on the
technique of melting-curve analysis. With this technique the
effect is exploited that double-stranded nucleic-acid chains are
able to dehybridize into single-stranded chains in the event of an
increase in temperature, a process which in this context is
described as "melting." The melting temperature depends, inter
alia, on the degree of complementarity of the two hybridization
partners.
Spec. 1 (emphasis added). Appellants' Specification further discloses that
Mirkin teaches:
With a melting curve that indicates the light extinction as a
function of the temperature, this can be observed as a steep
transition. Mirkin et al. report that they were able to distinguish
melting curves of nucleic acids, the segments of which were fully
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complementary to the base sequences of the oligonucleotides of
the functionalised nanoparticles, from those nucleic acids which
differed in one base. It is also reported to have been possible to
detect fully complementary nucleic acids in a mixture of fully
complementary nuclei[ c] acids differing in one base.
Spec. 2.
In other words, Appellants' Specification teaches that that there is a
method, known in the art, for assessing the degree of complementarity, i.e.,
the amount of complementary base pairs in two hybridized nucleic acid
sequences, viz., measuring the amount of energy required to dehybridize
(i.e., dissociate) the two strands. As such, Appellants' Specification teaches
that it was well known in the art specifically how to measure the "degree of
hybridization," caused by the amount of complementarity between the two
test sequences.
Furthermore, Appellants' Specification discloses that the "degree of
hybridization" measured prior to heating and dehybridization can be
similarly detected by the strength of hybridization measured by quantitative
means, e.g., by measurement of the optical density (OD) as a measure of the
extinction of the gold nanoparticles. See Spec. 22, Fig. 6 (showing
differences between curve 18 for a completely hybridized nucleic acid and
curve 19 representing a nucleic acid with a single base pair mismatch).
We are therefore not persuaded by the Examiner's reasoning that the
claim term "degree of hybridization" is indefinite. We consequently reverse
the Examiner's rejection of claims 21, 23, 24, 26, 27, and 38--41 on this
ground.
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B. Rejection under 35 U.S.C. § 112, first paragraph, as lacking
enablement
Issue
Appellants argue that the Examiner erred in finding that the rejected
claims contain subject matter that was not described in the Specification in
such a way as to enable one skilled in the art to make and use the invention.
App. Br. 18.
Analysis
The Examiner finds that the claims on appeal are directed to a generic
method for detecting, in a simultaneous manner, an infinite number of
nucleic acids that are present in any type of sample. Non-Final Act. 6.
For purposes of examination, the Examiner construes the limitation reciting
the "first oligonucleotide that hybridizes with a first segment of the one or
several nucleic acids to be detected" as encompassing an infinite number of
possible "first oligonucleotides" that will hybridize to any and all manner of
nucleic acids that are to be detected, be it individually or in a multiplex
manner. Id. The Examiner also finds that the source of the nucleic acid to
be detected can be construed as encompassing any nucleic acid, DNA or
RNA, that is found in any and all manner of life forms, e.g., bacteria,
viruses, plants, insects, mammals, etc. Id. at 6-7.
Appellants argue that the Examiner's enablement analysis appears to
be based on the assumption that the invention reflected by the presently
claimed subject matter resides in a particular type of oligonucleotide or
nucleic acid used in the invention. App. Br. 18. Appellants argue that their
claimed method is a universal detection method in that the method of claim
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21 and the kit of clam 40 can be practiced with any nucleic acid. Id.
According to Appellants, the method is not, and indeed cannot be, defined
by reference to particular oligonucleotides or nucleic acids, let alone a
particular genus, as the Examiner requires. Id. Rather, Appellants argue, the
claimed method is defined and claimed by the particular steps (a) to (f) of
the method, which method includes the hybridization and the
dehybridization of the nucleic acids to be detected to and from nanoparticle-
attached oligonucleotides, and the local heating of the nanoparticles. Id.
Appellants argue further that, the Examiner's findings to the contrary
notwithstanding, the claims are not unduly broad and are commensurate in
scope with the disclosures of Appellants' Specification. App. Br. 18-19.
