Ex Parte Miller

Patent Trials and Appeals Board

Nov 27, 2018

13380329 - (D) (P.T.A.B. Nov. 27, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/380,329 03/06/2012
108197 7590 11/29/2018
Parker Highlander PLLC
1120 South Capital of Texas Highway
Bldg. 1, Suite 200
Austin, TX 78746
UNITED ST A TES OF AMERICA
FIRST NAMED INVENTOR
Stefan Miller
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.
DEBE.POl l lUS 1551
EXAMINER
STEADMAN, DAVID J
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
11/29/2018 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
docket@phiplaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte STEP AN MILLER 1
Appeal2017-000833
Application 13/380,329
Technology Center 1600
Before RICHARD M. LEBOVITZ, RICHARD J. SMITH, and
RYAN H. FLAX, Administrative Patent Judges.
FLAX, Administrative Patent Judge.
DECISION ON APPEAL
This is a decision under 35 U.S.C. § 134(a) involving claims directed
to a fusion protein. Claims 1, 2, 4, 5, 31, and 43--46 are on appeal as
rejected under 35 U.S.C. § 103 and for obviousness-type double patenting.
We have jurisdiction under 35 U.S.C. § 6(b ).
We affirm.
1 Appellant identifies the Real Party in Interest as "Lysando AG." Appeal
Br. 3. Herein we reference the Specification of Dec. 22, 2011 ("Spec.");
Final Office Action of Aug. 12, 2015 ("Final Action"); Appeal Brief of Mar.
11, 2016 ("Appeal Br."); and Examiner's Answer of July 28, 2016
("Answer"); no Reply Brief was submitted.
Appeal2017-000833
Application 13/380,329
STATEMENT OF THE CASE
Independent claim 1 is representative and is reproduced below:
1. A fusion protein comprising the amino acid sequence
according to SEQ ID NO: 63-65, 67, 70 or 72-81.
Appeal Br. 20 (Claims Appendix). An election of species was made during
prosecution where the elected subject matter is SEQ ID NO: 72, which is a
fusion of indolicidin (amino acids 1-13 of SEQ ID NO: 72) and Cpl-I
(CPL-I) (amino acids 14-351 of SEQ ID NO: 72). See Final Action 3; see
also Spec. 17 (Table 4).
The following rejections are appealed:
Claims 1, 2, 31, 43, and 46 stand rejected under 35 U.S.C. § I03(a)
over Krieger,2 Borysowski, 3 Briers, 4 Sanz, 5 and Bulow. 6 Final Action 4--5.
Claims 4, 5, 44, and 45 stand rejected under 35 U.S.C. § I03(a) over
Krieger, Borysowski, Briers, Sanz, Bulow, and Terpe. 7 Id. at 8.
2 US 6,503,881 B2 (issued Jan 7, 2003) ("Krieger").
3 Jan Borysowski et al., Bacteriophage Endolysins as a Novel Class of
Antibacterial Agents, BACTERIOPHAGE ENDOLYSINS, 366-77 (2006)
("Borysowski").
4 WO 2010/023207 A2 (published Mar. 4, 2010) ("Briers").
5 Jesus M. Sanz & Jose L. Garcia, Structural studies of the lysozyme coded
by the pneumococcal phage Cp-1 Conformational changes induced by
choline, 187 EUR. J. BIOCHEM. 409-16 (1990) ("Sanz").
6 Lief Bulow & Klaus Mosbach, Multienzyme systems obtained by gene
fusion, 9 TIBTECH 226-31 (1991) ("Bulow").
7 K. Terpe, Overview of tag protein fusions: from molecular and
biochemical fundamentals to commercial systems, 60 Appl Microbial
Biotechnol 523-33 (2003) ("Terpe").
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Claims 1, 2, 31, 43, and 46 stand rejected under 35 U.S.C. § 103(a)
over Krieger, Borysowski, Li, 8 Sanz, and Bulow. Id. at 9.
Claims 4, 5, 44, and 45 stand rejected under 35 U.S.C. § 103(a) over
Krieger, Borysowski, Li, Sanz, Bulow, and Terpe. Id. at 12.
