Ex Parte Ilg et al

Patent Trial and Appeal Board

Feb 23, 2017

13133458 (P.T.A.B. Feb. 23, 2017)

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
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/133,458 06/08/2011 Thomas Simon Ilg 2008.023US 3419
31846
Merck
7590 02/24/2017 EXAMINER
Patent - Docket - RY 60-30 HOLLAND, PAUL J
126 East Lincoln Avenue
Rahway, NJ 07065-0907 ART UNIT PAPER NUMBER
1656
MAIL DATE DELIVERY MODE
02/24/2017 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 THOMAS SIMON ILG, VOLKER SPEHR,
andRALF WARRASS1
Appeal 2015-007386
Application 13/133,458
Technology Center 1600
Before ULRIKE W. JENKS, TAWEN CHANG,
and TIMOTHY G. MAJORS, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of manufacturing enzymatically active recombinant diguanylate cyclase
protein (DGC) that has a modified RXXD motif. The claims have been
rejected for failure to satisfy the written description requirement and as
obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 Appellants identify the Real Party in Interest as Intervet International BV.,
a wholly-owned subsidiary of Merck Sharp and Dohme Corp. (Br. 3.)
Appeal 2015-007386
Application 13/133,458
STATEMENT OF THE CASE
Appellants’ “invention is in the field of enzymatic synthesis of cyclic
di-guanosine monophosphate (c-di-GMP), by the coupling of two guanosine
triphosphate (GTP) molecules under the influence of diguanylate cyclase
(DGC).” (Spec. 1:6—9.) According to the Specification, “c-di-GMP[] is a
bacterial second messenger that has been implicated in biofilm formation”
and, as reported in the prior art, it is “contemplated to use the [c-di-GMP]
compounds as active ingredients in the treatment of a wide range of
infectious diseases, inflammatory diseases, autoimmune diseases, tumors”
and other conditions. {Id. at 1:15—29.)
The Specification indicates that prior methods of producing c-di-GMP
have been subject to low yields. {Id. at 2—3 passim.) According to the
Specification, “current enzymatic synthesis ... is hampered by a product
feedback inhibition” believed to be caused by “an allosteric binding site for
di-c-GMP [sic] [that] is responsible for non-competitive product inhibition
of DGC.” {Id. at 2:25—3:1.) Discussing a prior-art study, the Specification
reports “DGC mutants were identified in which an RXXD motif that was
found to be the core c-di-GMP binding site were changed.” {Id. at 3:3 4.)
According to the Specification, although “by preventing the feedback
inhibition [in this prior art process], some yield improvement could be
achieved,” the process “does not allow c-di-GMP to be produced on a
practical, industrial scale.” {Id. at 3:9-12.) Appellants thus disclose that,
“[i]n a broad sense, the present invention puts to use, by substantially
increasing the amount of DGC in the enzymatic coupling of GTP to c-di-
GMP, a method found to obtain DGC on a relatively large scale.” {Id. at
5:5-7.)
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Claims 4, 17—21, and 23 are on appeal. Claim 4 is illustrative:
4. A method for the manufacture of an enzymatically active
recombinant diguanylate cyclase protein (DGC) that has a
modified RXXD motif comprising
(i) overexpressing a gene in a bacterial host cell,
wherein the gene encodes an enzymatically active
recombinant DGC with an allosteric binding site for c-di-GMP
that has a modified RXXD motif,
and wherein the DGC produced by the bacterial host cell
accumulates in an inclusion body as a denatured recombinant
mutant DGC,
(ii) harvesting the denatured recombinant DGC from
the inclusion body thereby obtained, and
(iii) refolding the denatured recombinant DGC to form
an enzymatically active recombinant mutant DGC.
(Br. 29 (Claims App’x).)
The claims stand rejected as follows:
Claims 4, 17—21, and 23 under 35 U.S.C. § 112, first paragraph, for
failing to satisfy the written description requirement.
