Ex Parte Bout et al

Patent Trial and Appeal Board

May 22, 2017

13002797 (P.T.A.B. May. 22, 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
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/002,797 04/08/2011 Abraham Bout H-HS-00021 WO/US 4369
(527786)
24289 7590
Mallinckrodt LLC
675 McDonnell Boulevard
HAZELWOOD, MO 63042
05/24/2017 EXAMINER
TSAY, MARSHA M
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
05/24/2017 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):
patents @ mallinckrodt.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ABRAHAM BOUT, JOSEPH MARIA GRIMBERGEN, and
JACOB LAURENS KOOPMAN
Appeal 2017-0005181
Application 13/002,797
Technology Center 1600
Before RICHARD M. LEBOVITZ, RICHARD J. SMITH, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to a pharmaceutical fibrinogen
preparation that is homogeneous, comprising recombinant human
fibrinogen. The Examiner rejected the claims as anticipated under 35 U.S.C.
§102 and obvious under 35 U.S.C. § 103. We have jurisdiction under 35
U.S.C. § 6(b). The rejections are affirmed.
1 The Appeal Brief (“Appeal Br.”) 2 lists Profibrix B.V. as the real-party-in­
interest.
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STATEMENT OF THE CASE
Appellants appeal from the Examiner’s rejection of claims 15, 18, 27,
29, and 38—41. Final Action (“Final Act.”). The claims stand rejected as
follows:
1. Claims 15, 18, 38, 39, and 41 under 35 U.S.C. § 102(b) or, in the
alternative, under § 103(a) over Matsuyama et al. (EP 1 661 989 Al, publ.
May 31, 2006) (“Matsuyama”). Final Act. 3.
2. Claims 15, 27, 29, and 40 under 35 U.S.C. § 103(a) over
Matsuyama as evidenced by Rixon et al. (Characterization of a
Complementary Deoxyribonucleic Acid Coding for the a Chain of Human
Fibrinogen, 22 Biochemistry 3237—44 (1983)) (“Rixon”), Chung et al.
{Characterization of Complementary Deoxyribonucleic Acid and Genomic
Deoxyribonucleic Acid for the ft Chain of Human Fibrinogen, 22
Biochemistry 3244—50 (1983)) (“Chung I”), and Chung et al.
{Characterization of a Complementary Deoxyribonucleic Acid Coding for
the y Chain of Human Fibrinogen, 22 Biochemistry 3250—56 (1983))
(“Chung II”). Final Act. 5.
3. Claims 15, 18, 38, 39, and 41 under 35 U.S.C. § 102(b) or, in the
alternative, under § 103(a) over Huang et al. (US Pat. Publ. 2003/0221223
Al, publ. Nov. 27, 2003) (“Huang”). Final Act. 10.
4. Claims 15, 27, 29, and 40 under 35 U.S.C. § 103(a) over Huang in
view of Matsuyama, and evidenced by Rixon, Chung I, and Chung II. Final
Act. 11.
5. Claims 15, 18, 38, 39, and 41 under 35 U.S.C. § 103(a) over Roy et
al. {Assembly and Secretion of Recombinant Human Fibrinogen, 266 J. Bio.
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Chem. 4758—63 (1991)) ((“Roy (1991)”) also referred to as “Roy I”) in view
of Matsuyama. Final Act. 15.
6. Claims 15, 27, 29, and 40 under 35 U.S.C. § 103(a) over Roy
(1991) in view of Matsuyama, and evidenced by Rixon, Chung I, and Chung
II. Final Act. 17.
7. Claims 15, 18, 38, 39, and 41 under 35 U.S.C. § 103(a) over Roy et
al. (Over expression of Any Fibrinogen Chain by Hep G2 Cells Specifically
Elevates the Expression of the Other Two Chains, 269 J. Bio. Chem. 691—95
(1994)) ((“Roy (1994)”) also referred to as “Roy II”2) in view of
Matsuyama. Final Act. 20.
The nonstatutory obviousness-type double patenting rejection over
copending Application No. 13/520,615 is mooted because the copending
application is abandoned. Appeal Br. 12.
Appellants raise identical arguments for all seven rejections.