Claims 1, 2, 31, 43, and 46 stand rejected under 35 U.S.C. § 103(a)
over Krieger, Borysowski, Sanz, and Bulow. Id. at 14.
Claims 4, 5, 44, and 45 stand rejected under 35 U.S.C. § 103(a) over
Krieger, Borysowski, Sanz, Bulow, and Terpe. Id. at 16-17.
Claims 1, 2, 4, 5, 31, and 43--46 stand rejected for obviousness-type
double patenting over claims 1, 5, 6, 12, and 15 of Application No.
13/997,058 in view of Terpe. 9 Id. at 23-24.
DISCUSSION
"[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting aprimafacie case ofunpatentability. If
that burden is met, the burden of coming forward with evidence or argument
shifts to the applicant." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
Arguments made by Appellant in the Appeal Brief have been considered in
this Decision; arguments not so-presented are waived. See 3 7 C.F .R.
§ 4I.37(c)(l)(iv) (2015); see also Ex parte Borden, 93 USPQ2d 1473, 1474
8 Qingtian Li et al., Potential therapeutic efficacy of a bactericidal-
immunomodulatory fusion peptide against methicillin-resistant
Staphylococcus aureus skin infection, 86 APPL MICROBIOL BIOTECHNOL
305---09 (2010) ("Li").
9 Application No. 13/997,058 was abandoned July 26, 2017, for failure to
timely file a response to office action. See Notice dated February 8, 2018.
Therefore, this rejection is dismissed.
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(BP AI 2010) (informative) ("Any bases for asserting error, whether factual
or legal, that are not raised in the principal brief are waived.").
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). "[W]hen a patent
claims a structure already known in the prior art that is altered by the mere
substitution of one element for another known in the field, the combination
must do more than yield a predictable result." Id. at 416 (citing U.S. v.
Adams, 383 U.S. 39, 50-51 (1966)). "In determining whether the subject
matter of a patent claim is obvious, neither the particular motivation nor the
avowed purpose of the patentee controls. What matters is the objective
reach of the claim. If the claim extends to what is obvious, it is invalid
under§ 103." Id. at 419. "[C]ase law is clear that obviousness cannot be
avoided simply by a showing of some degree of unpredictability in the art so
long as there was a reasonable probability of success." Pfizer, Inc. v.
Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007) (citing In re Corkill, 771
F.2d 1496, 1500 (Fed. Cir. 1985)).
[M]otivation to combine is ... inextricably linked to the level of
ordinary skill. . . . If the level of skill is low, ... then it may be
rational to assume that such an artisan would not think to
combine references absent explicit direction in a prior art
reference. If, however, ... the level of skill is ... [high, as it is
here], then one can assume comfortably that such an artisan will
draw ideas from chemistry and systems engineering-without
being told to do so.
Dystar Textilfarben GmbH & Co. Deutsch/and KG v. CH Patrick Co., 464
F.3d 1356, 1370 (Fed. Cir. 2006). "[T]he question is whether there is
something in the prior art as a whole to suggest the desirability, and thus the
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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." In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004)
( citation omitted).
We note that the Examiner indicated the following:
In the interest of clarity it is noted that the rejections that
include the reference of Briers or Li are considered to be the most
relevant to the claimed invention. The rejections that [do not]
include ... Briers or Li were applied in the interest of compact
prosecution in the event that appellant was accorded their foreign
priority date and could remove the reference( s) of Briers and/ or
Li as prior art. However, as of the drafting of this examiner's
answer, the references of Briers and Li are still available as prior
art. Appellant has collectively addressed the rejections based on
Krieger, Borysowski, Sanz, and Bulow and optionally in view of
Briers or Li.
Answer 16. The Examiner is correct that Appellant's arguments focus on
the obviousness rejections as a unified group and address Briers and/or Li as
part of the cited prior art combination(s). See generally Appeal Br. 3-18.