Claims 4, 17—21, and 23 under 35 U.S.C. § 103(a) over Christen,2
Clark,3 and Yabuta,4 as further evidenced by Nierman.5
The Examiner withdrew the rejection under 35 U.S.C. § 112, first
paragraph, for lack of enablement. (Ans. 9.)
2 Beat Christen et al., Allosteric Control of Cyclic di-GMP Signaling, 281:42
The Journal of Biological Chemistry 32015-24 (2006) (“Christen”).
3 Eliana De Bemadez Clark, Protein refolding for industrial processes, 12
Current Opinion in Biotechnology 202—07 (2001) (“Clark”).
4 Yabuta et al., US 6,037,145, issued Mar. 14, 2000 (“Yabuta”).
5 W.C. Nierman et al., GenBank: AAK25247.1 (2007) (“Nierman”).
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WRITTEN DESCRIPTION
To satisfy the written description requirement, “the specification must
describe an invention understandable to [the] skilled artisan and show that
the inventor actually invented the invention claimed.” Ariad Pharms., Inc.
v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). “The
descriptive text needed to meet these requirements varies with the nature and
scope of the invention at issue, and with the scientific and technologic
knowledge already in existence.” Capon v. Eshhar, 418 F.3d 1349, 1357
(Fed. Cir. 2005).
The Examiner rejected all the claims on appeal for failure to satisfy
the written description requirement. (Ans. 2—5.) With respect to
independent claim 4, for example, the Examiner finds that the claims are
“drawn to a method for the manufacture of a genus of enzymatically active
recombinant mutant diguanylate cyclase proteins (DGC).” (Id. at 3.)
According to the Examiner, “[t]he structure of the genus of recombinant
mutant DGC is unlimited and the claim is interpreted as requiring the
recombinant mutant DGCs to remain enzymatically active.” (Id.)
Examiner’s basis for rejecting dependent claims 17—21 and 23 is
similar. (Id. at 3—4.) With respect to claim 18, for example, Examiner states
“[ojutside of the recited sequence at positions 153—156, the structures of the
recombinant mutant Caulobacter crescentus DgcAs are unlimited.” (Id. at
4.)
Although the Examiner finds the Specification shows reduction to
practice of a number of representative species of the claimed—mutant DGCs,
the Examiner asserts “[t]here is no prior-art or disclosed teaching regarding
which of the amino acids can vary in a [DGC] by either conservative or non-
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conservative substitutions and still result in an enzymatically active
recombinant mutant [DGC] comprising a modified RXXD motif.” {Id. at 4—
5.) More specifically, the Examiner finds “the specification fails to disclose
the modifications outside the RXXD motif of DGC that can be expressed in
inclusion bodies and form enzymatically active DGC.” {Id. at 10 (emphasis
added).)
Appellants argue that multiple examples of the claimed DGCs are
described in the Specification and, “the skilled artisan [] would readily
appreciate that the Specification, particularly in view of the relevant art,
amply describes the entire scope of the claimed invention.” (Br. 7.) As
evidence, Appellants cite Christen as showing the molecular structure and
function of DGCs, including mutants, were known. {Id. at 8.) Appellants
also contend the Examiner is improperly requiring a description of all
possible mutations of DGC outside the RXXD motif, yet “there is no
reference whatsoever in the claims” to such mutations. {Id. at 8—9.)
We find Appellants have the better position. As the Federal Circuit
notes, “there is no per se rule that an adequate written description of an
invention that involves a biological macromolecule must contain a recitation
of known structure.” Falko-Gunter Falkner v. Inglis, 448 F.3d 1357, 1366
(Fed. Cir. 2006). We are persuaded that, at the time of Appellants’ filing,
the structure and function of DGCs were known and would have been
reasonably understood by skilled artisans. {See Christen passim.) Christen
confirms, among other things, the presence of “highly conserved amino acid
sequence GG(D/E)EF [that] forms part of the catalytically active (A-site) of
the DGC enzyme.” (Christen 32015) Similarly, Christen describes a highly
conserved inhibitory (I-site) motif RXXD and observes: “[t]his suggested
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that c-di-GMP product inhibition could be a general regulatory mechanism
of bacterial diguanylate cyclases.” {Id. at 32018.) Thus, in at least two
aspects important to the claims, Christen reflects knowledge in the art of the
overall structure of DGCs, and the amino acid residues and location of the
sites responsible for enzymatic activation and inactivation.
