Ex Parte Nakaishi et al

Patent Trial and Appeal Board

May 10, 2016

12065450 (P.T.A.B. May. 10, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/065,450 01/13/2009
23373 7590 05/12/2016
SUGHRUE MION, PLLC
2100 PENNSYLVANIA A VENUE, N.W.
SUITE 800
WASHINGTON, DC 20037
FIRST NAMED INVENTOR
Tomoyuki Nakaishi
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.
Ql06334 9503
EXAMINER
WILSON, MICHAEL C
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
05/12/2016 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):
PPROCESSING@SUGHRUE.COM
sughrue@sughrue.com
USPTO@sughrue.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte TOMOYUKI NAKAISHI, TAKUYA SHINDO,
and TOMOKO AWA 1
Appeal2014-000422
Application 12/065,450
Technology Center 1600
Before ERIC B. GRIMES, JEFFREY N. FRED MAN,
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 feline
proteins produced in eggs of a transgenic chicken, which have been rejected
as obvious. We have jurisdiction under 35 U.S.C. § 6(b ).
We affirm.
STATEMENT OF THE CASE
"The technology concerned comprises using gene-transferred
(transgenic) animals to produce desired proteins." (Spec. 2.) "More
1 Appellants identify the Real Party in Interest as Kaneka Corporation. (Br.
3.)
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Application 12/065,450
particularly, it relates to the expression of feline-derived erythropoietin in [a]
transgenic bird." (Id. at 1.)
Claims 26-33 and 35-37 are on appeal. Claim 26 is illustrative:
26. A polyethylene glycol-modified feline protein which is
obtained by extracting the feline protein from an egg laid by a
transgenic chicken, and chemically modifying the protein with
polyethylene glycol,
wherein the transgenic chicken comprises a nucleic acid
sequence encoding a feline protein operably linked to a
promoter, wherein the feline protein is secreted into an egg laid
by the transgenic chicken.
(Br. 24 (Claims App'x.).)
The Examiner rejected all the claims on appeal under 35 U.S.C. §
103 (a) as obvious over Lilli co, 2 Harvey, 3 and I varie, 4 in view of Nakamura, 5
Burg '7 42, 6 Burg 'O 17, 7 and Krishnan. 8 (Final Act. 2-3 .)
DISCUSSION
Issue
Has the Examiner established by a preponderance of the evidence that
claims 26-33 and 35-37 would have been obvious over Lillico, Harvey, and
Ivarie, in view ofNakamura, Burg '742, Burg '017, and Krishnan?
2 Lillico et al., Transgenic chickens as bioreactors for protein-based drugs,
10 DRUG DISCOVERY TODAY 3: 191-96 (2005) ("Lillico").
3 Harvey et al., U.S. 7,812,215 B2, issued Oct. 12, 2010 ("Harvey").
4 Ivarie et al., U.S. 6,730,822 Bl, issued May 4, 2004 ("Ivarie").
5 Nakamura et al., EP 1 333 036 Al, published Aug. 6, 2003 ("Nakamura").
6 Burg et al., U.S. 6,340,742 Bl, issued Jan. 22, 2002 ("Burg '742").
7 Burg et al., WO 01/02017 A2, published Jan. 11, 2001 ("Burg '017").
8 Krishan et al., EP 1 013 288 A2, published Jun. 28, 2000 ("Krishnan").
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Application 12/065,450
Findings of Fact
1. Lilli co teaches the use of transgenic chickens as bioreactors for
production of proteins, including erythropoietin ("EPO").
Pharmaceutical proteins produced in eggs might have
significant advantages for specific target drugs, including
appropriate glycosylation, lower costs than either cell culture or
transgenic mammalian systems and faster scale-up.
***
A potential advantage of using chickens as bioreactors is that
some of the oligosaccharide moieties added to nascent
polypeptides in the chicken have greater similarities with the
sugars used by humans than those of other mammals.
***
Production of human proteins in hens could be the method of
choice for some proteins that are toxic to mammals. For
example, although expression of human erythropoietin in the
mammary glands of rabbits had a deleterious effect, it is
unlikely that human erythropoietin will be active in chickens.
(Lillico pp. 192, 193 (reference citation omitted).)