Therefore, we consider the rejections similarly as a group, addressing the
combination of Krieger, Borysowski, Sanz, Bulow, and Briers or Li (the
rejections not including Briers or Li are subsumed by those that do). For the
rejections of claims 4, 5, 44, and 45, we note that Terpe is also included in
the prior art combination; however, Appellant argued only that "Terpe
cannot possibly address the numerous deficiencies in the combination of
Krieger, Borysowski, Sanz and Bulow," thus the rejections including the
Terpe reference are considered with the rejections based on the
aforementioned prior art combination, as a group. Appeal Br. 18. Appellant
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has not argued the claims separately and we find claim 1 representative;
therefore, all claims fall with claim 1.
Findings of Fact (FF)
Unless otherwise indicated below, we agree with and adopt the
Examiner's findings of fact and rationale. The following findings of fact
highlight certain evidence.
FFl. Li disclosed "a bactericidal-bactericidal fusion peptide
human B-defensin 3-lysozyme," which "showed the best bactericidal
activity in vitro" for controlling MRSA. Li 305 (abstract), 307 (Fig.
1 ).
FF2. Li further disclosed "[fJusion strategy and
immunomodulatory factors should be utilized in novel antimicrobial
peptide development." Li 305 (abstract).
FF3. Further to the preceding findings of fact, Li disclosed that
B-defensin is an antimicrobial peptide (AMP), where, to date, "[ m Jore
than 1,000 AMP from various sources are now identified." Li 305.
FF4. Krieger disclosed "treating microorganism-caused
infections using cationic peptides or a combination of cationic
peptides and antibiotic agents." Krieger 1: 18-21.
FF5. Further to the preceding finding of fact, Krieger disclosed
"[ o ]ne cationic peptide found in neutrophils is indolicidin" and
"'indolicidin' refers to an antimicrobial cationic peptide." Krieger
2:3-5, 7: 11-12.
FF6. Krieger disclosed "enhancing the antibiotic activity of
lysozyme or nisin, comprising administering lysozyme or nisin with a
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cationic peptide," and also "fusions of cationic peptides," and "[t]he
combination of cationic peptides and lysozyme or nisin may improve
their antibacterial effectiveness and allow use in situations in which
the single agent is inactive or inappropriate." Krieger 4:38--41,
13:40--47, 27:63---66, 101:20-30 (Example 9).
FF7. Krieger disclosed:
Lysozymes disrupt certain bacteria by cleaving the
glycosidic bond between N-acetylglucosamine and N-
acetylmuramic acid in the polysaccharide component of bacterial
cell walls. However, lysozyme exhibits only weak antibacterial
activity with a narrow spectrum of activity. The addition of
cationic peptide may improve the effectiveness of this activity
and broaden the spectrum of activity.
Krieger 28: 1-7; see also Appeal Br. 6-7 ("strictly speaking,
'lysozyme' could theoretically refer to any enzyme of any source
displaying the activity of cleaving the glycosidic bond between the
NAM and NAG sugars of the peptidoglycan backbone"), 8
(lysozymes, whether hen egg white lysozymes or CPL- I, "all cleave
the same bond"); and Michiels Declaration 10 ,r 4 ("strictly speaking,
'lysozyme' could theoretically refer to any enzyme of any source
displaying the activity of cleaving the glycosidic bond between the
NAM and NAG sugars of the peptidoglycan backbone"), ,r,r 6, 7
(lysozymes, whether hen egg white lysozymes of CPL- I, "all cleave
the same bond."); see also Callewaert11 127 (cited by Appellant's
10 Declaration of Prof. Dr. Chris W. Michiels Under 3 7 C.F .R. § 1.13 2 dated
June 8, 2015 ("Michiels Declaration").
11 Lien Callewaert & Chris W. Michiels, Lysozymes in the Animal Kingdom,
35 (1) J. BIOSCI. 127---60 (2010) ("Callewaert").
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submitted Michiels Declaration ,r 6, but stating "Lysozymes (EC
3 .21.17) are hydrolytic enzymes, characterized by their ability to
cleave the B-(1,4 )-glycosidic bond between N-acetylmuramic acid and
N-acetylglucosamine in peptidoglycan, the major bacterial cell wall
polymer. In the animal kingdom, three major distinct lysozyme types
have been identified - the c-type ( chicken or conventional type), the g-
type (goose-type) and the i-type (invertebrate type) lysozyme."); see
also Nakimbugwe 12 41 (also cited in the Michiels Declaration ,r 6, but
similarly to Callewaert indicating "L ysozymes (EC 3 .2 .1.1 7) are 1, 4-
B-N-acetylmuramidases, cleaving the glycosidic bond between the C-1
of N-acetylmuramic acid (NAM) and the C-4 of N-acetylglucosamine
(NAG) in the bacterial peptidoglycan (PG). They are widespread in
nature," and indicating an investigation into six different types of
lysozymes, including two commercially available ones (hen egg white
lysozyme and Streptomyces globisporus I MIL lysozyme)).