Appellants’ Specification, which references Christen’s studies in the
background and detailed description, presupposes the skilled person’s
knowledge of the basic structural and functional features of DGCs. {See
Spec. 2, 3, 4, 6.) The Specification goes on, however, to describe a working
example of recombinant Caulobacter crescentus CC3285 diguanylate
cyclase DgcA protein, having a modified RXXD motif at amino acid 153—
156. (Spec. 14.) Consistent with Christen’s teachings, the Specification
further describes twelve specific mutations at RXXD that produce
enzymatically active DGC. {Id. at 4—5; see also Christen 32021, Table 2
(listing inhibitory and non-inhibitory DGC I-site mutant proteins).) And, as
for the incorporation of mutant proteins in inclusion bodies and refolding as
recited in the claims, Appellants’ Specification suggests this involves known
techniques requiring only routine skill. (Spec. 5:23—24 (“[tjechniques for
the refolding of protein inclusion bodies are known to the skilled person”);
Spec. 6:28—29 (“over-expression of DGC so as to produce the inclusion
bodies, can be done in ways generally known in the art.”).)
Considering the disclosures of the Specification, in conjunction with
the background knowledge possessed by ordinarily skilled persons in this
art, we are not persuaded that claims lack adequate written descriptive
support. Appellants’ Specification provided examples and the
preponderance of the evidence indicates that DGCs are enzymes with a
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reasonably well-known structure and function. On this record, Appellants
need not provide a description that would cover every hypothetical mutation
of the enzyme outside of the RXXD motif as suggested by the Examiner.
Finally, we observe that the Examiner states the rejection “would be
withdrawn if parts (i) and (iii) of claim 4 were amended to remove the term
‘mutant’ that modifies the DGC.” (Ans. 5, 10.) Even supposing such an
amendment were made, the claims still require recombinant DGC having “a
modified RXXD motif’ and thus the DGC, based on this modification, is
necessarily mutant.6 7The Examiner’s offer to withdraw the rejection is
therefore confusing and calls into question the basis of the rejection.
For these reasons, we reverse the Examiner’s rejection of claims 4,
17—21, and 23 under 35 U.S.C. § 112, first paragraph, for failing to satisfy
the written description requirement.
OBVIOUSNESS
Issue
Has the Examiner established by a preponderance of the evidence that
claims 4, 17—21, and 23 would have been obvious under 35 U.S.C. § 103(a)
over Christen, Clark, and Yabuta, as further evidenced by Nierman?
Findings of Fact (FF)
The Examiner’s findings of fact and statement of the rejection are
provided at pages 5—8 and 10-14 of the Examiner’s Answer. (See also
6 See also Spec. 4:24—25 (“the term ‘DGC’ refers to a mutant diguanylate
cyclase (DGC) comprising a modified RXXD motif.”).
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8/4/14 Final Act. 14—21.) The following findings of fact are provided for
emphasis.
FF 1. Christen teaches “[cjyclic di-guanosine monophosphate [c-di-
GMP] is a bacterial second messenger that has been implicated in biofilm
formation, antibiotic resistance, and persistence of pathogenic bacteria in
their animal host.” (Christen 32015.) Christen teaches further
[b]y using a combination of genetic, biochemical, and modeling
techniques we demonstrate that an allosteric binding site for c-
di-GMP (I-site) is responsible for non-competitive inhibition of
DGCs. ... In vivo selection experiments and kinetic analysis of
the evolved I-site mutants led to the definition of an RXXD motif
as the core c-di-GMP binding site. Based on these results and
based on the observation that the I-site is conserved in a majority
of known and potential DGC proteins, we propose inhibition of
DGCs is of fundamental importance for c-di-GMP signaling and
cellular homeostasis.
