Ex Parte Bleck et al

Patent Trial and Appeal Board

Feb 14, 2014

10759315 (P.T.A.B. Feb. 14, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/759,315 01/16/2004 Gregory T. Bleck GALA 08484 9065
72960 7590 02/14/2014
Casimir Jones, S.C.
2275 DEMING WAY, SUITE 310
MIDDLETON, WI 53562
EXAMINER
POPA, ILEANA
ART UNIT PAPER NUMBER
1633
MAIL DATE DELIVERY MODE
02/14/2014 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 GREGORY T. BLECK, ROBERT D. BREMEL, and
LINDA U. MILLER
____________

Appeal 2012-006609
Application 10/759,315
Technology Center 1600
____________

Before DONALD E. ADAMS, ERICA A. FRANKLIN, and
ULRIKE W. JENKS, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL1
This appeal under 35 U.S.C. § 134 involves claims 1-10, 12, 14-18,
20-26, 28, and 30-41 (App. Br. 3). Examiner entered rejections under 35
U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 The Real Party in Interest is Catalent Pharma Solutions, LLC (App. Br. 3).
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STATEMENT OF THE CASE
The claims are directed to a method for producing a protein of
interest. Claim 1 is representative and is reproduced in the Claims Appendix
of Appellants’ Brief.
Claims 1-10, 12, 14-18, 20, 21, 28, 30-34, and 41 stand rejected under
35 U.S.C. § 103(a) as unpatentable over the combination of Mathor,2 Burns,3
Felts,4 Schott,5 and Persons.6
Claims 1-10, 12, 14-18, 20, 21, 26, 28, 30-38, and 41 stand rejected
under 35 U.S.C. § 103(a) as unpatentable over the combination of Mathor,
Burns, Felts, Schott, Persons, and Schroder.7
Claims 1-10, 12, 14-18, 20-24, 26, 28, 30-34, and 39-41 stand rejected
under 35 U.S.C. § 103(a) as unpatentable over the combination of Mathor,
Burns, Felts, Schott, Persons, Primus,8 and Kolb.9

2 Mathor et al., Clonal analysis of stably transduced human epidermal stem
cells in culture, 93 PRO. NATL. ACAD. SCI. USA, MEDICAL SCIENCES 10371-
10376 (1996).
3 Burns et al., Vesicular stomatitis virus G glycoprotein pseudotyped
retroviral vectors: Concentration to very high titer and efficient gene
transfer into mammalian and nonmammalian cells, 90 PROC. NATL. ACAD.
SCI. USA 8033-8037 (1993).
4 Felts et al. High-Titer Retroviral Vectors for Gene Delivery,
12 STRATEGIES 74-77 (1999).
5 Schott et al., Effects of Infection Rate and Selection Pressure on Gene
Expression from an Internal Promoter of a Double Gene Retroviral Vector,
22 SOMATIC CELLS AND MOLECULAR GENETICS 291-309 (1996).
6 Persons et al., An Improved Method for Generating Retroviral Producer
Clones for Vectors lacking a Selectable Marker Gene, 24 BLOOD CELLS,
MOLECULES, AND DISEASES 167-182 (1998).
7 Schroder et al., Overexpression of Recombinant Human Antithrombin III in
Chinese Hamster Ovary Cells Results in Malformation and Decreased
Secretion of Recombinant Protein, 53 BIOTECH. BIOENG. 547-559 (1997).
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Claims 1-10, 12, 14-18, 20, 21, 25, 28, 30-34, and 41 stand rejected
under 35 U.S.C. § 103(a) as unpatentable over the combination of Mathor,
Burns, Felts, Schott, Persons, and Naldini.10

ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Appellants disclose that the “intrinsic instability of [multiple
transgene integration] may be due to the characteristic head-to-tail mode of
integration which promotes the loss of coding sequences by homologous
recombination” (Spec. 2: 13-16).
FF 2. Appellants disclose that “the high genomic stability and protein
expression levels of the host cells of the present invention are thought to be
due to unique properties of the integrating vectors (e.g., retroviral vectors)”
(id. at 32: 19-21; see January 16, 2014 Oral Hearing Transcript 12-14).