FF8. Krieger disclosed a list of"[ e ]xamples of native cationic
peptides" suitable for use in its invention, including "Defensins-beta"
and "Indolicidins." Krieger Table 1; see also supra FFI-FF3 (Li
discloses a fusion of B-defensin and lysosome ).
FF9. Briers disclosed "endolysin to which a peptide stretch
with membrane or LPS disrupting activity is fused," "for use as a
12 Dorothy Nakimbugwe et al., Cell Wall Substrate Specificity of Six
Different Lysozymes and Lysozyme Inhibitory Activity of Bacterial Extracts,
259 FEMS MICROBIOL LETT 41--46 (2008) ("Nakimbugwe").
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medicament," and as a "pharmaceutical composition." Briers
Abstract.
FF 10. Further to the preceding finding of fact, Briers disclosed
that fusing an endolysin with a cationic peptide advantageously
"enhance[ es] the cationicity of said endolysin," "particular[ly] for the
treatment or prevention of Gram-negative bacterial contamination."
Briers 1:7-10, 1:21-23.
FF 11. Further to the preceding findings of fact, Briers
confirmed that lysozymes are endolysins. Briers 1:32-35, 8:22-26,
12 (Table).
FF 12. Further to the preceding findings of fact, Briers disclosed
that the term "fusion protein" refers to an endolysin with, preferably, a
cationic and/or polycationic peptide. Briers 6:29-7:3; see also supra
FF4-FF8 (Krieger teaching and suggesting pairing cationic peptides,
such as indolicidin and P-defensin, with lysozyme, e.g., a type of
endolysin).
FF 13. Borysowski disclosed that endolysins are produced in
phage-infected bacterial cells, induce lysis of bacterial cells, are
capable of degrading peptidoglycan when applied externally to
bacteria cell walls causing rapid lysis, were originally developed with
a view to killing bacterial colonies, and hold promise for treatment of
systemic infections. Borysowski 366 (abstract).
FF14. Borysowski disclosed that "there is an urgent need for the
development of novel antibacterial agents" and "[ e ]ndolysins seem to
be very promising in this regard." Borysowski 374.
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FFI5. Borysowski also confirmed that lysozymes are a type of
endolysin. Borysowski 367.
FFI6. Borysowski disclosed that CPL-I (Cpl-I) is a phage
lysozyme that has, advantageously, proven highly efficient for
decolonizing bacteria, that CPL- I exposure does not diminish its
therapeutic efficacy in vivo (lack of immuno-resistance/tolerance ),
that CPL- I is thermostable, and that CPL- I has reportedly acted
synergistically with antibiotics. Borysowski 371, 373, 374.
FF 17. Sanz disclosed that CPL- I is a lysozyme that can,
advantageously, be readily overproduced in E.coli to supply amounts
needed, and which has a known amino acid sequence. Sanz 409
(abstract), 413 (Fig. 5), 414.
FFI8. Bulow disclosed that, advantageously, "[i]fthe entire
primary sequences of[] native enzymes are maintained in the fusion
enzymes, the enzymes usually retain most of their native specific
activities despite being fused together." Bulow 230.
FF 19. Based on the preceding findings of fact, one of ordinary
skill in the art would have combined and fused the cationic peptide
indolicidin with the lysozyme CPL-I as an anti-bacterial composition
or pharmaceutical formulation. See, e.g., Answer 7-10, 17-21.
