Ex Parte Plank et al

Board of Patent Appeals and Interferences

Nov 20, 2009

09895019 (B.P.A.I. Nov. 20, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte CHRISTIAN PLANK and CHRISTIAN BERGEMANN
__________

Appeal 2008-0023291
Application 09/895,019
Technology Center 1600
__________

Decided: November 20, 2009
__________

Before RICHARD M. LEBOVITZ, FRANCISCO C. PRATS, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 of the Examiner’s rejection of
claims reciting methods of transfecting cells in the presence of a magnetic
field. Our jurisdiction is under 35 U.S.C. § 6(b).
We affirm.

1 The inventors, Christian Plank and Christian Bergemann, are the real
parties in interest (App. Br. 1).
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STATEMENT OF THE CASE
Claims 1-5, 8-10, 19-21, 23, and 24 stand rejected and appealed (App.
Br. 1).2 Claims 1, 23, and 24, the independent claims, are representative and
read as follows:
1. A method for transfecting a cell comprising the step of
bringing a complex comprising one or more vectors and one or
more magnetic particles in contact with a cell by applying a
suitable magnetic field, wherein said magnetic field is a
permanent field, and wherein said one or more vectors are
introduced into said cell.

23. A method for transfecting a cell comprising bringing a
complex in contact with a cell by applying a suitable magnetic
field, said complex comprising (a) one ore more vectors; and
(b) one or more magnetic particles; wherein said vector(s) are
not naked DNA and not an adeno-associated virus; and wherein
said magnetic field is a permanent field.

24. The method for transfecting cells in a high-throughput
assay comprising bringing a complex in contact with a cell by
applying a suitable magnetic field, said complex comprising (a)
one or more vectors; and (b) one or more magnetic particles;
wherein said vector(s) are not naked DNA and not an adeno-
associated virus; and wherein said magnetic field is a
permanent field.

The Examiner cites the following documents as evidence of
unpatentability:

2 Appeal Brief entered February 20, 2007. While claim 11 is also listed
among the appealed claims, and is listed on the first page of the Final
Rejection as being rejected (see Final Rejection mailed April 5, 2006), the
Examiner did not include claim 11 in any of the grounds of rejection
specifically advanced in the Final Rejection or the Answer.

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Chan US 5,753,477 May 19, 1998
Taylor US 5,831,062 Nov. 3, 1998
Dannenberg US 6,200,760 B1 Mar. 13, 2001

A.S. Lübbe, Physiological aspects in magnetic drug-targeting, 194
JOURNAL OF MAGNETISM AND MAGNETIC MATERIALS, 149-155, (1999).

O. Boussif, A versatile vector for gene and oligonucleotide transfer
into cells in culture and in vivo: Polyethylenimine, 92 PROCEEDINGS OF THE
NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
7297-7301 (August 1995).

The following rejections are before us for review:
Claims 1, 2, 9-10, 20, and 23 stand rejected under 35 U.S.C. § 103(a)
as being unpatentable over Lübbe and Taylor (Ans. 3-4).3
Claims 1, 3, 5, and 19 stand rejected under 35 U.S.C. § 103(a) as
being unpatentable over Lübbe, Taylor, and Chan (Ans. 4-6).
Claims 1, 3, and 4 stand rejected under 35 U.S.C. § 103(a) as being
unpatentable over Lübbe, Taylor, Chan, and Boussif (Ans. 6-8).
Claims 1, 8, 21, and 24 stand rejected under 35 U.S.C. § 103(a) as
being unpatentable over Lübbe, Taylor, and Dannenberg (Ans. 8-10).

OBVIOUSNESS -- LÜBBE AND TAYLOR
ISSUE
The Examiner finds that Lübbe “teaches a method of delivering an
agent (specifically, an anti-cancer agent) to a cell using a permanent
magnetic field and magnetic particles” (Ans. 3). The Examiner concedes,