8 Primus et al., Self-Reactive Antibody Expression by Human Carcinoma
Cells Engineered with Monoclonal Antibody Genes, 53 CANCER RES. 3355-
3361 (1997).
9 Kolb et al., Expression of a recombinant monoclonal antibody from a
bicistronic mRNA, 16 HYBRIDOMA 421-426 (1997) (Abstract).
10 Naldini et al., In Vivo Gene Delivery and Stable Transduction of
Nondividing Cells by a Lentiviral Vector, 272 SCIENCE 263-267 (1996).
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FF 3. Appellants’ Table 13 is reproduced below:

Appellants’ Table 13 illustrates the number viral integrations, or “copy
number” achieved for the various transduced cells, or “Colony #” tested and
the amount of protein, represented in “pg/cell/day” encoded by a gene of
interest, produced for each cell line, or colony, listed (Spec 102: Table 13;
see generally January 16, 2014 Oral Hearing Transcript 4: 16 - 5: 18).
FF 4. Mathor suggests the transduction of a host cell with a retroviral
vector at a multiplicity of infection (MOI) of 30, wherein the retroviral
vector contains a gene of interest that encodes a protein of interest; clonally
selecting a host cell expressing the gene of interest; and purifying the protein
encoded by the gene of interest (Ans. 7).
FF 5. Mathor’s Table 1 is reproduced below:

Mathor’s Table 1 illustrates the number of proviral integrations achieved for
various transduced cells, or “clone[s],” tested and the amount of protein,
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encoded by a gene of interest, produced, “[i]n culture” or “[i]n serum,” for
each cell, or clone, listed (Mathor 10374: Table 1; see generally January 16,
2014 Oral Hearing Transcript 13: 10-21 (suggesting that differences in
protein expression can result from the particular location of the host cell
genome into which a particular retroviral vector integrates)).
FF 6. Examiner finds that Mathor fails to suggest an immortal cell line and
relies on Burns to suggest immortal cell lines and retroviral vectors capable
of transducing the immortal cell line (Ans. 8).
FF 7. Examiner finds that the combination of Mathor and Burns fails to
“specifically . . . [suggest] serial transduction to . . . obtain [a host] cell
comprising in its genome from 20 to about 100 integrated vectors,” but finds
that Mathor “do[es] . . . [suggest] that protein expression is directly
proportional to the integration events (i.e. copy number)” and that Felts
suggests “that the advantage of retroviral vectors is that the copy number of
integrated provirus can easily be controlled by varying the multiplicity of
infection” (id. at 8-9; see also Mathor 10376: col. 1, ll. 6-9 (“The rate of
secretion of the exogenous protein by cultures generated by single clones
was proportional to the number of integrations per progenitor cells”); Felts
74: col. 1, ll. 27-30 (“An additional advantage of retroviral vectors is that the
copy number of integrated provirus can be easily controlled by varying the
multiplicity of infection”)).
FF 8. Schott suggests that “serially transducing cells with a retroviral
vector carrying an internal promoter driving the expression of a gene of
interest, wherein higher MOI result in higher integration events and wherein
the expression and stability of the gene of interest directly correlates with the
number of integrated retroviral vectors” (Ans. 9).
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FF 9. Examiner relies on Persons to suggest that it was known in the art,
prior to Appellants’ filing date, to repeatedly transduce cells with retroviral
vectors at a MOI (Ans. 9; Persons 167: Abstract (“Viral preparations of a
vector lacking a selectable marker were used to repeatedly transduce
exponentially growing packaging cells at a high multiplicity of infection
(MOI)”)).
FF 10. Examiner relies on Schroder to suggest “the amplification of hATIII
expression in CHO cells via DHFR-mediated gene amplification in the
presence of methotrexate” (Ans. 10).
FF 11. Examiner relies on Primus to suggest “a method of expressing a
monoclonal IgG2a antibody in[] a tumor cell, wherein the tumor cell is
transduced with two different vectors, one encoding the heave and the other
encoding the light chain” (id. at 12).
FF 12. Examiner relies on Kolb to suggest “concurrent synthesis of both
heavy and light chains of the monoclonal antibody A1 by using bicistronic
expression cassette comprising an internal ribosomal entry site” (id.).
FF 13. Examiner relies on Naldini to suggest “lentiviral vector for the stable
transduction of non-dividing cells” (id. at 13).
FF 14. Bleck declares that “[a]t the time of the invention . . . it would have
been expected that increasing the copy number of retroviral vectors past 20
would result in methylation, inactivation and instability” (Fourth Declaration
of Dr. Gregory Bleck11 4: ¶ 4; see generally January 16, 2014 Oral Hearing
Transcript 6: 1-4 (“JUDGE ADAMS: . . . I believe all the arguments in both
[Bleck] declarations, were with regard to this methylation [concern]; is that
right? MR. JONES: Yeah”)).