Appellants contend that claim 21 requires that the oligonucleotide must, at
least partially, match the nucleic acid to be detected and because, in
principle, the method is suitable to detect any nucleic acid conceivable, be it
from a natural source or artificially created, any limitation to only certain
oligonucleotides would unduly limit the claim's scope. Id. at 19.
Appellants argue that the claims are not defined by the
oligonucleotides used, but rather, by the particular steps of the detection
method. Id. Appellants also note that, whereas the Examiner's rejection
points to the numerous sources of naturally-occurring nucleic acids, ranging
from viruses to mammals, this does not affect the enablement of the claims,
since the method of claim 21 does not depend on the source of the
oligonucleotide or nucleic acid. Id.
The Examiner responds, agreeing that the claimed method
encompasses the detection of a nucleic acid of interest which can come from
any conceivable source, the method set forth in the claims requires the use of
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"a first oligonucleotide that hybridizes with a first segment of at least one of
the one or several nucleic acids to be detected" and, in claim 26, "a second
oligonucleotide that hybridizes with a second segment of at least one of the
one or several nucleic acids." Ans. 34--35. The Examiner finds that, given
such requirements, it is essential that one have knowledge of the nucleotide
sequence of the target such that the essential starting materials, the first and
second oligonucleotides, could be identified and produced so that one could
practice the claimed method. Id. at 35. The Examiner finds that, absent
knowledge of the nucleotide sequence of the target, one would not know if a
probe of an undefined nucleotide sequence was actually hybridizing to the
target or to some other sequence that happened to be present in the nucleic
acid molecule (e.g., a wholly different gene present in a chromosomal
sequence). Id.
We are not persuaded by the Examiner's reasoning. We do not
dispute the Examiner's findings with respect to the wide, almost infinite,
variety of oligonucleotide sequences in nature. See Non-Final Act. 7-8.
Nevertheless, it is certainly well known in the art that hybridization of
nucleic acid sequences follow discrete and rigid rules for base pair binding,
i.e., adenine-thymine/uracil, and cytosine-guanine binding. Consequently, it
is similarly well known in the art that, for any known oligonucleotide
sequence, a complementary oligonucleotide sequence can be predicted via
the base pairing rules. It is this common knowledge in the art that forms the
ultimate basis for Appellants' claimed method.
Appellants' claims are directed to: "A process for detecting one or
several nucleic acids" by, inter alia, combining "a first oligonucleotide that
hybridizes with a first segment of at least one of the one or several nucleic
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acids to be detected." Thus, the claim applies universally to the detection of
any known nucleic acid sequence because the complementary
oligonucleotide can be determined according to the base pairing rules that
are universally known throughout, and which, indeed, form the basis of the
art.
In other words, for the purposes of Appellants' claims, it matters not
at all what the known nucleotide sequence to be detected in the sample may
actually be, because a complementary oligonucleotide probe can be obtained
or constructed by methods well known in the art. Furthermore, we agree
with Appellants that a person of ordinary skill in the art would know the
nature of the nucleic acid sought to be detected in a given situation. We
consequently reverse the Examiner's rejection upon this ground.
C.
Issue
Rejection under 35 U.S.C. § 112, first paragraph, as lacking written
descriptive support
Appellants argue the Examiner erred in finding that the claims do not
meet the written description requirement because they fail to "provide a full,
clear and concise description of the genus encompassed by the claims so that
one would readily be able to determine if a species fell within the claim's
scope." App. Br. 22 (quoting Non-Final Act. 17).
Analysis
Appellants point out that the claims neither recite nor require any
genus of oligonucleotide sequences. According to Appellants, contrary to
the Examiner's findings, a specific oligonucleotide sequence (or group of
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oligonucleotide sequences) is not an essential starting material to practice
the claimed method. Id. at 23. Rather, Appellants assert, the essential
starting material is any oligonucleotide, and therefore no experimentation is
required at all to practice the invention. Id. Instead, contend Appellants, the
detection method of claim 21 can be practiced in a straightforward manner
for any nucleic acid sequence the user of the method chooses. Id.