3 Examiner’s Answer mailed on October 5, 2007.
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however, that “Lubbe does not teach that the agent is a nucleic acid vector”
(id. at 4).
To meet that limitation, the Examiner cites Taylor as teaching “a
vector comprising a nucleic acid encoding human interferon. Taylor teaches
that the vector can be used to treat a tumor, thus indicating that the vector is
an anti-cancer agent” (id.).
Based on the two references’ teachings, the Examiner concludes that
an ordinary artisan would have considered it obvious to “modify the method
taught by Lubbe such that the agent that is delivered using the permanent
magnetic field and magnetic particle(s) is a non-adeno-associated
vector/non-naked vector encoding human interferon, with a reasonable
expectation of success” (id.).
The Examiner reasons that an ordinary artisan would have been
prompted to deliver Taylor’s vector by Lübbe’s methods because the
“anti-cancer agent of Lübbe and the anti-cancer agent of Taylor are
equivalent anti-cancer agents” (id.). The Examiner urges that “[s]ince the
method of Lubbe can be used to deliver an anti-cancer agent, it would have
been obvious that the method could be used to deliver any equivalent anti-
cancer agent. The vector encoding human interferon (taught by Taylor) is
one such equivalent anti-cancer agent” (id. (citing MPEP §§ 2144.06-
2144.08)).
Appellants contend that, because the drug delivered by Lübbe’s
magnetic particles, epirubicin, differs significantly from Taylor’s interferon-
encoding nucleic acids with respect to structure and physiochemical
properties, the Examiner erred in finding that the two substances are
equivalent anti-cancer agents, and therefore also erred in finding that Lübbe
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and Taylor teach or suggest all of the limitations in the rejected claims (App.
Br. 5-6; see also Reply Br. 3-5). Moreover, Appellants argue, because of the
significant differences between the anti-cancer agents of the two references,
and the resulting lack of equivalency of the two therapeutic agents, the
Examiner erred in finding that an ordinary artisan would have been
motivated to modify the references’ teachings in the manner posited by the
Examiner (App. Br. 7-9).
Appellants further argue that, given the significant differences
between the two references’ therapeutic agents, an ordinary artisan would
not have reasonably expected to be able to deliver Taylor’s interferon-
encoding nucleic acids with Lübbe’s magnetic particles (id. at 9). Thus,
Appellants conclude, the Examiner “failed to establish all three elements
necessary for a prima facie case of obviousness” (id. at 11).
Appellants do not present separate arguments directed to individual
claims or groups of claims subject to this ground of rejection. We select
claim 1 as representative of the rejected claims. See 37 C.F.R.
§ 41.37(c)(1)(vii).
In view of the positions advanced by Appellants and the Examiner,
the issue with respect to this rejection is whether Appellants have shown that
the Examiner failed to make a prima facie case that an ordinary artisan
would have considered claim 1 obvious in view of Lübbe and Taylor.

FINDINGS OF FACT (“FF”)
1. Lübbe discloses that “[m]agnetic drug-targeting should be safe and
effective, i.e. with the least amount of magnetic particles a maximum of drug
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should be easily administered and transported to the site of choice” (Lübbe
149).
2. Lübbe investigated the physiological aspects of the magnetic drug
targeting technique using a “ferrofluid” which consisted of a colloidal
suspension of 50-150 nm magnetic particles made from iron oxides and
hydroxides coated in starch derivatives that allowed for ion exchange
binding of the drug, as well as drug desorption under physiological
conditions (id. at 150).
3. Lübbe performed experiments in rats, mice, and humans, in which
high energy permanent magnets were placed at predetermined locations
outside the subjects’ bodies, including at tumor sites in some subjects (id. at
150-154). Lübbe administered the magnetic particles, which had the drug
epirubicin reversibly bound to them, and evaluated how the particles
behaved, and whether they localized to the areas of the subjects’ bodies
adjacent to the magnets (id.).
4. Based on the experiments, Lübbe concluded that “MDT[ magnetic
drug targeting]-treatment was used successfully in mice and in man” (id. at
149 (Abstract)).
5. Lübbe further elaborated on the results of the experiments:
The perfused tumor blood vessels are crucial to
determine the amount of the ferrofluid and the length of the
magnetic field application needed for successful treatment. If
mathematical extrapolations from small to large animals and,
ultimately, to man are needed for the first patient trials, further
clinical studies are mandatory to optimize the system. As a
result from the clinical trial, the best possible particle size must
be determined in the patient setting to increase the efficacy of
magnetic drug-targeting. Then, such a technology could be
utilized for targeting of tumors, blood vessels and infectious
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sites with special drugs, cytokine-induced killer cells, biological
response modifiers, gene products and drugs . . . .