11 Fourth Declaration of Dr. Gregory Bleck, executed September 17, 2009.
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FF 15. Bleck declares that “[t]he data in Table 1 of Mathor . . . cannot be
extrapolated to a situation where there are 20 integrations,” because “[i]t is
impossible to do a valid statistical analysis or curve fit based on the data in
Mathor . . .. For example, . . . the data could indicate a plateau or upside-
down U shaped curve” (Fourth Declaration of Dr. Gregory Bleck 5: ¶ 6; see
also Fifth Declaration of Dr. Gregory Bleck12 2: ¶ 5 (Mathor “teaches that
transgene expression correlates with number of integrations over the range
of 1 to 8 integrations. Transgene expression decreased when a cell line with
15 integrations was analyzed”); see also id. at 3: ¶ 7; App. Br. 7; Reply Br.
5; FF 5; Cf. FF 3).
FF 16. Bleck declares that Bestor13
identif[ied] two hypothetical roles of genomic methylation
patterns. . .. The second role is that cytosine methylation is part
of a genome defense system which inactivates parasitic
sequences such as transposable elements and proviral DNA
(i.e., integrated retroviruses). . .. This second role of
methylation is directly relevant to the present invention which
utilizes high levels of integrated retroviral vectors.
(Fifth Declaration of Dr. Gregory Bleck 6: ¶ 8; App. Br. 10; Cf. Bestor 366:
col. 2, ll. 30-35 (“None of the hypothetical functions of cytosine methylation
(and this includes the . . . host-defense functions) has the support of
compelling experimental evidence, and all, some, or none of the hypotheses
may be valid”); see generally January 16, 2014 Oral Hearing Transcript 10:
10 - 12: 15.)
FF 17. Bleck declares that while Garrick’s14 “vector construction was not a
retroviral vector,” Garrick “provides evidence that the state of the art was

12 Fifth Declaration of Dr. Gregory Bleck, executed September 14, 2010.
13 Bestor et al., Creation of genomic methylation patterns, 12 NATURE
GENETICS 363-367 (1996).
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that increasing copy number leads to methylation and inactivation of
transgenes” (Fifth Declaration of Dr. Gregory Bleck 7: ¶ 8; App. Br. 11; Cf.
Garrick 56: col. 1, ll. 23-26 (“These findings establish that the presence of
multiple homologous copies of a transgene within a concatameric array can
have a repressive effect upon gene expression in mammalian systems”
(emphasis added)).
FF 18. Bleck declares that Cherry15, “co-authored by two of the leading
scientists in the field,” suggests the “role of methylation in the inactivation
of proviral genes” (Fifth Declaration of Dr. Gregory Bleck 7: ¶ 8; App. Br.
11-12; see also Fifth Declaration of Dr. Gregory Bleck 8-9: ¶ 8 (Svoboda16
“note[s] that all of the data so far point[s] to the important role of
methylation in provirus silencing in general and that strategies for
preventing methylation should contribute to more efficient gene transfer in
the future”); id. at 9: ¶ 8 (Ellis17 suggest that “vectors are frequently silenced
and that a better understanding of the mechanism of vector silencing is
needed” and Challita18 “provide data that shows that lack of expression
following retroviral transduction is due to methylation”); App. Br. 13; Cf.