(Id.)
FF 2. Christen teaches a method of recombinant overexpression and
purification of hexahistadine tagged DgcA (diguanylate cyclase A, CC3285)
mutants from Caulobacter crescentus in Escherichia coli. (See, e.g., id. at
32015-16, 32018-19 (Fig. 5), 32021 (Table 2).)
FF 3. Christen teaches various DgcA I-site mutant proteins, having a
mutation at the RXXD motif, and having no feedback inhibition from c-di-
GMP. (Id. at 32019—21.) Christen teaches mutant DGC proteins exhibiting
no inhibition include, for example, those having a modified amino acid
sequence of the RXXD motif that is GMGG, VMGG, GGNH, and RESE,
among others. (Id. at 32021 (Table 2).) With respect to one such protein
(DgcA0244, which corresponds to a modified RXXD motif that is VMGG),
Christen teaches “dgcA0244, the allele coding for a DGC that completely
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lacks feedback inhibition, resulted in a more than 100-fold increased cellular
level of c-di-GMP as compared with cells expressing wild-type dgcA.'” (Id.
at 32020.)
FF 4. Nierman teaches DGC or GGDEF-domain family proteins
(CC3285) from Caulobacter crescentus with the residues RESD at amino
acids 153—156. (Nierman 1.) The RESD residues of Nierman correspond to
the RXXD motif disclosed in Christen. (See, e.g., Christen 32018, 32021
(Table 2 (wild type DgcA with motif RESD).)
FF 5. Clark teaches “[ijnclusion body refolding processes are poised
to play a major role in the production of recombinant proteins.” (Clark 202.)
Clark teaches “[expression of genetically engineered proteins in bacteria
often results in the accumulation of the protein product in inactive insoluble
deposits inside the cells, called inclusion bodies.” (Id. at 202
(Introduction).) Clark further teaches
expressing a protein in inclusion body form can be advantageous.
Large amounts of highly enriched proteins can be expressed as
inclusion bodies. Trapped in insoluble aggregates, these proteins
are for the most part protected from proteolytic degradation. If
the protein of interest is toxic or lethal to the host cell, then
inclusion body expression may be the best available production
method.
(Id. (emphasis added).)
FF 6. Clark teaches a number of renaturation processes for refolding
proteins produced in inclusion bodies and improving yields. (See, e.g., id. at
202-3, 205-6, Fig. 1, Table 1.)
FF 7. Yabuta teaches processes for producing “a large amount of a
desired polypeptide ... at a low cost.” (Yabuta Abstract.) More
specifically, Yabuta teaches “a large amount of S. aureus V8 protease can be
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efficiently produced at low cost using a safe host such as E. coli according to
gene recombination procedures.” (Id.) Yabuta discloses “preferably the
desired polypeptide or protein is formed as a fusion protein and . . .
intracellularly accumulated in insoluble inclusion bodies, so as to prevent the
bad effects of the produced polypeptide or protein on the growth and
survival of the host cell.” (Id. at 3:34—39.) Yabuta discloses that, following
expression and excision of the desired protein, “a large amount of S. aureus
V8 protease could be produced by a simple process by refolding the excised
protease to regenerate the active enzyme.” (Id. at 4:49-51.)
Analysis
Appellants argue the patentability of the claims as a group. We thus
select claim 4 as representative. 37 C.F.R. § 41.37(c)(l)(iv).
The Examiner finds that Christen teaches a method of overexpression
of enzymatically active DGC mutants from C. crescentus in E. coli (bacterial
host cell) where the DGC mutant comprises a modification in the RXXD
motif. (Ans. 6.) The Examiner finds Christen teaches that “recombinant
expression of a diguanylate cyclase comprising a modified RXXD motif
changed to VMGG that is able to produce cyclic diGMP without feedback
inhibition.” (Id. at 8.)