(Id. at 155 (citation omitted).)
6. Taylor discloses that a variety of different tumors, including breast
cancers, can be treated “using a nucleic acid construct comprising an
expression control sequence and an human interferon consensus [(IFN-con)]
gene which is operatively linked to said expression control sequence,
wherein the nucleic acid construct is capable of eliciting efficient and
constant expression of the gene over a long period of time” (Taylor, col. 2,
ll. 51-56).
7. Taylor discloses that producing endogenous interferon in tumor cells,
“through the use of a viral vector to integrate the IFN-con gene into a series
of tumor cell lines, led to the inhibition of tumor growth in vitro and in vivo
and to alteration of the genotype of the cells, thus providing a useful human
cancer gene therapy model” (id. at col. 2, ll. 57-61).
8. Taylor discloses that a number of viral vectors can be used to deliver
the nucleic acid construct, including retroviruses, adeno-associated viral
(AAV) vectors, and adenoviruses (id. at col. 3, l. 64 through col. 4, l. 38).
For example, Taylor discloses that in “one embodiment of the present
invention, an adenovirus vector, adenovirus-5, is chosen as the vehicle to
deliver and express IFN-con via direct in vivo application. The final
construct can be made with the IFN-con gene inserted in any of several
regions of the adenovirus vector” (id. at col. 4, ll. 38-42).
9. Taylor discloses that, because interferons act at the cell surface, the
IFN-con nucleic acid construct also has sequences that encode the
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appropriate signal peptide allowing the interferon to be secreted from the
transfected cell (id. at col. 4, l. 63, through col. 5, l. 10).
10. Taylor discloses that the viruses can be administered “by procedures
well known to those skilled in the pharmaceutical arts, e.g., direct delivery to
the target tumor or cell, intranasally, intravenously, intramuscularly,
subcutaneously, and through oral administration, either alone or in
combination” (id. at col. 6, ll. 10-14). In Examples 2 through 5, using mice
and hamsters, Taylor describes injecting the IFN-con gene-containing virus
either directly into the subjects’ tumors, or into the same location where the
tumor cells were administered (id. at col. 8, l. 38, through col. 10, l. 6).
11. It is undisputed that epirubicin is a chemotherapeutic compound that
“is positively charged at physiological pH and has a molecular weight of
about 550 Daltons” and that “the human interferon consensus gene is highly
negatively charged and has a molecular weight of at least 198,000 Daltons”
(App. Br. 5).

PRINCIPLES OF LAW
As the Supreme Court pointed out in KSR Int' l Co. v. Teleflex
Inc., 550 U.S. 398, 418 (2007), “a patent composed of several elements is
not proved obvious merely by demonstrating that each of its elements was,
independently, known in the prior art.” Rather, the Court stated:
[I]t can be important to identify a reason that would have
prompted a person of ordinary skill in the relevant field to
combine the elements in the way the claimed new invention
does . . . because inventions in most, if not all, instances rely
upon building blocks long since uncovered, and claimed
discoveries almost of necessity will be combinations of what, in
some sense, is already known.
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Id. at 418-419 (emphasis added).
The Court advised, however, that in determining whether the prior art
supplied a reason for practicing the claimed subject matter, the analysis
“need not seek out precise teachings directed to the specific subject matter of
the challenged claim, for a court can take account of the inferences and
creative steps that a person of ordinary skill in the art would employ.” Id. at
418; see also id. at 421 (“A person of ordinary skill is . . . a person of
ordinary creativity, not an automaton.”).
The Court thus ultimately reaffirmed that “when a patent ‘simply
arranges old elements with each performing the same function it had been
known to perform’ and yields no more than one would expect from such an
arrangement, the combination is obvious.” Id. at 417 (quoting Sakraida v.
Ag Pro, Inc., 425 U.S. 273 (1976)).
The Court reasoned that “if a technique has been used to improve one
device, and a person of ordinary skill in the art would recognize that it would
improve similar devices in the same way, using the technique is obvious
unless its actual application is beyond his or her skill.” Id. at 418.
The Court also reaffirmed the obviousness of substituting one
equivalent for another:
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill has good reason to pursue
the known options within his or her technical grasp. If this
leads to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense. In that
instance the fact that a combination was obvious to try might
show that it was obvious under § 103.

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Id. at 421.
However, while the Supreme Court verified that a conclusion of
obviousness requires an expectation of success, as noted by our reviewing
court, “[o]bviousness does not require absolute predictability of success. . . .
For obviousness under § 103, all that is required is a reasonable expectation
of success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988).