14 Garrick et al., Repeat-induced gene silencing in mammals, 18 NATURE
GENETICS 56-59 (1998).
15 Cherry et al., Retroviral Expression in Embryonic Stem Cells and
Hematopoietic Stem Cells, 20 MOLECULAR AND CELLULAR BIOLOGY 7419-
7426 (2000).
16 Svoboda et al., Retroviruses in foreign species and the problem of
provirus silencing, 261 GENE 181-188 (2000).
17 Ellis et al., The beta-globin locus control region versus gene therapy
vectors: a struggle for Expression, 59 CLINICAL GENETICS 17-24 (2001).
18 Chillita et al., Lack of expression from a retroviral vector after
transduction of murine hematopoietic stem cells is associated with
methylation in vivo, 91 PROC. NATL. ACAD. SCI. USA 2567-2571 (1994).
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Cherry 7419: Abstract (“Long-term passage of infected . . . cells resulted in
methylation-mediated silencing, while short-term expression was
methylation independent” (emphasis added)); see also Fifth Declaration of
Dr. Gregory Bleck 8: ¶ 8 (Niwa19 suggests that “[n]ewly acquired retroviral
vectors [(e.g., short-term expression)] are treated by cells in a different
manner from proviral sequences that have been integrated into the genome
in the distant past and essentially become endogenous [(e.g., long-term
expression)]”); App. Br. 12-13; see generally January 16, 2014 Oral Hearing
Transcript 7: 23 - 8: 6 (making clear that: (1) Cherry is “relevant to what
people at the time [of Appellants’ invention] were thinking” and that (2)
Appellants’ claim 1 does not require long-term stability or production of
Appellants’ gene of interest); id. (“Cherry is just talking about methylation
issues after a long-term passage. Your claim doesn’t require a long-term
passage”); see also Challita 2567: Abstract and col. 1, ll. 10-15
(“Transcriptional expression from . . . [retrovirus] was detected at a high
level in the primary,” (e.g., short-term expression) cells, but transcriptional
inactivity was observed in secondary and tertiary (e.g., long-term) cultures;
therefore, “[a]lthough Moloney murine leukemia virus . . .-based retroviral
vectors are currently the most efficient vehicles for gene transfer into a
variety of cell types . . ., the long-term . . . expression from the viral . . .
elements has been unsatisfactory” (emphasis added)).

19 Niwa et al., Independent Mechanisms Involved in Suppression of the
Moloney Leukemia Virus Genome during Differentiation of Murine
Teratocarcinoma Cells, 32 CELL 1105-1113 (1983).
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FF 19. Bleck declares that Mehtali20 suggests “that methylation of an
introduced transgene increases with increasing copy number and that
expression of the transgene decreases with increasing copy number after
initially increasing” (Fifth Declaration of Dr. Gregory Bleck 8: ¶ 8; App. Br.
12; Cf. Mehtali 179: Abstract (establishing that Mehtali’s conclusions are
based on “tandem arrays of a fusion construct”); FF 1; see generally January
16, 2014 Oral Hearing Transcript 6: 9 - 7: 8 (making clear that Mehtali’s
disclosure is limited to “tandem arrays” of a fusion construct, which is
distinguishable from the retroviral integration suggested by Mathor
(emphasis added)).
ANALYSIS
The combination of Mathor, Burns, Felts, Schott, and Persons:
Based on the combination of Mathor, Burns, Felts, Schott, and
Persons, Examiner concludes that, at the time Appellants’ invention was
made, it would have been prima facie obvious to “serially transduce . . . cells
with [retroviral vectors containing a gene of interest at] high MOIs (such as
MOIs of 1,000) to achieve 20 or more [retroviral] integration events [in the
cells], with a reasonable expectation of success” in producing a protein
encoded by the gene of interest (Ans. 9).
Appellants emphasize that Mathor did not exemplify a clone with
more than 15 retroviral copies or integrations (App. Br. 7-9; Reply Br. 5; see
FF 5 and 15). While Appellants’ experimental results establish that
variability in protein expression existed between clones with varying