2. Harvey and Ivarie teach production of proteins, including EPO, in
eggs of transgenic chickens. For example, Harvey teaches
The present invention can be used to express, in large yields
and at low cost, a wide range of desired proteins including
those used as human and animal pharmaceuticals, diagnostics,
and livestock feed additives .... [P]roteins ... are desirably
expressed in the oviduct and deposited in eggs according to the
invention .... [and] include ... erythropoietin (EPO).
(Harvey, col. 24, 11. 49--61; see also, id. at col. 53, 11. 35-57, claims 1 and
14; see also, Ivarie col. 19, 11. 24--35, claims 1-7.)
3. Krishnan teaches "a method of treating domestic and livestock
animals (particularly cats, dogs, and pigs) for anemia by administering
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Application 12/065,450
expression vectors encoding canine, feline, or porcine erythropoietin."
(Krishnan Abstract). Krishan discloses the sequence of feline EPO (SEQ ID
NO: 2) having a signal sequence. (Id. at 3, 11. 4---6, Fig. 2.)
4. Nakamura teaches benefits of PEG-modified EPO compared to
unmodified native and recombinant human EPO produced in animal host
cells (e.g., CHO cells). According to Nakamura, "the general recognition of
the relationship between the molecular weight of PEG used for conjugation
and in vivo activity of EPO was that EPO conjugated with higher molecular
weight PEG showed more improved plasma retention and hence greater and
more sustained efficacy." (Nakamura i-f 12; see also, id. at i-fi-12-11, 13-15,
Figs. 3--4.) Comparative testing "confirm[ ed] that the PEG-conjugated
EPOs ... had greater and more sustained in vivo efficacy than unconjugated
native EPO." (Id. at i-f 28; see also, id. at 29.) Nakamura further teaches
"[ s ]ustained release preparations of PEG-conjugated EPO are more
advantageous than those of native erythropoietin, in that PEG conjugation
stabilizes erythropoietin activity ... and shows much longer plasma
retention than native erythropoietin." (Id. at i-f 35.)
5. Burg '742 and Burg '017 also teach benefits of PEG-modified
glycosylated EPO. (See, e.g., Burg '017 Abstract, pp. 1-3; Burg. '742
Abstract, cols. 1-2.). The "present conjugates have an increased circulating
half-life and plasma residence time, decreased clearance, and increased
clinical activity in vivo." (Burg. '742 Abstract). These references further
teach that PEG-modified EPO "show[s] superior activity and the prolonged
half life of the pegylated EPO species [compared to unmodified EPO]
indicated by the significantly increased amounts of reticulocytes and the
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shift of the reticulocytes count maximum using the same dose per mouse."
(Id. at col. 18, Fig. 3; Burg '017 p. 27, Fig. 3.)
Principles of Law
Section 103 generally bars patentability unless "the improvement is
more than the predictable use of prior art elements according to their
established functions." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 417
(2007). Moreover, "when unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art." In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed.
Cir. 1991).
Analysis
The Examiner rejected all the claims on appeal as obvious. According
to the Examiner, it was known in the art to produce "exogenous
erythropoietin (EPO) extracted from an egg laid by a transgenic chicken,"
such as shown in Lillico, Harvey, and Ivarie. (Ans. 2.) Because this prior
art did not expressly disclose that the EPO was feline EPO, the Examiner
cites Krishnan as teaching the relevant amino acid sequence for that protein. 9
(Id. at 2.) The Examiner finds that skilled persons at the time of the
invention "would have been motivated to replace the EPO described in
Lillico, Harvey and Ivarie with the feline EPO described by Krishnan to
9 The Examiner finds that Krishnan discloses "feline EPO (including the
signal sequence)" and that the sequence of feline EPO in Krishnan "shares
97% identity with SEQ ID NO: 1 which meets the limitations of claims 28
and 29." (Id.)
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produce feline EPO in a bioreactor [a transgenic chicken] for treatment" and
specifically to produce feline EPO to treat anemia in cats. (Id. at 3.)
The Examiner finds that Lillico, Harvey, Ivarie, and Krishnan did not
disclose EPO modified with polyethylene glycol (PEG) after EPO is
extracted from an egg as in the present claims. (Id. at 3--4.) The Examiner
thus turns to Nakamura, Burg '017, and Burg '742, each of which teaches
PEG-modified EPO and the benefits of the modified protein. (Id.)