Indolicidin was recognized as a suitable, alternative, cationic peptide
that could be substituted for the P-defensin of Li's disclosed fusion
peptide of human P-defensin 3-lysozyme in view of Krieger's
teaching that P-defensin and indolicidin are both cationic peptides
suitable for its disclosed invention, particularly because Krieger
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discloses the advantages of pairing such cationic peptides with
lysozyme. Id. One of ordinary skill in the art would also have fused
Krieger's disclosed (taught to be combined) cationic peptide, e.g.,
indolicidin, and a lysozyme in view of Briers' s disclosure that fusion
of cationic peptides and endolysins, e.g., lysozymes, result in
improved anti-bacterial compositions. Supra FFI-FFI 8; see also
Answer 4--5, 9-10 (see quote infra discussing combining, modifying
prior art, rationale therefor, and expectation of success).
FF20. In view of Li, Borysowski, and Sanz, as well as Krieger,
including the lysozyme CPL-I (FFI6) in an anti-bacterial protein
fusion with the cationic peptide indolicidin (FF5, FFI2) would be an
obvious choice because CPL- I was a well-known lysozyme that could
be readily produced and was understood to be effective. Supra FF1-
FFI8; see also Answer 4--5, 9-10 (see quote infra discussing
combining, modifying prior art, rationale therefor, and expectation of
success).
FF21. In view of Li, Briers, and Bulow, one of ordinary skill in
the art would have expected that upon fusing indolicidin and CPL- I,
each of these anti-bacterial components would retain most of its
native, specific activity and, in view of Krieger, Briers, and Li, one
would have expected the combination and fusion of indolicidin and
CPL- I to improve the overall anti-bacterial activity of the pair. Supra
FF1-FFI8; see also Answer 4--5, 9-10 (see quote infra discussing
combining, modifying prior art, rationale therefor, and expectation of
success).
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Analysis
The Examiner determined claims 1, 2, 31, 43, and 46 would have been
obvious over the combination of Krieger, Borysowski, Briers or Li, Sanz,
and Bulow, and that claims 4, 5, 44, and 45 would have been obvious over
this same prior art combination also including Terpe. Final Action 4--23 and
Answer 2-26 (collectively citing and/or discussing Krieger 2:3-9, 2:36-42,
3:63---65, 4:38--41, 7:5-12, Table 1, 13:40--47, 15:23-24, 27:63-28:7, 39:66-
67, 45:29-35, 101:20-30; Borysowski 366,367,369,371,372; Briers
abstract, 1:9-10, 1:21-24, 1:32-2:1, 8:22-32; Li 305,307,308; Sanz 409,
413,414; Bulow 230; Terpe 523-25). Further, the Examiner determined:
At the time of the invention, it would have been obvious
to one of ordinary skill in the art to combine the references of
Krieger, Borysowski, Sanz, Briers, and Bulow to fuse Krieger's
indolicidin analogue with the endolysin lysozyme Cpl-I into a
single fusion protein, which fusion protein would comprise the
amino acid sequence of SEQ ID N0:72 herein.
One would have been motivated to use the endolysin
lysozyme Cpl-I as Krieger's antibacterial lysozyme because
Cpl- I is a lysozyme and Borysowski teaches Cpl- I is an
antibacterial lysozyme. One would have been motivated to fuse
Krieger's indolicidin analogue with the endolysin lysozyme Cpl-
I into a single fusion protein in order to enhance the
antimicrobial activity of Cpl- I because Krieger teaches
indolicidin synergistically enhances the antibacterial activity of
lysozyme, Briers teaches fusing a cationic peptide and an
endolysin, including an endolysin lysozyme, which has the
beneficial effect of enhancing antibacterial activity, [ and,
alternatively, Li teaches enhancing the activity of an
antimicrobial peptide by fusion with lysozyme,] and Borysowski
teaches the benefit of the dual antibacterial activity of endolysins
comprising sequences similar to those of cationic antimicrobial
peptides, i.e., antibacterial activity of the lysozyme, which
cleaves peptidoglycan and antibacterial activity of the cationic
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sequence, which enables interactions with the negatively charged
bacterial membrane.
One would have had a reasonable expectation of success
to fuse Krieger's indolicidin analogue with the endolysin
lysozyme Cpl-I lysozyme into a single fusion protein because
Krieger teaches the sequence of indolicidin analogue, Sanz
teaches the sequence of the endolysin lysozyme Cpl-I, Briers
teaches a method for fusing the sequences of a cationic peptide
and a lysozyme, [and, alternatively, Li teaches a method for
fusing the sequences of a cationic peptide and a lysozyme,] and
Bulow teaches the polypeptides of a fusion usually retain most
of their native specific activities.