The Examiner finds, however, that Christen does not teach that the
host cell accumulates the recombinant DGC in an inclusion body, or the
harvesting or refolding steps of claim 4. (Id. at 7.) The Examiner thus turns
to Clark. According to the Examiner, Clark teaches “expression of proteins
in inclusion body form can be advantageous because it contains large
amounts of highly enriched proteins protected from proteolytic degradation.”
(Id.) The Examiner finds Clark also teaches “more efficient refolding
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methods [for proteins harvested from inclusion bodies] ... for commercial
purposes.” (Id.) The Examiner further cites to Yabuta as teaching an E. coli
expression system where recombinant fusion proteins are accumulated in
inclusion bodies to prevent harm to the host cell, the subsequent harvesting
of the desired protein from the inclusion body, and the refolding of the
protein to generate an active enzyme. (Id. at 7—8.)
The Examiner concludes it would have been obvious to combine the
teachings of Christen, Clark, Yabuta, and thus arrive at the method of claim
4. (Id. at 8.) The Examiner reasons the skilled artisan would have been
motivated to produce overexpressed, mutant DGCs described in Christen in
inclusion bodies because Clark and Yabuta “acknowledge the benefit of
protein expression in inclusion bodies for protecting proteins from
proteolytic degradation, host cell toxicity, and producing in high quantities
for commercial purposes.” (Id.) The Examiner further reasons that
one of ordinary skill in the art desiring to produce large quantities
of mutant DGC would recognize the toxicity of a mutated RXXD
motif in DGC to host cells as taught by Christen [] and would
look to Clark and Yabuta to develop a method for overexpression
of these proteins in the form of inclusion bodies.
(Id. at 12.) According to the Examiner, it was “known by those of ordinary
skill in the art that proteins can be expressed in inclusion bodies through
variations in host cells, growth temperature, and expression duration” (id. at
8) and that “refolding proteins and enzymes retaining biological activity” is
a “technique [that] is well known and predictable to those of ordinary skill in
the art” as evidenced by Clark and Yabuta (id. at 12). For these reasons, the
Examiner concludes the skilled person would have predictably made the
combination of Christen, Clark, and Yabuta with a reasonable expectation of
success. (See id. at 8 and 12—13.)
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We agree with the Examiner’s findings, reasoning, and conclusion
that claim 4 would have been obvious over the cited art.
It would have been obvious and desirable to the skilled artisan to
produce larger quantities of DGC mutants lacking c-di-GMP inhibition.
(Ans. 12.) Reinforcing this point, Christen states that its results “make[]
DGCs a valuable target for drug design to develop new strategies against
bio-film-related diseases,” suggesting that additional production and testing
of DGC’s, including Christen’s mutants, would have been undertaken.
(Christen 32015.) And Appellants’ Specification acknowledges that the
prior art recognized c-di-GMP (which requires DGC for enzymatic
synthesis) as a valuable agent for treating various diseases. (Spec. 1:15—29)
In an obviousness inquiry, we “read[] the prior art in context,” and in view
of relevant “background knowledge possessed by a person having ordinary
skill in the art.” Randall Mfg. v. Rea, 733 F.3d 1355, 1362 (Fed. Cir. 2013)
(quoting KSR Int 7 Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007)).
Prior to Christen, confounding larger-scale production of c-di-GMP
was the inhibition of DGC caused by binding of c-di-GMP at the I-site
(RXXD) motif. But Christen teaches a mutated DGC having a modified
RXXD motif that effectively tums-off this negative feedback mechanism,
thus addressing the problem. (FF 1—3.)
A skilled person, seeking to produce greater quantities of c-di-GMP,
would therefore desire higher levels of Christen’s uninhibited enzyme. Yet,
as the Examiner and Appellants both acknowledge, Christen teaches that
production of a large amount of mutated DGC is toxic to the host cell. (Ans.