According to the Examiner, those of ordinary skill in the art would have
modified with PEG the feline EPO produced by a transgenic chicken "to
increase efficacy without losing activity as described by Nakamura ... and
increased circulating half-life and plasma residence time, decreased
clearance and clinical activity [of the PEG-modified EPO] as described by
Burg." (Id. at 4.) The Examiner concludes that the "structure of the final
product described by the combined teachings in the art has the exact same
structure as the PEG-modified feline EPO described by applicants." (Id.)
We agree with the Examiner. Lillico, Harvey, and Ivarie all teach use
of transgenic chickens to produce EPO in eggs. (See, e.g., Ivarie claim 1
("A method for producing an exogenous interferon a or erythropoietin
protein in an egg of a chicken"; FF 1, 2.) Also, the benefits of using
chickens as a bioreactor in this way for production of human and animal
proteins are plainly stated in the art. (Id. at col. 19, 11. 24--27: "The
invention can be used to express, in large yields and at low cost, a wide
range of desired proteins including those used as human and animal
pharmaceuticals, diagnostics, and livestock feed additives."; FF 2.)
Extending these teachings to produce feline EPO (FF 3) is simply the
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predictable application of a known technique to a known sequence encoding
a known protein. KSR, 550 U.S. at 417 ("If a person of ordinary skill in the
art can implement a predictable variation, and would see a benefit of doing
so, § 103 likely bars its patentability. ")
PEG-modified EPO was also known in the art, along with its benefits.
(FF 4, 5.) As the Examiner correctly points out, those benefits include, for
example, increased efficacy, circulating half-life, and plasma residence time
of the modified EPO, such as recited in Nakamura and the two Burg
references. (Id.; Ans. 4.) The Examiner's reasons for extending these
teachings to a feline EPO produced in a transgenic chicken - to obtain the
benefits of PEG-modified EPO known in the art - are thus rationally based
and supported by persuasive evidence.
For these reasons, we conclude that the Examiner established a prima
facie case that the claims would have been obvious.
Appellants raise several arguments in response to the Examiner's
rejections, but we find none of these arguments persuasive. We address
each argument in tum below.
Appellants argue the invention achieves unexpectedly superior results
in multiple respects. Appellants' first argument focuses on the amount of
feline EPO versus non-feline proteins produced in the eggs of transgenic
chickens. Appellants cite the amount of B-lactamase produced in an egg as
shown in Ivarie at "10 to 70 µg per egg, assuming 40 milliliters of egg white
per egg" and compare that with the 420 µg/ml of feline EPO produced in
egg white according to the Specification. (Br. 10.) Similarly, Appellants
cite a disclosure in the Specification that human EPO produced in a
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Application 12/065,450
transgenic bird "is about 10 µg/ml." (Id.) Because more feline EPO was
produced (e.g., "240 times larger than that of Ivarie"), Appellants conclude
"the feline protein accumulated according to the present invention achieves
unexpectedly superior results compared to the cited prior art of record." (Id.
at 11.)
We are not persuaded. Appellants' comparison of the production
yields of different proteins with different molecular weights is flawed. (Ans.
6.) The reason that more feline EPO was produced than human EPO could
be attributable to a variety of factors, including the much larger size of
human EPO. (Id. at 7 ("human EPO = 34 kDa, feline EPO = 20.9 kDa").
Appellants have also not shown that the results in the Specification were
obtained using an expression vector and expression control sequences that
are comparable to those used in the prior art. As the Examiner noted, "any
differences between the claimed invention and the prior art may be expected
to result in some differences and properties." (Id. at 6.)
Moreover, as the Examiner found, Appellants have not demonstrated
that their comparisons are between the invention and the closest prior art.
(Id. ("the amount of antibody or B-lac is irrelevant because it does not
accurately describe the closest prior art (claim 14 of Harvey and claim 1 of
Ivarie)".) 10 In re Baxter Travenol Labs., 952 F.2d at 392. Appellants fail to
10 See also, id. at 7 ("The amount of protein in '922 and '923 [cited in the
Specification for the 10 µg/ml human EPO figure]) is irrelevant because it
does not accurately describe the closest prior art (EPO made in transgenic
chickens specifically claimed in claims 14 of Harvey and 1 oflvarie).".)