ANALYSIS
Appellants’ arguments do not persuade us that the Examiner failed to
make a prima facie case that an ordinary artisan would have considered
claim 1 obvious in view of Lübbe and Taylor.
At the outset, we acknowledge, as Appellants argue, that Lübbe’s
epirubicin is significantly different from Taylor’s interferon gene-containing
virus (see FF 11).
However, the agents used in both references share the common
property that optimum therapeutic benefit is obtained when the agent is
localized at the tumor site (see FF 4, 10). In fact, given that Taylor’s virus
must contact the tumor cells to allow transfection of the interferon gene (see
FF 7, 10), an ordinary artisan would have reasonably inferred that it would
be desirable to use a tumor targeting technique, such as Lübbe’s magnetic
drug targeting, to ensure the presence of the viruses at the desired tumor
location.
We are therefore not persuaded that the differences between the two
therapeutic agents would have dissuaded an ordinary artisan from using
Lübbe’s magnetic particles to deliver Taylor’s viruses to the target tumors,
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nor are we persuaded that the references’ combined disclosures fail to teach
or suggest all of the limitations in claim 1.
We are also not persuaded that an ordinary artisan would have lacked
a reasonable expectation that Taylor’s virus could be delivered by Lübbe’s
magnetic targeting methods. Based on the results of its study, Lübbe states
that its methods would be applicable to a variety of therapeutic agents
having widely varying properties, including drugs, cells, and gene products
(FF 5). Lübbe also discloses that the magnetic particles are prepared to have
ion exchange binding moieties on their surfaces (FF 2).
Appellants point to no evidence of record suggesting that an ordinary
artisan would have been unable to determine, through routine
experimentation, ion exchange-type binding moieties suitable for delivering
therapeutic agents other than epirubicin. To the contrary, given Lübbe’s
disclosure that its techniques were amenable to delivery of a variety of
therapeutics, such as cells, which have properties much different than
epirubicin, it appears on the current record that an ordinary artisan seeking to
deliver Taylor’s virus by Lübbe’s targeting methods would have expected
that adapting Lübbe’s particles in the desired manner would be routine.
Appellants argue that Lübbe discloses that further trials are required to
optimize the process, and that Lübbe therefore concedes that any potential
applications of its techniques beyond the references’ explicitly disclosure are
unpredictable (Reply Br. 6).
As noted above, Lübbe discloses:
If mathematical extrapolations from small to large
animals and, ultimately, to man are needed for the first patient
trials, further clinical studies are mandatory to optimize the
system. As a result from the clinical trial, the best possible
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particle size must be determined in the patient setting to
increase the efficacy of magnetic drug-targeting. Then, such a
technology could be utilized for targeting of tumors, blood
vessels and infectious sites with special drugs, cytokine-
induced killer cells, biological response modifiers, gene
products and drugs . . . .

(Lübbe 155.)
We are not persuaded that an ordinary artisan viewing this disclosure
would have lacked a reasonable expectation that Taylor’s virus could be
successfully delivered using Lübbe’s technique. It is well settled that
“[o]bviousness does not require absolute predictability of success.” In re
O’Farrell, 853 F.2d at 903-04.
We agree that Lübbe suggests that its methods require additional trials
to determine particle sizes that optimize drug delivery. However, we see
nothing in Lübbe suggesting that this optimizing process would require
anything beyond routine experimentation. To the contrary, Lübbe explicitly
states that magnetic drug targeting “was used successfully in mice and in
man” (Lübbe 149 (Abstract)).
Thus, rather than suggesting that its technique was just a promising
field that should be further explored, an ordinary artisan would have
understood Lübbe as disclosing its experiments as demonstrating the
therapeutic viability of the magnetic targeting method with respect to the
model drug used, and the amenability of the technique to a variety of other
agents upon mere optimization of parameters. We are therefore not
persuaded that an ordinary artisan would have lacked a reasonable
expectation that Taylor’s virus could be successfully delivered using
Lübbe’s technique.
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In sum, for the reasons set forth above, we are not persuaded that the
Examiner failed to make a prima facie case of obviousness with respect to
claim 1. We therefore affirm the Examiner’s rejection of claim 1 as obvious
over Lübbe and Taylor. Claims 2, 9-10, 20, and 23 fall with claim 1. See 37
C.F.R. § 41.37(c)(1)(vii).
OBVIOUSNESS -- LÜBBE, TAYLOR, AND CHAN
Claims 1, 3, 5, and 19 stand rejected under 35 U.S.C. § 103(a) as
being unpatentable over Lübbe, Taylor, and Chan (Ans. 4-6). The Examiner
again cites Lübbe and Taylor as suggesting the claimed features discussed
above (id. at 5).
Chan is cited as teaching “a method for transfecting a cell comprising
bringing a complex comprising one or more vectors and one or more
magnetic particles in contact with a cell by applying a suitable
electromagnetic field” (id.). The Examiner further cites Chan as teaching
“that the magnetic particles can be coupled to oligo or poly- cations/anions”
(id.), thus allowing the magnetic particles to be complexed to the
pharmaceutical agent, which can be a naked DNA vector or an adenovirus,
and which can be delivered to cells in vivo or in vitro (id. at 5-6).
Based on the references’ teachings, the Examiner concludes that an
ordinary artisan would have considered it obvious to modify Lübbe’s
method “such that the agent that is delivered using the permanent magnetic
field is a nucleic acid vector (as taught by Taylor) wherein the nucleic acid
vector is linked by a physical linkage to the magnetic particles and wherein
the complex further comprises a polycation (as taught by Chan)” (id. at 6).
Appellants reiterate their arguments regarding the deficiency of the
combination of Lübbe and Taylor, and further argue that Chan teaches away
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from the claimed invention (App. Br. 11-13; see also Reply Br. 7-8).
Specifically, Appellants argue, despite being aware of the prior art use of
permanent magnetic fields to target therapeutic agents to cells, Chan teaches
the requirement of using a pulsed magnetic field to achieve nucleic acid
delivery (id. at 12-13).
Appellants cite the Declaration of Dr. C. Plank in support of this
argument (id. at 13).
Dr. Plank states:
Having knowledge of the teachings of Widder et al., US
5,753,477, and the later teaching of Lübbe et al., and
combining said teachings, the expert in the field would
necessarily conclude, in the absence of any known
evidence to the contrary, that the application of a
permanent magnetic field on non-covalent magnetic
particle-nucleic acid entities is unsuitable for transfecting
a cell if not combined with “a secondary high magnetic
pulse (2 to 50 Teslas)” in order “for the particles to
accelerate to a high enough velocity to penetrate a single
cell membrane or multi-cell layers”.