We agree with Appellants. As we have explained in the preceding
section of this Decision, Appellants method is universally applicable to any
known nucleic acid sequence, and thus does not require the recitation of any
genus or genera of oligonucleotides. In other words, the particular nucleic
acid sequence of an oligonucleotide is entirely immaterial to the practice of
Appellants' claimed method, apart from a knowledge of the target nucleotide
sequence itself. The Examiner makes no findings or conclusion that the rest
of the method recited in the claims lacks written descriptive support in the
Specification. As such, we are not persuaded by the Examiner's prima facie
conclusion that the claims lack written descriptive support, and we reverse
the Examiner's rejection.
D.
Issue
Rejection under 35 U.S.C. §§ 101 and 112, first paragraph, as lacking
specific utility
Appellants argue that the Examiner erred in concluding that the claims
on appeal lack utility because the "claims do not distinguish between those
nucleic acids that do and do not have utility." App. Br. 23 (quoting Non-
Final Act. 27).
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Analysis
Appellants argue that the method to which the claims are directed can
be used to ascertain whether a nucleic acid of interest, with a particular
nucleotide sequence decided upon by the user, is present in a particular
sample. App. Br. 23. Appellants note that such analyses are routinely
performed in laboratories around the world for an uncountable number of
reasons, including the diagnosis of diseases in humans and animals, basic
biotechnological and medical research and monitoring the spread of
pathogens. Id. Appellants argue that, whereas there are other methods of
nucleic acid detection available, the method of claim 21, owing to the fact
that it no longer requires heating the entire sample but instead relies on local
heating, is considerably faster, thereby improving the usefulness of such
analyses. Id.
The Examiner acknowledges that there are known nucleic acids that
would satisfy the utility requirement, but finds the claimed method and kit
are not so limited. Ans. 39. Rather, the Examiner finds that the claimed
method and kit fairly encompass the detection of wholly uncharacterized
sequences, as well as artificial sequences. Id.
We are not persuaded by the Examiner's reasoning. Appellants'
claims are directed to: "A process for detecting one or several nucleic acids."
As such, the utility of the claimed method is self-evident: it is useful for
identifying the presence of one or more given nucleic acids in a sample. It is
not necessary that Appellants demonstrate that all uses of the method be
directed to the identification of useful nucleic acids as such, rather, what is
required is that the claimed method possess a specific utility. We agree with
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Appellants that it does, viz.; the identification of the presence of a given
nucleic acid sequence in a sample.
Furthermore, Appellants' Specification provides an exemplary
embodiment demonstrating how the claimed method can be used to
determine the degree of hybridization of several oligonucleotide sequences.
See Spec. 21-27. As such, it demonstrates that a person of ordinary skill in
the art could utilize Appellants' method to obtain the desired result, i.e.,
identification of the presence of a nucleic acid in a sample. We thus find
that Appellants' Specification discloses "a specific and substantial utility"
for the claimed method. See In re Fisher, 421 F.3d 1365, 1371 (Fed. Cir.
2005). We consequently reverse the Examiner's rejection of the claims.
E. Rejection under 35 U.S.C. § 103(a) as being obvious
Issue
Appellants argue that the Examiner erred in finding that the claims on
appeal are obvious over references cited in Appellants' Specification (i.e.,
Mirkin, Jacobson, and Hamad-Schifferli). App. Br. 25.
Analysis
The Examiner finds that Appellants' Specification discloses that
Mirkin teaches a process for detecting nucleic acids in which gold
nanoparticles that are functionalized with oligonucleotides are used. Non-
Final Act. 30 (citing Spec. 1-2). The Examiner finds that Appellants'
Specification discloses that Mirkin teaches that the nucleic acids to be
detected and the gold nanoparticles bound to the probe oligonucelotides are
hybridized, and that the nanoparticles of the nucleic acids are connected to
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form large aggregates, resulting in a broadening and red shift of their particle
plasmon resonance. Id. at 30-31. The Examiner further finds that the
Specification discloses that Mirkin teaches that if the temperature of the
sample is increased stepwise, a dehybridization - and, as a consequence, a
dissolution of the aggregates - occurs at a melting temperature that is
characteristic of the nucleic acid to be detected, and that a melting curve that
indicates the light extinction as a function of the temperature can be
observed as a steep transition. Id. The Examiner finds that Appellants'
Specification indicates that Mirkin teaches that the melting curves of nucleic
acids, the segments of which were fully complementary to the base
sequences of the oligonucleotides of the functionalized nanoparticles, could
be distinguished from those nucleic acids which differed in one base. Id.