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address these shortcomings and their conclusion of "unexpected results" thus
lacks adequate support. 11
Appellants contend claims 28 and 29 are separately patentable, but
merely repeat the arguments comparing different proteins and yields. (Br.
12.) We reject this argument for the same reasons noted above.
Appellants next argue the claimed polyethylene glycol-modified
feline protein achieves unexpectedly superior results compared to
unmodified feline proteins. (Id. at 15-16.) Appellants rely on Figure 7 of
the Specification, which Appellants contend shows testing of PEG-modified
feline EPO for hematopoietic activity (measured by reticulocyte count)
compared to unmodified feline EPO and human EPO (EPOGEN). (Id.)
According to Appellants, the modified feline EPO "achieves strong activity
compared to administration of a comparable feline protein that is not PEG-
modified ... the protein that is not chemically modified by PEG has only
very weak hematopoietic activity or no activity at all in the absence of PEG
modification." (Id. at 17.) Because, Appellants contend, the knowledge in
the art was that protein activity decreases when PEG is added, Appellants
11 Appellants also argue that "[a]s a result of few glycosylations, the claimed
protein can be accumulated in a large amount without affecting the condition
of the host transgenic chicken." (Br. 11.) The point of this argument, and
how it shows any unexpected results, is unclear. The claims are to the
protein, not a method of expressing the protein in a transgenic chicken that
differs from the known techniques. Nor do the claims recite the number or
type of glycosylations arising from use of a transgenic chicken as the
bioreactor. In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005) (the
unexpected results must be "commensurate in scope with the degree of
protection sought by the claimed subject matter.").
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Application 12/065,450
conclude "the effect achieved by the claimed polyethylene glycol-modified
feline protein is unexpected at least because of the significantly increased
magnitude of protein activity." (Id. at 18.)
Although the results in Figure 7 of the Specification show greater
activity of the PEG-modified feline EPO for a portion of the testing duration,
Appellants have not persuaded us that such a result was unexpected.
Appellants argue that "Nakamura warns that very high molecular weight
PEG inhibits the hematopoietic effect of EPO." (Id.) Yet Nakamura teaches
that the conventional belief in the art was that "in vivo activity of EPO ...
conjugated with higher molecular weight PEG showed more improved
plasma retention and hence greater and more sustained efficacy." (FF 4.)
As stated by the Examiner, "applicants' analysis must take into
account secondary considerations about what was known about PEG
modification." (Ans. 11.) This includes the collective teachings of the art,
including Burg '017 and Burg '742, which also show "superior activity and
the prolonged half life of the pegylated EPO species indicated by
significantly increased amounts of the reticulocytes." (FF 5 (emphasis
added).) Even the Specification, when describing Figure 7, attributes the
results as "[p ]resumably ... due to an improvement in in vivo stability of
erythropoietin as brought about by modification with PEG" -just as taught
in the prior art by Nakamura. (Spec. 41, 11. 27-32; FF 4 ("[s]ustained release
preparations of PEG-conjugated EPO are more advantageous than those of
native erythropoietin, in that PEG conjugation stabilizes erythropoietin
activity").)
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Application 12/065,450
Appellants argue the prior art "teach[ es] away from PEG modification
of a protein having no activity." (Br. 15.) This argument, like Appellants'
argument concerning unexpected results, rests upon Appellants' contention
that PEG-modification decreases protein activity. (Id.) But, as discussed
above, the prior art teaches that PEG modification results in increased in
vivo activity of the protein in various respects. (Ans. 10; FF 4--5.)
Moreover, Figure 7 in the Specification - even if it shows limited activity
of unmodified feline EPO - was not known prior to the filing and
publication of the present application. As such, it cannot be relied upon to
evidence a "teaching away" known to those of skill in the art at the time of
the invention. We thus find Appellants' argument unpersuasive.
Appellants also argue that feline protein extracted from a transgenic
chicken's egg is "structurally different from the protein of Krishnan." (Br.
13.) In support, Appellants cite a declaration from Tomoyuki Nakaishi,
Ph.D., 12 which estimates through Western blot testing the molecular weights
of "feline EPO produced by a mammalian expression system, e.g., CHO
cells" compared to "feline EPO produced by a transgenic chicken." (Deel.