Therefore, the fusion protein and pharmaceutical
composition of claims 1, 2, 31, 43, and 46 would have been
obvious to one of ordinary skill in the art at the time of the
invention.
Answer 4--5, 9--10 (paragraphing added for readability); see also FFI-FF2I
(highlighting certain evidence). We find no error in the Examiner's
determinations and adopt the Examiner's findings of fact and rationale.
Appellant's primary argument is that the skilled artisan would read
Krieger's disclosure of pairing lysozyme with indolicidin to refer
specifically to egg white lysozymes in contrast to the elected species which
is the phage lysozyme CPL- I. See Appeal Br. 6. As support for this
argument, Appellant cites the Michiels Declaration ( along with Callewaert
and Nakimbugwe), which concludes:
Applicant has submitted considerable evidence that the enzyme
Krieger was referring to is egg white lysozyme. I have reviewed
that evidence and the supporting arguments (see RCE
Submission filed October 17, 2014) and wholeheartedly agree
with applicant's conclusion. In particular, would conclude that
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when Krieger is referring to "lysozyme", this has to be
interpreted as being hen egg white lysozyme.
Michiels Declaration ,r 4. The Michiels Declaration goes on to conclude that
such an express definition by Krieger excludes other types of endolysins,
e.g., amidases and endopeptides (these are other categories of endolysins,
along with lysozymes-see FFll, FF15, and Spec. 2:13-17), without
explaining why an exclusion of unclaimed endolysins is relevant. Id. The
Michiels Declaration further states that, although all lysozymes function
identically by cleaving the same bond, the different types of lysozymes
function differently in that they have different amino acid sequences and
different ancestral origins and evolutionary paths. Id. ,r,r 6-7. Again, if the
known universe of lysozymes functions by cleaving the same bond as stated
by Michiels Declaration and, hence, would be understood to kill bacteria
similarly, neither Appellant's Brief nor Michiels Declaration offers an
explanation as to why these alleged differences matter to the obviousness of
utilizing a lysozyme from a different source than Krieger to prepare a fusion
protein with indolicidin.
Moreover, we find no persuasive evidence on this appeal record that
Krieger's disclosed lysozymes are restricted to just one type of lysozyme,
i.e., those derived from hen egg whites. Krieger never indicates this.
Moreover, the Michiels Declaration, other than its conclusory statements to
the contrary, supports the fact that, even though there are several types of
lysozymes, the class of proteins called lysozymes function the same way by
cleaving the same bond and, in this way, would be considered functionally
interchangeable where the objective is to kill bacteria cells.
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Appellant also argues Krieger does not teach fusing cationic peptides,
like indolicidin, with entire proteins like lysozymes, but only discloses
fusion with short peptides. Appeal Br. 9--10. Appellant further contends
that Krieger's disclosure of administering cationic peptides with lysozymes
does not refer to a fusion of the two. Id. at 11. Appellant further argues that
the skilled artisan would not have reasonably expected that the improved
effect (improvements in anti-bacterial properties) achieved by combining
indolicidin and lysozyme, as disclosed by Krieger (at, e.g., Example 9),
would be attainable in a fusion of these components because Krieger reports
results for other examples in more detail than it does for Example 9. Id. at
11-12. Appellant also argues that there would have been no reason to
combine Krieger's and Sanz's teachings because Krieger's lysozymes are
not the endolysins mentioned in Sanz. Id. at 13.
Appellant's arguments are not persuasive.
"Non-obviousness cannot be established by attacking references
individually where the rejection is based upon the teachings of a
combination of references. . . . [The reference] must be read, not in
isolation, but for what it fairly teaches in combination with the prior art as a
whole." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). The
Examiner rejected the claims over a combination of references, not Krieger
individually. As explained above, even if Krieger were limited to hen
lysozyme (which it is not), it would have been obvious to one of ordinary
skill in the art to have substituted it for the CPL-I lysozyme because they
cleave the same bond. Michiels Declaration ,r,r 6-7. Therefore, Appellant's
arguments over Krieger alone are not persuasive.