The Examiner next finds that Appellants' Specification discloses that
Jacobson teaches a gold nanoparticle covalently bonded to a loop-shaped
nucleic acid segment, which connects the self-complementary ends of a
hairpin-shaped DNA molecule to one another. Non-Final Act. 31 (citing
Spec. 3--4). The Examiner finds the Specification discloses that Jacobson
teaches that the gold nanoparticle is excited to generate heat by means of
inductive coupling to a magnetic radio-frequency field, in order to increase
the local temperature of the DNA molecule that is bound to the nanoparticle;
in this way, dehybridization of the self-complementary DNA strands is
induced. Id. The Examiner finds that Appellants' Specification discloses
that Jacobson also teaches a process in which a first oligonucleotide is bound
to a gold nanoparticle at one end and bear a fluorophore at the other, and that
complementary oligonucleotides are bound to a streptavidin-jacketed
agarose bead and hybridize with the first oligonucleotide. Id. The Examiner
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finds that the Specification discloses that Jacobson teaches that
dehybridization is subsequently induced, either by a local increase of
temperature by means of exciting the gold nanoparticles in a magnetic radio-
frequency field or by increasing the temperature of the sample. Id.
The Examiner concludes that it would have been obvious to a person
of ordinary skill in the art to have modified the method of Mirkin with the
heating means of Jacobson to enable the ordinary artisan more precise,
direct, and uniform heating of the nanoparticles and the coupled hybridized
nucleic acids, thereby improving the effective determination of the melting
curves of nucleic acids, and therefore better determine the presence of a
nucleic acid analyte in a sample. Non-Final Act. 34. The Examiner finds
that, in view of the well-developed state of the art, and the use of the
inductive heating of the nanoparticles for the same reason, a person of
ordinary skill in the art would have been amply motivated and would have
also had a reasonable expectation of success in combining the references.
Id.
Appellants argue that Mirkin teaches the general concept of detecting
nucleic acids by means of measuring melting curves. App. Br. 26.
According to Appellants, melting curve analysis techniques exploit the
effect that double-stranded nucleic-acid chains are able to dehybridize into
single-stranded chains in the event of an increase in temperature, a process
which in this context is described as "melting." Id. Appellants contend that
the melting temperature depends, inter alia, on the degree of
complementarity of the two hybridization partners. Id. Appellants argue
that Mirkin teaches that, after a nucleic acid to be detected is allowed to
hybridize with an oligonucleotide serving as a probe, the degree of
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hybridization is measured, and the temperature of the sample is controlled
by means of a heating block: if the temperature of the sample is raised above
a certain value, melting will occur, thereby changing the degree of
hybridization. Id. Appellants assert that the detection method of Mirkin
relies upon the fact that the temperature of the sample can be controlled with
enough precision to render the differences in the obtained melting curves
suitable as an indication of the presence of a certain nucleic acid. Id. at 26-
27. Appellants emphasize that Mirkin teaches heating the entire sample. Id.
at 27.
Appellants argue that, in contrast to the teachings of Mirkin, their
claimed method does not heat the entire sample, rather, the claimed method
demonstrates that it is sufficient to merely locally heat areas of hybridization
by means of binding the probes to nanoparticles and exciting these
nanoparticles to generate heat. App. Br. 27.
Appellants argue that Jacobson teaches the use of a radio-frequency
magnetic field to heat nanocrystals covalently linked to DNA, thereby
remotely controlling the hybridization of the DNA. App. Br. 27-28.
Appellants argue that neither Mirkin nor Jacobson address the problem of
nucleic acid detection, or contemplate that nanoparticle excitation could be
exploited for the purpose of nucleic acid detection. Id. at 28. Appellants
further argue that although the concluding paragraph of Hamad-Schifferli
lists numerous possible applications, nucleic acid detection is not among
them. Id.
Specifically, Appellants argue that the references fail to teach the use
of electromagnetic radiation to excite ( and thereby heat) the nanoparticles.