(Id. at Evidence Appendix (Page 3 of Declaration of Dr. C. Plank).)
Because Chan teaches that a pulsed magnetic field is required to
deliver nucleic acids to cells, Appellants argue, a person of ordinary skill in
the art would have been “have been led in a direction divergent from the
path that was taken by the Appellants,” and would not have been prompted
to use a permanent magnetic field as recited in the claims (App. Br. 13).
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Appellants do not present separate arguments directed to individual
claims or groups of claims subject to this ground of rejection. We again
select claim 1 as representative of the rejected claims. See 37 C.F.R.
§ 41.37(c)(1)(vii).
In view of the positions advanced by Appellants and the Examiner,
the issue with respect to this rejection is whether Appellants have shown that
the Examiner failed to make a prima facie case that an ordinary artisan
would have considered claim 1 obvious in view of Lübbe, Taylor, and Chan.

FINDINGS OF FACT (“FF”)
12. Chan discloses that, in one prior art method, magnetic microparticles
complexed with a chemotherapeutic agent were “held in [a] desired location
via an external static permanent magnet. It has been reported that these
complexes are internalized by tumor cells in vitro and in vivo following
intra-peritoneal (ip) injection, possibly through passive phagocytosis
process” (Chan, col. 1, ll. 41-45).
13. Chan discloses, however, that “controlled localization of drug carriers
including this type of magnetic microspheres or conventional liposomes has
been difficult to achieve. Despite efforts to impart specificity by modifying
surface charge, varying vesicle size and varying lipid components,
intravascular administration of such carriers results in their uptake
predominately by the reticuloendothelial system” (id. at col. 1, ll. 46-52).
14. To address the shortcomings in such prior art, Chan discloses methods
that “utilize super-paramagnetic and/or ferromagnetic microparticles to carry
substances into cells via a pulsed magnetic field” (id. at col. 2, l. 66, through
col. 3, l. 1).
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15. Chan discloses:
In general, because of the short duration (micro- to milli-
seconds) of a pulse in a high magnetic field (2 to 50 Teslas),
two stages of magnetic induction are required to act on the
particles in order for the particles to accelerate to a high enough
velocity to penetrate a single cell membrane or multi-cell
layers.