20 Mehtali et al., The methylation-free status of a housekeeping transgene is
lost at high copy number, 91 GENE 179-184 (1990).
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retroviral copy numbers, 21 Appellants contend that Mathor’s single
exemplified clone with 15 retroviral copies exhibited lower protein
production than a clone with 8 retroviral copies (App. Br. 7-9; Reply Br. 5;
FF 5; Cf. FF 3). Appellants, therefore, direct attention to a number of
documents in an effort to support their contention that, at the time of
Appellants’ claimed invention, a person of ordinary skill in this art would
not have reasonably expected that a host cell with more than 8 retroviral
copies would have: (1) been capable of expressing a protein of interest from
a gene carried by a retrovirus, or (2) expressed a protein of interest at a
lower rate than a host cell with 8 or less retroviral copies (App. Br. 9-17; see
also Fourth and Fifth Declarations of Dr. Gregory Bleck). According to
Appellants, the evidence of record supports a conclusion that a host cell with
more than 8 retroviral copies would methylate the viral nucleic acid and
thereby inhibit or decrease protein expression from the retrovirus (App. Br.
9-17). Therefore, Appellants contend that a person of ordinary skill in this
art, at the time of Appellants’ claimed invention, would not have “be[en]
motivated to make such a population of cells [, i.e., a host cell population
with more than 8 retroviral copies] in the first place” and any contrary
conclusion by Examiner is based in hindsight (Reply Br. 7; see id. at 6). We
are not persuaded.

21 Appellants’ Table 13 establishes that: (1) colony # 13(Neo-), having a
retroviral copy number of 1, expressed 3 pg/cell/day; (2) colony # 5, having
a retroviral copy number of 2, expressed 0.7 pg/cell/day; and (3) colony #
15, having a retroviral copy number of 3, expressed 1.3 pg/cell/day (see FF
3). Stated differently host cells with retroviral copy numbers of 2 and 3
expressed less protein than a host cell with a single retroviral copy.
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Notwithstanding Appellants’ contentions and the evidence
Appellants’ rely upon to support their contentions, we find no error in
Examiner’s conclusion that the evidence relied upon by Examiner supports a
conclusion that, in general, there is a direct correlation between (a) the
amount of protein of interest obtained from a host cell and (b) the number of
retroviral copies, carrying a gene of interest that is capable of expressing the
protein of interest, that are integrated into that particular host cell (Ans. 9;
FF 5, 7, 8, and 15). The evidence of record also supports a conclusion, and
Appellants “agree[,] that clones having the same number of integrations can
express different levels of a protein,” resulting, inter alia, from the location
of the host cell genome into which a particular retrovirus integrates (App.
Br. 9; FF 5 (wherein Appellants’ representative recognized that it was
known in the art, at the time of Appellants’ claimed invention, that the level
of protein expressed from a retrovirus can depend on the particular location
of the host cell genome into which a particular retroviral vector integrates);
see also FF 3 and 5 (wherein both Appellants’ data (FF 3) and Mathor’s data
(FF 5) illustrates that while some variability between individual clones
having the same number of retroviral copies exists, there is a general trend
toward higher expression levels of a protein of interest as the number of
retroviral copies, carrying a gene capable of expressing the protein of
interest, increases in a particular host cell)).
Appellants’ reliance on Bestor fails to support their contention that a
person of ordinary skill in this art would have reasonably expected the “host
[or genome]-defense system” of a host cell to decrease, or otherwise inhibit,
expression of retroviral vectors (App. Br. 10-11; Cf. FF 16 (Bestor
concludes that “[n]one of the hypothetical functions of cytosine methylation
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(and this includes the . . . host-defense functions) has the support of
compelling experimental evidence, and all, some, or none of the hypotheses
may be valid”)). The same is true of Appellants’ reliance on Cherry, which
as Appellants’ point out is “co-authored by two of the leading scientists in
the field” and is “relevant to what people at the time [of Appellants’
invention] were thinking” (FF 18). According to Cherry, methylation is a
concern for “long-term passage of infected . . . cells . . . while short-term
expression [of retroviral infected cells] was methylation independent” (FF
18 (emphasis added); see also FF 18 (Niwa suggests that “[n]ewly acquired
retroviral vectors [(e.g., short-term expression)] are treated by cells in a
different manner from proviral sequences that have been integrated into the
genome in the distant past and essentially become endogenous [(e.g., long-
term expression)]”)). The foregoing is consistent with Challita, which
suggests that “[t]ranscriptional expression from . . . [retrovirus] was detected
at a high level in the primary,” (e.g., short-term expression) cells, but
transcriptional inactivity was observed in secondary and tertiary (e.g., long-
term) cultures; therefore, “[a]lthough Moloney murine leukemia virus . . .-
based retroviral vectors are currently the most efficient vehicles for gene
transfer into a variety of cell types . . ., the long-term . . . expression from the
viral . . . elements has been unsatisfactory” (FF 18). Appellants’ claim 1 is
not limited to long-term expression from a viral vector (see Appellants’
Claim 1; see also FF 18).
Appellants failed to establish that a person of ordinary skill in this art
would have expected retrovirus to integrate into a host cell in concatameric
or tandem arrays, therefore Appellants’ reliance on Garrick and Mehtali is
not persuasive (see FF 17 and 19; see also FF 1; Cf. FF 2).
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For the reasons set forth above, when viewed as a whole, Appellants’
evidence of non-obviousness fails to support their contentions. Therefore, in
sum, we are left with Appellants’ unsupported contention that, since
Mathor’s single of example of a host cell with more than 8 retroviral copies
had a lower level of expression than a host cell with 8 retroviral copies, a
person of ordinary skill in this art would have concluded that a host cell with
more than 8 retroviral copies would express less protein of interest than a
host cell with 8 or less retroviral copies (see generally App. Br. 7-9).
As was made clear at the January 16, 2014 Oral Hearing, Appellants’
claim 1 does not require long-term: stability, expression from a gene of
interest, or production of protein from a gene of interest (see FF 18).
Further, despite Appellants’ contentions to the contrary, the evidence on this
record supports a conclusion that: (1) host clones having the same number of
integrations can express different levels of a protein and (2) there is, in
general, a direct correlation between (a) the amount of protein of interest
obtained from a host cell and (b) the number of retroviral copies, carrying a
gene of interest that is capable of expressing the protein of interest, that are
integrated into that particular host cell (FF 5, 7, and 8). Stated differently,
the preponderance of evidence on this record supports a conclusion that
despite some variation between individual host cells, a person of ordinary
skill in this art, at the time of Appellants’ claimed invention, would have
reasonably expected that the production of a protein of interest, within the
scope of Appellants’ claim, will increase as more copies of a retrovirus
expressing a gene of interest are integrated into the host cell.
When taken as a whole, the preponderance of evidence on this record
supports Examiner’s conclusion that the combination of Mathor, Burns,
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Felts, Schott, and Persons makes obvious the subject matter of Appellants’
claim 1.