Appellants argue that electromagnetic radiation is not disclosed in Mirkin;
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rather, Mirkin teaches the use of conventional heating of the entire sample,
and Jacobson and Hamad-Schifferli both teach the use of a radio-frequency
magnetic field produced by a coil wrapped around a quartz cuvette holding
the sample. Id. Appellants contend that such a field cannot be equated with
electromagnetic radiation, which is associated with electromagnetic waves
that propagate themselves without the continuing influence of the moving
charges that produced them. Id. (citing Appellants' Exhibit C, Wikipedia,
"Electromagnetic Radiation" available at: https://en.wikipedia.org/wiki/
Electromagnetic_radiation (last visited October 22, 2018) ). Appellants
argue that, in contrast, the magnetic field used in experiments by Jacobson
and Hamad-Schifferli is a so-called "near field," which depends on a
different mechanism for their production than far fields, and also upon
different terms in Maxwell's equation. Id. Appellants assert that the
designation "radiation" in the term "electromagnetic radiation" excludes
near fields. Id. at 29 ( citing Ex. C, page 11 ).
Appellants argue that they have realized that, contrary to a simple near
field, a beam of electromagnetic radiation can be precisely controlled and
shaped, and that this makes it possible to precisely target the nanoparticles
and control exactly the amount of energy transferred to the nanoparticles as
totally different absorption mechanisms (e.g., plasmon resonance) can be
exploited. App. Br. 29. Appellants contrast this mechanism to the
limitations of the methods of Jacobson and Hamad-Schifferli to employing
inductive heating via magnetic fields. Id.
We are not persuaded by Appellants' argument. Jacobson expressly
teaches that:
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A modulator in accordance with the invention [i.e., a
nanoparticle attached to an oligonucleotide; see Jacobson ,r 9]
absorbs energy, which may be broadcast as a signal, and transfers
or transduces this energy to the associated nucleic acid molecule.
The applied energy is generally magnetic, electric, or
electromagnetic in nature, and may be, for example, a magnetic
field, a radio-frequency (RF) or other broadcast signal, or
optical radiation (e.g., visible, infrared, or ultraviolet light).
Accordingly, a modulator is chosen for sensitivity to a preferred
energy signal. Certain metals ( e.g., gold, in colloidal or non-
colloidal form, silver, copper), magnetic materials ( e.g. iron
oxide), and semiconductors (e.g., silicon, cadmium selenide,
cadmium sulfide, cadmium telluride, indium phosphide, indium
arsenide, gallium arsenide) are responsive to RF and/or optical
energy.
Jacobson ,r 33 (emphases added). Jacobson also teaches that: "In preferred
embodiments of the invention, a modulator is useful to regulate nucleic acid
hybridization .... " Id. at ,r 12. We consequently find that, contrary to
Appellants' assertion, Jacobson expressly teaches the limitation of claim 1
reciting: "heating the first fraction with electromagnetic radiation."
Appellants next argue that Mirkin does not teach local heating, let
alone nanoparticle-induced local heating; rather, Appellants argue, Mirkin
assumes that the whole sample must be heated to perform a melting curve
analysis. App. Br. 30. Jacobson, Appellants argue, teaches merely that the
excitation of nanoparticles can induce dehybridization; Appellants assert that
Jacobson does not deal with the problem of nucleic acid detection, nor does
it contemplate that nanoparticle excitation could be exploited for the purpose
of nucleic acid detection. Id.
Furthermore, Appellants argue, the cited references teach away from
their attempted combination, because a skilled artisan would have assumed
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that the heating method of Jacobson is unsuitable for the melting curve
analysis of Mirkin. App. Br. 31. According to Appellants, one key property
of the method of Mirkin is the resolution on the temperature scale, which
allows the user to distinguish changes in hybridization that arise from
temperature changes on the order of 1 °C. Id. (citing, e.g., Mirkin ,r 278).
According to Appellants, Mirkin teaches that a prerequisite for
making use of the high resolution is that the temperature in the sample can
be controlled precisely, which is achieved by raising the temperature very
slowly and by stirring the sample "to ensure homogeneity throughout the
experiment." Id. citing Mirkin ,r 344). In other words, Appellants argue,
Mirkin teaches that the temperature must be kept homogeneous throughout
the sample, i.e., the temperature must not differ from one place in the sample
to another. Id.