(Id. at col. 3, ll. 62-67).
16. Chan discloses that suitable coatings for its magnetic particles include
dextran which has been “chemically modified and conjugated with other
proteins or polyamines such as poly-L-lysine, polyarginine or other
biopolymers with positive charges. These chemical modifications allow for
binding of nucleic acids through ionic interaction” (id. at col. 6, ll. 14-17).
17. Chan discloses that “[d]epending on the particular coating, a number
of substances can be carried via the magnetic microparticles. For example,
nucleic acids, including plasmids, genetic constructs, ribozymes, viruses, or
proteins can be complexed onto magnetic microparticles which have been
coated with positively-charged biopolymers or cationic lipids” (id. at col. 6,
ll. 33-38).
18. Chan discloses that its techniques “may be used with any type of cell
preparation, including cells affixed or adhered to a surface, cells suspended
in solution, tissue explants and tissues in situ. Primary cells and established
cell lines, germ-line as well as somatic cells are amenable to the present
methods” (id. at col. 6 ll. 61-65).
PRINCIPLES OF LAW
In KSR the Supreme Court reaffirmed that claims are likely to be
unobvious “when the prior art teaches away” from their practice. KSR, 550
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U.S. at 416. The Court noted that it had held claims to be unobvious where
the prior art warned of risks involved in using the claimed elements. Id.
(citing United States v. Adams, 383 U.S. 39, 51-52 (1966)).
Similarly, as stated by our reviewing court, “[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 Kahn, 441 F. 3d 977, 990 (Fed. Cir. 2006) (quoting In re
Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994)).
However, the Federal Circuit has also advised:
[O]ur case law does not require that a particular combination
must be the preferred, or the most desirable, combination
described in the prior art in order to provide motivation for the
current invention. “[T]he question is whether there is
something in the prior art as a whole to suggest the desirability,
and thus the obviousness, of making the combination,” not
whether there is something in the prior art as a whole to suggest
that the combination is the most desirable combination
available. See In re Beattie, 974 F.2d [1309,] 1311 (internal
quotation omitted; emphasis added). . . . [A] finding that the
prior art as a whole suggests the desirability of a particular
combination need not be supported by a finding that the prior
art suggests that the combination claimed by the patent
applicant is the preferred, or most desirable, combination.
In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004).
Ultimately, therefore, when evaluating claims for obviousness, “the
prior art as a whole must be considered. The teachings are to be viewed as
they would have been viewed by one of ordinary skill.” In re Hedges, 783
F.2d 1038, 1041 (Fed. Cir. 1986).
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Thus, “in a section 103 inquiry, ‘the fact that a specific [embodiment]
is taught to be preferred is not controlling, since all disclosures of the prior
art, including unpreferred embodiments, must be considered.’” Merck &
Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 807 (Fed. Cir. 1989)
(quoting In re Lamberti, 545 F.2d 747, 750 (CCPA 1976))

ANALYSIS
Appellants’ arguments do not persuade us that the Examiner failed to
make a prima facie case that an ordinary artisan would have considered
claim 1 obvious in view of Lübbe, Taylor, and Chan.
We note, as Appellants argue, Chan’s disclosure of using a pulsed,
rather than permanent, magnetic field to internalize magnetic
particle-nucleic acid complexes into cells (FF 14-15). We are not persuaded,
however, that this disclosure amounts to a teaching away from using a
permanent magnetic field, as recited in claim 1.
It might be true that Chan teaches pulsed fields as being the preferred
method of delivering nucleic acid vectors to cells. Nonetheless, the fact that
Taylor was able to achieve a therapeutic effect merely by injecting its anti-
cancer viruses at the tumor site (FF 10) demonstrates that a pulsed magnetic
field, while disclosed by Chan as desirable, is not necessary for providing an
anti-tumor effect when using viruses to transfect the tumor cells.
Moreover, Chan in fact acknowledges that an external permanent
magnet was capable of holding magnetic particle-drug complexes at a
desired tumor site, allowing internalization of the drug by the tumor cells
(FF 12). The suitability of using permanent magnets to localize therapeutic
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agents to tumors is bolstered by Lübbe’s disclosure that the technique can be
used to successfully treat tumors (FF 4-5).
Thus, while an ordinary artisan reading Chan might have considered a
pulsed magnetic field to be the preferred technique, Appellants’ arguments,
even as supported by the Plank Declaration, do not persuade us that Chan’s
teaching would have undermined the artisan’s understanding that Lübbe’s
method of using a permanent magnet was an alternative, albeit less
preferred, way of targeting magnetic particle-anticancer agent complexes to
desired sites on a patient’s body. Further, given Chan’s disclosure that
magnetic particles can be used to target viral vectors to tumor cells (see FF
17), we agree with the Examiner that an ordinary artisan would have had a
reasonable expectation that Chan’s coating would allow reversible
complexing of Taylor’s anticancer viruses to Lübbe’s magnetic particles,
which in turn would allow localization of the viruses to the desired tumor
sites in the presence of an appropriately located permanently magnetic field.
For similar reasons, Dr. Plank’s reasoning is not persuasive. The
Examiner relied on Chan for teaching coated particles, not the pulsed
magnetic field. As stated above, despite Chan’s teaching, Taylor taught that
nucleic acids could be used therapeutically to transfect cells, even without
magnetic targeting. Therefore, Dr. Plank’s testimony that “one high
magnetic field pulse must be applied in addition in order to transfect cells” is
not supported by the evidence.
We are therefore not persuaded that Chan provides a sufficient
teaching away from the claimed process to undermine the Examiner’s prima
facie case of obviousness with respect to claim 1. We therefore affirm the
Examiner’s rejection of that claim as being obvious over Lübbe, Taylor, and
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Chan. Claims 3, 5, and 19 fall with claim 1. See 37 C.F.R.
§ 41.37(c)(1)(vii).