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Appellant's argument that Krieger does not teach fusing cationic
indolicidin with entire proteins like lysozymes, but only with short peptides,
is not persuasive in view of Li's disclosure of a fusion of a similar cationic
peptide (P-defensin) and a lysozyme (CPL-I) and Briers's disclosure of
fusing endolysins ( e.g., lysozymes) and cationic or polycationic peptides
(e.g., indolicidin). See FFI-FF3, FF9-FFI2. In other words, even if
Krieger's disclosure were related to short peptides, both Li and Brier
disclose the fusion of longer polypeptides. Appellant's argument that
Krieger's disclosure of administering cationic peptides with lysozymes does
not refer to a fusion of the two is likewise not persuasive in view of
Krieger's suggestion to pair indolicidin and lysozymes and the disclosures of
Li and Briers that teach a fusion, rather than mere combination, is effective
and was within the skill in the art. Id.; see also FF5-FF8.
Appellant's argument that the skilled artisan would not have
reasonably expected that the improved effect (improvements in anti-bacterial
properties) by combining indolicidin and lysozyme, as disclosed by
Krieger's Example 9, would be attainable in a fusion of these components
because Krieger reports results in more detail for other examples as
compared to Example 9 is not persuasive in view of Bulow, which teaches
and suggests that the anti-bacterial active properties of indolicidin and
CPL-1 lysozyme would be retained upon their fusion and Krieger's
indication that combining the two would improve their effectiveness. FF6,
FF7, FFI8. Moreover, Li provides evidence that such a fusion would
effectively kill MRSA. FF 1.
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Appellant's argument that there would have been no reason to
combine Krieger's and Sanz's teachings because Krieger's lysozymes are
not the endolysins mentioned in Sanz is not persuasive because the cited
prior art combination teaches and suggests that lysozymes are a type of
endolysin, that cationic peptides, like indolicidin, can be fused with
endolysins, e.g., lysozymes including CPL-I specifically, and that such
fusions are expected to and actually do effectively kill bacteria. See
generally supra Findings of Fact.
Appellant argues further that there would have been no reasonable
expectation of success in combining the prior art to achieve the invention
because the art is unpredictable. Appeal Br. 13. As support, Appellant
submits and cites the Biebl Declaration. 13 The Biebl Declaration stated,
"We have performed an experiment testing the antibacterial activity a fusion
protein of cpll and indolicin ( cpll-indolicin), and compared it to (i) ( egg
white) lysozyme, (ii) lysozyme + indolicidin (i.e., as separate compounds)
and (iii) a fusion protein of lysozyme and indolicidin." 14 Biebl Declaration
,r 3. The Biebl Declaration further states that,
The results, which are shown below, suggest that for the tested
S. pneumoniae strain, a combination of lysozyme + indolicidin
(much as described by Krieger) does not yield any effect going
beyond lysozyme on its own. Moreover, a fusion falling within
the scope of the present claims would be much more effective
13 Declaration of Manfred Biebl under 37 C.F.R. § 1.132 dated June 9, 2015
("Biebl Declaration").
14 Indolicidin (the cationic peptide of the claims' elected species) is an
antimicrobial peptide; we assume the Biebl Declaration's use of the term
"indolicin" in paragraph 3 is a typographical error and intends to refer to
indolicidin.
17
Appeal2017-000833
Application 13/380,329
than a fusion of egg white lysozyme with indolicidin, which was
again only about as effective as lysozyme + indolicidin[,]
and goes on to produce the following graph, without more, which is also
reproduced in the Appeal Brief (at 14):
!l.l!l
Streptococcus pneumoniae OSMZ 14378 UCC
S61; 20 mM HEPES pH 7,4, 150 mM NaCl; 0,5
µM Protein
: ,:
1 ~
: ~
0.4 ;,.,. .. ~,--.................. ., .......................... '"""'":"< -~~~-
. ~
"
...•... !.y,i-,;/'.iffl'" ,. !O>tl.Qi>cicli;, :_;_:
· ,, • !.%<>.')'!l:>11·~',