The combination of Mathor, Burns, Felts, Schott, Persons, and Schroder:
Having found no deficiency in the combination of Mathor, Burns,
Felts, Schott, and Persons, we are not persuaded by Appellants’ contention
that Schroder fails to make up for Appellants’ alleged deficiency in the
combination of Mathor, Burns, Felts, Schott, and Persons (see App. Br. 17;
Reply Br. 9).

The combination of Mathor, Burns, Felts, Schott, Persons, Primus, and
Kolb:
Having found no deficiency in the combination of Mathor, Burns,
Felts, Schott, and Persons, we are not persuaded by Appellants’ contention
that Primus and Kolb fails to make up for Appellants’ alleged deficiency in
the combination of Mathor, Burns, Felts, Schott, and Persons (see App. Br.
18; Reply Br. 9).

The combination of Mathor, Burns, Felts, Schott, Persons, and Naldini:
Having found no deficiency in the combination of Mathor, Burns,
Felts, Schott, and Persons, we are not persuaded by Appellants’ contention
that Naldini fails to make up for Appellants’ alleged deficiency in the
combination of Mathor, Burns, Felts, Schott, and Persons (see App. Br. 18;
Reply Br. 9).
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CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness.
The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Mathor, Burns, Felts, Schott, and Persons is
affirmed. Claims 2-10, 12, 14-18, 20, 21, 28, 30-34, and 41 fall with
claim 1.
The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Mathor, Burns, Felts, Schott, Persons, and Schroder
is affirmed. Claims 2-10, 12, 14-18, 20, 21, 26, 28, 30-38, and 41 fall with
claim 1.
The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Mathor, Burns, Felts, Schott, Persons, Primus, and
Kolb is affirmed. Claims 2-10, 12, 14-18, 20-24, 26, 28, 30-34, and 39-41
fall with claim 1.
The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Mathor, Burns, Felts, Schott, Persons, and Naldini
is affirmed. Claims 2-10, 12, 14-18, 20, 21, 25, 28, 30-34, and 41 fall with
claim 1.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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