OBVIOUSNESS -- LÜBBE, TAYLOR, CHAN, AND BOUSSIF
Claims 1, 3, and 4 stand rejected under 35 U.S.C. § 103(a) as being
unpatentable over Lübbe, Taylor, Chan, and Boussif (Ans. 6-8). The
Examiner relies on Lübbe, Taylor, and Chan for the teachings discussed
above, but concedes that “Chan does not teach that the polycation is PEI
[polyethyleneimine]” (id. at 7).
To meet that limitation the Examiner cites Boussif as disclosing that
“PEI can be used as ‘a highly efficient vector for delivering oligonucleotides
and plasmids both in vitro and in vivo’” (id. at 7-8 (quoting Boussif 7297)).
Based on the references’ combined teachings, the Examiner concludes that
an ordinary artisan would have considered it obvious to use PEI on the
surface of magnetic particles to deliver a nucleic acid vector to cells in the
presence of a permanent magnetic field (id.).
Appellants argue only that Boussif’s disclosure of PEI as a nucleic
acid deliver agent “does not address the deficiencies in Lubbe, Taylor, and
Chan” previously discussed (App. Br. 14; see also Reply Br. 8-9).
However, for the reasons set forth above, we are not persuaded that
the Examiner failed to make a prima facie case of obviousness with respect
to Lübbe, Taylor, and Chan. As Appellants point to no other deficiency in
the Examiner’s prima facie case, we affirm the Examiner’s rejection of
claims 1, 3, and 4 as being obvious over Lübbe, Taylor, Chan, and Boussif.

OBVIOUSNESS -- LÜBBE, TAYLOR, AND DANNENBERG
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Claims 1, 8, 21, and 24 stand rejected under 35 U.S.C. § 103(a) as
being unpatentable over Lübbe, Taylor, and Dannenberg (Ans. 8-10). The
Examiner relies on Lübbe and Taylor for the teachings discussed above, but
concedes that “[n]either Lubbe nor Taylor teach that the method of using a
permanent magnetic field can be used to deliver a vector to a cell in vitro
and in a high through-put assay” (id. at 9).
To meet that limitation, the Examiner cites Dannenberg as teaching “a
method of delivering a vector to a cell in vitro wherein the method utilizes a
high through-put assay” (id.). Based on the references’ combined teachings,
the Examiner concludes that an ordinary artisan would have considered it
obvious to modify Lübbe’s method “such that the agent that is delivered
using the permanent magnetic field and magnetic particle(s) is a vector and
wherein the method delivers the agent to a target cell in vitro in a high
through-put assay with a reasonable expectation of success” (id.).
Appellants reiterate their contention that the combination of Lübbe
and Taylor fails to make a prima facie case, and further argue that
Dannenberg does not remedy that deficiency (App. Br. 14-15). Moreover,
Appellants argue, given that Dannenberg transfects cells by electroporation,
Taylor transfects cells using viral vectors, and Lübbe does not transfect cells
at all, “a person of ordinary skill in the art would not have been motivated to
combine or modify these references to provide a method for transfecting a
cell with a complex of a vector and a magnetic particle by applying a
permanent magnetic field” (id. at 15). Rather, Appellants urge that the
Examiner improperly reconstructed the claimed invention using hindsight
(id.; see also Reply Br. 14-15).
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Appellants again do not present separate arguments directed to
individual claims or groups of claims subject to this ground of rejection. We
again select claim 1 as representative of the rejected claims. See 37 C.F.R.
§ 41.37(c)(1)(vii).
In view of the positions advanced by Appellants and the Examiner,
the issue with respect to this rejection is whether Appellants have shown that
the Examiner failed to make a prima facie case that an ordinary artisan
would have considered claim 1 obvious in view of Lübbe, Taylor, and
Dannenberg.
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23
FINDINGS OF FACT (“FF”)
19. Dannenberg discloses processes for “screening agents as candidates
for drugs or sources of drugs for prophylaxis or treatment of human
disorders caused or mediated by cyclooxygenase-2 and/or matrix
metalloproteinases” (Dannenberg, abstract).
20. Dannenberg describes its screening method as follows:
Cells transfected with a construct comprising a 5'-flanking
region of the human cyclooxygenase-2 gene or equivalent
thereof, e.g., synthetic equivalent therefor, or other
transcriptional promoter element of the human cyclooxygenase-
2 gene ligated to a reporter gene are treated with an activator of
cyclooxygenase-2 promoter activity. The agent being screened
is tested for its ability to suppress stimulation of the
cyclooxygenase-2 promoter. The agent is a candidate as a drug
or source of a drug for prophylaxis or treatment of mammalian
disorders caused or mediated by cyclooxygenase-2 expression
if stimulated promoter activity is reduced by the agent.