Appellants also have not provided separate arguments for the dependent
claims. Consequently, we have considered all the rejections together with
claim 15 as representative as it is the only independent claim involved in the
appeal. Claims 18, 27, 29, and 38-41 stand or fall with claim 15.
37 C.F.R. § 41.37(c)(l)(iv).
CLAIM
Claim 15 reads as follows:
15. A pharmaceutical fibrinogen preparation that is
homogeneous comprising recombinant human fibrinogen that is
free of protease inhibitors, is in a homogeneous form, and is
biologically active,
2 This publication appears to be cumulative to Roy (1991).
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wherein the recombinant human fibrinogen has an alpha
chain, a beta chain and a gamma chain,
wherein more than 85% of the recombinant human
fibrinogen is in an intact form, as measured by an SDS-PAGE
or Western blotting analysis,
wherein the alpha chain is: 1) a 644 amino acid chain
according to SEQ ID No. 8; 2) a 625 amino acid chain
according to amino acids 20 to 644 of SEQ ID No. 8; 3) a 610
amino acid chain according to amino acids 20 to 629 of SEQ ID
No. 8; 4) an 866 amino acid chain according to SEQ ID No. 11;
or 5) a chain according amino acids 20 to 866 of SEQ ID No.
11,
wherein the beta chain is: 1) a 491 amino acid chain
according to SEQ ID No. 9; or 2) a 461 amino acid chain
according to amino acids 31 to 491 of SEQ ID No. 9,
wherein the gamma chain is: 1) a 437 amino acid chain
according to SEQ ID No. 10; 2) a 411 amino acid chain
according to amino acids 27 to 437 of SEQ ID No. 10; 3) a 453
amino acid chain according to SEQ ID No. 13; or 4) a 427
amino acid chain according to amino acids 27 to 453 of SEQ ID
No. 13, and
wherein the recombinant human fibrinogen is prepared
by a method comprising the steps of:
culturing a cell comprising:
1) three nucleotide sequences each encoding the alpha
chain, the beta chain and the gamma chain of the recombinant
human fibrinogen, wherein the three nucleotide sequences are
optimized for expression in a mammalian cell culture system
under conditions wherein the recombinant human fibrinogen is
produced; or
2) a nucleotide construct comprising three nucleotide
sequences each encoding the alpha chain, the beta chain and the
gamma chain of the recombinant human fibrinogen, wherein
the three nucleotide sequences are optimized for expression in
the mammalian cell culture system under conditions wherein
the recombinant human fibrinogen is produced,
wherein the three nucleotide sequences each have a GC
content of at least 60%, and wherein codons for the cis-acting
sites are removed; and
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recovering the recombinant human fibrinogen.
CLAIM INTERPRETATION
Independent claim 15 is directed to a “pharmaceutical fibrinogen
preparation that is homogeneous comprising recombinant human fibrinogen
that is free of protease inhibitors, is in a homogeneous form, and is
biologically active.”
The phrase “pharmaceutical. . . preparation” is not defined in the
Specification. Appellants also do not provide a definition or guide us to the
Specification where such a preparation is disclosed. Nonetheless, the
Specification describes administration of recombinant fibrinogen to a
human, e.g., intravenously, and describes medical uses of it. Spec. 2:15—29;
8:22—36. Based on these disclosures, we interpret a pharmaceutical
fibrinogen preparation to be a preparation that is suitable for administration
to a subject for medical applications.
The term “homogenous” is also not expressly defined in the
Specification. The Specification, however, teaches that fibrinogen present in
the blood has a “high degree of heterogeneity” due to “[variations [that]
arise through genetic polymorphisms, differences in glycosylation and
phosphorylations, (partial) proteolysis of the carboxy-terminal part of the Aa
chain and alternative splicing.” Spec. 1:19-22. The Specification describes
expression of specific a, P, y fibrinogen chains in a cell culture system. Id.
at 3:18—7:31. The Specification teaches “[i]n contrast to plasma derived
fibrinogen, the fibrinogen preparation produced by this [expression in cell
culture system] method will be rather homogeneous because specific
fibrinogen chains are produced.” Id. at 8:16—18. In view of this disclosure,
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we interpret “homogenous” to mean a fibrinogen comprised of the same
specific a, P, y chains, rather than a mixture of different chain variants as
found naturally in blood.