12; Br. 24; Christen 32020 (“all proteins from class 2 mutants showed no
feedback inhibition in vitro, arguing that their in vivo toxicity is the result of
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uncontrolled run-off DGC activity.”).) It would, however, have been
obvious for the skilled person to have applied a known and reasonably
predictable solution to this problem of toxicity — namely, causing the host
cell to produce the mutant protein (i.e., Christen’s DGCs) in inclusion bodies
as taught by Clark and Yabuta. Clark, for example, relates to large-scale
production of genetically engineered proteins and teaches that “[i]f the
protein of interest is toxic or lethal to the host cell, then inclusion body
expression may be the best available production method.” (FF 5.)
We further agree with the Examiner that Clark and Yabuta teach the
harvesting and refolding steps of claim 4. (FF 5—7.) Absent persuasive
evidence to the contrary, we are not persuaded these steps would involve
more than the routine skill of the artisan.
Appellants raise a number of arguments concerning strain DgcA0244,
described in Christen. Appellants contend “DgcA0244 does not overexpress
the enzyme DGC” and that expression “is in the range” of the wild type
strain. (Br. 22.) Appellants further contend “the only thing that is expressed
at a high level in DgcA0244 is c-di-GMP, which is not toxic.” {Id. at 23.)
And, according to Appellants,
the present invention does not relate to strains like strain
DgcA0244 that can be grown in vivo, but rather pertains to
almost all of the other such mutants that lack feedback-control,
and therefore cannot be grown in vivo because they do suffer
from the toxic effects of the overexpression of DGC.
(Id.)
These contentions are not persuasive. Appellants focus on one strain
to the exclusion of Christen’s other relevant teachings. Yet, as Appellants
concede, “almost all other host cells that express mutants of DGC that lack
feedback-control cannot be grown in vivo because these cells suffer from
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the toxic effects caused by overexpression of DGC.” (Id.) These other
mutants are encompassed within claim 4’s scope. In addition, although in
one portion of Christen’s experiments, mutant DgcA0244 is selected
because of similar expression levels with wild type DgcA, that is not
inconsistent with Christen’s overall observation that “at elevated protein
levels, DGCs that lack feedback control are toxic in vivo.'” (Christen 32019.)
In fact, the reasonable takeaway from Christen is that DgcA0244 was used
in that instance because, due to its lower expression relative to other
mutants, it was less likely to harm the host cell while still showing that
uninhibited DGC produces greater levels of c-di-GMP compared to wild
type. (FF 3.) That does not, however, suggest that production of DgcA0244
(or for that matter, any of the uninhibited mutants) at elevated protein levels,
would avoid host-cell toxicity, just as Christen predicts. Appellants’
contention that the invention does not relate to strain DgcA0244 of Christen
is also unpersuasive because that strain corresponds to a DgcA I-site mutant
having a modified RXXD motif that is VMGG, which is expressly recited in
at least claims 17 and 18.
Appellants argue Christen was “merely investigating DGC mutants”
and that, “if any relevant teaching is provided by Christen . . ., it is that the
skilled artisan should stop trying to identify mutations that produce more
DGC and consequently, more c-di-GMP, because such strains would not be
expected to be able to grow in vivo.” (Br. 23—24.) Appellants contend the
skilled person would use strain DgcA0244 and no other. (Id. at 24.)
We are not persuaded. The teachings and knowledge of the art do not
begin and end with Christen. Appellants argument fails to account for the
teachings of Clark and Yabuta, which disclose a particular solution for
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producing large amounts of desired proteins that are otherwise toxic to
bacterial host cells — inclusion bodies. (FF 5—7.) Appellants’contention
that Christen “fail[s] to inspire any solution” (Br. 24) is an unpersuasive
attack on Christen’s teachings alone. In re Merck & Co., 800 F.2d 1091,
1097 (Fed. Cir. 1986) (“Non-obviousness cannot be established by attacking
references individually where the rejection is based upon the teachings of a
combination of references.”)7 In addition, even if the skilled person used
DgcA0244, they would be motivated to produce more of it, and the solution
provided in Clark and Yabuta would allow them to do so with a reasonable
expectation of success.