(Id. at col. 2, l. 61, through col. 3, l. 5.)
21. Dannenberg discloses that “[e]ither transient systems or stably
transfected cell lines can be used” in its screening process (col. 4, ll. 43-44).
22. Dannenberg discloses that “[t]ransfection to provide a stable system,
i.e., a stably transfected cell line, is obtained by standard methods” (col. 5, ll.
28-29).
23. Dannenberg discloses that a “preferred method of transfection to
provide a transient system involves utilizing electroporation, very preferably
square wave electroporation. The electroporation causes temporary
openings in the cells whereby the construct can enter inside the cell” (id. at
col. 4, ll. 54-58).
24. Dannenberg discloses:
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In a very preferred method, a single electroporation is utilized
to transfect cells which are subsequently diluted with additional
cell culture medium to a volume such as to provide aliquots
thereof of the same composition for a plurality of wells, e.g., 96
wells, for use for determinations, to provide a high throughput
system and standardization without the need to use a
standardizing plasmid.

(Id. at col. 5, ll. 18-24.)

ANALYSIS
Appellants’ arguments do not persuade us that the Examiner failed to
make a prima facie case that an ordinary artisan would have considered
claim 1 obvious in view of Lübbe, Taylor, and Dannenberg. As discussed
above, we agree with the Examiner that the combination of Lübbe and
Taylor by itself renders the method of claim 1 prima facie obvious. We do
not agree with Appellants that Dannenberg’s disclosure undermines that
conclusion.
We note, as Appellants argue, that Dannenberg discloses the
desirability of using electroporation to transiently transfect cells in its high
throughput screening system (FF 23, 24). However, Dannenberg also
discloses that cells stably transfected by “standard methods” are useful in
such a system (FF 22).
As disclosed by Taylor, transfection of cells in vivo, or in vitro, can be
accomplished using a viral vector (see FF 7). Thus, given Dannenberg’s
disclosure that standard methods of transfection can be used to generate test
cells in a high throughput screening method, and given Taylor’s disclosure
that viral vectors were useful in accomplishing transfection, we are not
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25
persuaded that Dannenberg undermines the Examiner’s conclusion of
obviousness with respect to claim 1.
Moreover, in view of Lübbe’s disclosure that a variety of different
agents, when complexed with magnetic particles, can be localized to target
cells in the presence of a permanent magnet (FF 5), we are not persuaded
that an ordinary artisan would have considered it unobvious to use that
technique to target viral vectors to cells in a high throughput screening
method.
In sum, because Appellants’ arguments do not persuade us that the
Examiner erred in concluding that claim 1 would have been obvious in view
of Lübbe, Taylor, and Dannenberg, we affirm the Examiner’s rejection of
that claim over those references. Because they were not argued separately,
claims 8, 21, and 24 fall with claim 1. See 37 C.F.R. § 41.37(c)(1)(vii).

SUMMARY
We affirm the Examiner’s rejection of claims 1, 2, 9-10, 20, and 23
under 35 U.S.C. § 103(a) as being unpatentable over Lübbe and Taylor.
We affirm the Examiner’s rejection of claims 1, 3, 5, and 19 under 35
U.S.C. § 103(a) as being unpatentable over Lübbe, Taylor, and Chan.
We affirm the Examiner’s rejection of claims 1, 3, and 4 stand
rejected under 35 U.S.C. § 103(a) as being unpatentable over Lübbe, Taylor,
Chan, and Boussif.
We affirm the Examiner’s rejection of claims 1, 8, 21, and 24 under
35 U.S.C. § 103(a) as being unpatentable over Lübbe, Taylor, and
Dannenberg.

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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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