Appellants contend that, in contrast, Jacobson and Hamad-Schifferli
teach that the temperature modulation achieved is locally confined. App. Br.
31 (citing Jacobson ,r,r 82, 83, Hamad-Schifferli). Appellants point to
paragraph [0083] of Jacobson, which states that inductive heating of the
nanocrystal is sufficiently localized, such that surrounding molecules are not
substantially affected. Id. Appellants therefore contend that the temperature
distribution that results from nanoparticle heating is not homogeneous at all,
pointing to Jacobson's teaching that, at a distance of 10 nm or more,
dehybridization is significantly inhibited. Id. ( citing Jacobson ,r 82).
Appellants assert that these teachings suggest a very steep temperature
gradient around the nanoparticle, which would render the method useless for
DNA detection in view of the fact that the length of a typical target DNA
from Mirkin corresponds to approximately 8 to 25 nm in length. Id. at 32.
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We are not persuaded by Appellants' arguments. Jacobson expressly
teaches that:
A modulator [i.e., a nanoparticle] is preferably linked to a
specific nucleic acid, most preferably via a covalent bond. A
modulator may be provided in a form that interacts directly with
a nucleic acid to form a modified nucleic acid linked to the
modulator. Alternatively, the modulator may be provided in a
form that is incorporated into a nucleic acid during synthesis.
Modulators of the invention are useful to remotely control
reactions involving nucleic acids. In preferred embodiments of
the invention, a modulator is useful to regulate nucleic acid
hybridization, DNA/protein interactions, RNA/protein
interactions, PNA/protein interactions, DNA replication,
transcription, reverse transcription, or RNA translation.
Jacobson ,r,r 11-12 ( emphasis added). We interpret the phrase reciting: "is
useful to regulate nucleic acid hybridization" as relating to using the energy
imparted to the modulator by electromagnetic energy to dehybridize the
nucleic acid. Jacobson thus provides support for the Examiner's findings.
Furthermore, the passages of Jacobson and Hamad-Schifferli cited by
Appellants relate to the slight effect of excitation of the modulator on
nucleic acids that are not bound to the modulator. For example, the
paragraph of Hamad-Schifferli quoted by Appellants begins: "One important
property is the ability to address molecules with a nanocrystal [i.e., a
modulator/nanoparticle] while having a lesser effect on molecules not bound
to a nanocrystal. If induction heating of the nanocrystal is sufficiently
spatially localized, it will afford selectivity." Hamad-Schifferli 154. The
passage quoted by Appellants reads: "This slight amount of Z dehybridized
in the RFMF sample is presumably due to the proximity of the molecules
associated with tetrameric avidin (intermolecular separation is expected to
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be 2: 10 nm" thus refers to the slight amount of dehybridization in nucleic
acids that are not covalently bound to a nanoparticle. See App. Br. 32
(quoting Hamad-Schifferli 154). Paragraph [0082] of Jacobson, upon which
Appellants similarly rely, begins by stating: "An important feature of the
invention is the ability to address molecules with an antenna selectively
while having a lesser effect on molecules which are not bound to a
nanocrystal antenna." (Emphasis added). The passage relied upon by
Appellants thus refers to the negligible effect of electromagnetic radiation on
nearby nucleic acids that are not conjugated to nanoparticles.
We find neither of these references teach or suggest away from
combining the cited prior art. We consequently affirm the Examiner's
rejection of the claims on this ground.
DECISION
The Examiner's rejections of claims 21, 23, 24, 26, 27, and 38--41
under 35 U.S.C. § 112, first paragraph, for lack of enablement and written
descriptive support, are reversed.
The Examiner's rejection of claims 21, 23, 24, 26, 27, and 38--41
under 35 U.S.C. § 112, second paragraph, is reversed.
The Examiner's rejection of claims 21, 23, 24, 26, 27, and 38--41
under 35 U.S.C. § 101 is reversed.
The Examiner's rejection of claims 21, 23, 24, 26, 27, and 38--41
under 35 U.S.C. § 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
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AFFIRMED
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