1-5). According to Appellants, the Declaration shows "distinct mobility"
between the proteins and Appellants argue "it is readily apparent that the
molecular weights of the feline proteins differ according to the expression
system." (Br. 13.)
The Examiner's rejection is, however, based on the combination of
references: expressing the feline EPO sequence disclosed in Krishnan, but in
12 Signed Jan. 10, 2012, included in the Evidence Appendix of the Brief.
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a different expression system (i.e., a transgenic chicken) as taught in Lillico,
Harvey, and Ivarie. Appellants thus attack the prior art individually in
pointing out that proteins produced in transgenic chickens have different
molecular weights than proteins produced in mammalian systems - an
analysis that fails to address the rejection as presented. 13 In re Merck & Co.,
Inc., 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.").
Appellants argue the "Examiner improperly applies an inherency
rationale to sustain an obviousness rejection." (Br. 18.) Yet Appellants fail
to explain where that occurs. Appellants cite "properties unknown in the
prior art," but do not explain why this is relevant and where such
"properties" are found in the language of the claims. (Id. at 18-19.) If
Appellants mean "having few glycosylations," as discussed elsewhere, the
number or type of glycosylations is not a claim limitation. At bottom, the
Examiner finds that the combination of express teachings in the prior art
produces the claimed protein (Ans. 4), and we have been presented with no
persuasive evidence to the contrary.
13 One of skill in the art would expect structural differences between two
proteins based on the type of expression system used. (Lillico 193; Ans. 8-
9.) Appellants' related argument that "[f]ewer glycosylations ofEPO
produced in a transgenic bird was not known in the prior art" (Br. 14) is
unpersuasive because Lillico teaches that expression of proteins in
transgenic chickens is expected to result in different glycosylation relative to
expression in other mammalian systems. (Lillico 193.)
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Finally, Appellants argue "[g]lycosylation characteristic[ s] are not
predictable." (Br. 19.) Appellants thus argue that "a person having ordinary
skill in the art would not have predicted the properties of the claimed
polyethylene glycol-modified feline protein." (Id.) Absolute predictability
is, however, not required - only a reasonable probability of success. 14
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007)
("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 ... the expectation of success need only be reasonable, not
absolute.") And Appellants have presented no persuasive evidence to show,
based on the knowledge and state of the art at the time of the invention, that
the skilled person would not have combined the teachings of the prior art
with a reasonable expectation of success. Based on the record before us, we
14 Appellants say "[g]lycosylation characteristics depend on the combination
of the protein and the production system." (Br. at 20.) That was known.
(See, e.g., Lillico pp. 192-193.) Rather than help Appellants' argument, this
shows that persons skilled in the art would expect some differences between
protein structure and thus activity depending on the protein and whether it
was produced in, for example, a transgenic chicken or a mammalian cell.
This reveals the flaw in Appellants' (unsupported) claim that persons of skill
in the art would expect feline EPO produced in transgenic chickens to
behave just like human EPO. (Br. 20-21.) Even if feline EPO produced in a
transgenic chicken has one level of activity (shown in Figure 7 of the
Specification) and human EPO produced in a transgenic chicken has a
different level of activity (shown in Iijima et al., US 2009/0064351 Al), we
are unpersuaded the art was so unpredictable that the person of skill in the
art at the time of the invention would not have combined the prior art to
arrive at the claimed protein. Notably, the evidence Appellants rely on to
show unpredictability- Figure 7 and Iijima - was also unavailable to
skilled artisans at the time of the invention.
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conclude the person would have predictably combined the prior art in the
manner proposed by the Examiner to produce PEG-modified feline EPO
within the scope of the claims.
Conclusion of Law
With the exception of claims 28 and 29, addressed above, Appellants
have not presented separate argument for any of the claims, such that the
remaining claims fall with claim 26. 37 C.F.R. § 41.37(c)(l)(iv). We
conclude that the Examiner has established by a preponderance of the
evidence that claims 26-33 and 35-37 would have been obvious.
SUMMARY
We affirm the rejections of claims 26-33 and 35-37 as obvious under
35 U.S.C. § 103(a) based on Lillico, Harvey, and Ivarie, in view of
Krishnan, Nakamura, Burg '017 and Burg '742.
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
14