Appellants argue the Examiner is “merely attempting to cobble
together the present invention using Applicants’ Specification as a
blueprint.” (Br. 24.) We are unpersuaded. As noted above, the skilled
artisan would have been motivated to produce large amounts of mutated
DGC, as a catalyst to producing more c-di-GMP, but would have been aware
of the toxicity reported in Christen. The solution is provided in Clark and
Yabuta, which teach production of large volumes of genetically engineered
proteins in bacterial host cells, and to avoid degradation of the protein and
toxicity to the host. (FF 5—7.) The skilled person, in view of these teachings
7 For similar reasons, we find unpersuasive Appellants’ arguments that there
are no teachings in Christen, Clark, or Yabuta of DGCs being expressed in
inclusion bodies or that the toxic effect of over-expression of DGCs lacking
feedback control could be overcome with inclusion bodies. (Br. 24, 26.) No
one reference teaches each of these elements, but the elements are taught or
suggested based on the combination of references. (See also Br. 25
(“Christen [] make no suggestion whatsoever that inclusion bodies might be
desirable.”).)
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and background knowledge in the art, would have predictably arrived at the
subject matter of claim 4 without resort to Appellants’ disclosure.
Appellants attempt to dismiss the teachings of Yabuta because its
preferred embodiment uses fusion bodies comprising a desired polypeptide
and a protective polypeptide, which are then expressed and form inclusion
bodies. (Br. 25.) As the Examiner points out, Appellants’ claims employ
the open-ended claim language “comprising” and “has.” (Ans. 13.)
Appellants contend the term “comprising” relates to the method steps and
not the recombinant DGC itself, and argues the Examiner is applying too
broad a meaning to the word “has.” (Br. 25—26.)
We agree with the Examiner. Appellants do not persuasively point to
any language of the claim that definitively excludes a fusion protein. In any
event, as noted by the Examiner, Yabuta “is cited to demonstrate the general
state of the art of recombinant protein expression and inclusion body
formation [and to show] that the technique of formation of inclusion bodies
is a well-known method in the prior art to circumvent the toxicity ... on host
cell production.” (Ans. 13—14.) In other words, the Examiner’s
combination does not require the fusion proteins from Yabuta’s preferred
constructs be used with Christen’s DGCs, particularly where other art
(Clark) does not require a fusion protein. In re Keller, 642 F.2d 413, 425
(CCPA 1981) (“[t]he test for obviousness is not whether the features of a
secondary reference may be bodily incorporated into the structure of the
primary reference”).
Finally, Appellants argue that it is clear from Clark and Yabuta that
“handling of inclusion bodies is often a frustrating trial-and-error process”
and that DGCs are enzymes that need to be refolded to regain catalytic
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activity. (Br. 26.) Appellants contend the prior art does not teach how to
carry out these steps with a reasonable likelihood of success. {Id. at 27.)
We are not persuaded. Clark applies to proteins broadly, and Yabuta
specifically describes formation of an enzyme in inclusion bodies along with
subsequent harvesting and refolding to regenerate the active enzyme, which
Yabuta describes as “a simple process.” (FF 5—7.) We are not persuaded
these techniques would be beyond the abilities of the ordinarily skilled
person, especially where Appellants’ Specification suggests otherwise.
(Spec. 5:23—24 (“[techniques for the refolding of protein inclusion bodies
are known to the skilled person”); Spec. 6:28—29 (“over-expression of DGC
so as to produce the inclusion bodies, can be done in ways generally known
in the art.”).)
Conclusion of Law
The Examiner established by a preponderance of the evidence that
claim 4 would have been obvious over Christen, Clark, and Yabuta, as
further evidenced by Merman. Claims 17—21 and 23 have not been argued
separately and therefore fall with claim 4. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We reverse the rejection of claims 4, 17—21, and 23 under 35 U.S.C.
§112, first paragraph, for failure of the written description requirement.
We affirm the rejection of claims 4, 17—21, and 23 under 35 U.S.C.
§ 103(a) over Christen, Clark, and Yabuta, as evidenced by Merman.
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Appeal 2015-007386
Application 13/133,458
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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