The claim requires the fibrinogen to be “biologically active.” The
Specification defines the term: “In the context of the present invention,
‘biologically active’ fibrinogen refers to fibrinogen which polymerizes into
fibrin in the presence of thrombin.” Id. at 7:18—19.
The claim also recites that “more than 85% of the recombinant human
fibrinogen is in an intact form, as measured by an SDS-PAGE or Western
blotting analysis.” The Specification teaches:
In the context of the present invention, fibrinogen or a
fibrinogen chain is “in intact form” when the amino acid
sequence contains all the amino acids which were encoded for
by the nucleotide sequence, optionally without the amino acids
which are removed during normal cell (secretion) processing.
Id. at 4:14-17.
The fibrinogen of claim 15 is product-by-process claim because the
fibrinogen is claimed as a product of a cell culture method. A product-by­
process limitation defines a product in terms of how it is made. SmithKline
Beecham Corp. v. Apotex Corp., 439 F.3d 1312, 1315 (Fed. Cir. 2006).
“[E]ven though product-by-process claims are limited by and defined by the
process, determination of patentability is based on the product itself.” In re
Thorpe, 111 F.2d 695, 697 (Fed. Cir. 1985). Consequently, when comparing
the claimed fibrinogen to the prior art, we must determine whether the
recited process steps impart a structure or characteristic to the recombinant
product that distinguishes it from products made by other processes. With
respect to this comparison, the cells recite “culturing a cell” but do not
define the type of cell; thus, the claimed fibrinogen is not restricted as to the
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cell type it is produced in.
FINDINGS OF FACT
Matsuyama
Ml. Matsuyama describes a process for producing recombinant
human fibrinogen in an animal cell, such as a CHO cell. Matsuyama 1,
19, 45.
M2. The cell is transformed with 1) an expression vector encoding
alpha-chain and gamma-chain, and 2) expression vector encoding beta-chain
and gamma-chain. Id. 119.
M3. The gamma-chain gene is in “an equal amount to a 1000-fold
amount” relative to the alpha- and beta-chain genes. Id.
M4. “According to the method of mixing-expressing genes encoding
three kinds of proteins constituting human fibrinogen, a recombinant
producing cell which highly expresses fibrinogen, and a process for
producing the same are provided.” Id. 124.
M5. Figure 2, reproduced below, shows a Western blot of culture
supernatant from a transformed CHO cell. Id. 149.
M6.
1 2 3 4
. i, 1 -'
CL
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M7. A CHO cell was cultured overnight in YMM medium
comprising fetal calf serum (FCS) and “on a next day, a medium was
exchanged with a YMM medium containing no FCS, this was cultured at
37°C for 4 days . . ., and fibrinogen present in the culturing supernatant was
used for analysis.” Id.
M8.
Results thereof are shown in Fig. 2. It was confirmed that,
under reduction, fibrinogen produced in the CH001-1-2
culturing supernatant contains a protein having the same size as
that of borhyl containing fibrinogen derived from plasma. In
addition, these three bands were coincident with molecular
weigh[t]s of the known respective fibrinogen chains: a chain;
66kDa, P chain; 52kDa, y chain; 46.5kDa.
Id. at 51.
Fig. 2 shows “lane 3: CH001-1-2 culture supernatant (8pl/lane), lane
4: CH001-1-2 culture supernatant (24pl/lane).” Id. 126.
M9. Matsuyama investigated the “producing ability of a recombinant
fibrinogen producing cell... at self-free culturing.” Id. 1 52. “[T]he cell
established by the method of the present invention attained up to about
270jig/ml of a production amount on a serum-free medium regarding
fibrinogen production, and it was shown that the cell is a highly productive
cell which has not previously been obtained.” Id. 1 53.
M10. Matsuyama teaches the recombinant human fibrinogen can be
used as an antigen to produce antibodies, and
as a tissue adhesive utilizing agglutination property of fibrin,
for hemostasis, closure of a wound site, adhesive or suturing
reinforcement of a nerve, a tendon, a vessel and a tissue, and
therapy over a wide range such as closure of air leakage in lung,
or as a suitable drug for a base of regeneration medicine for the
purpose of tissue regeneration.
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Id. H64, 65.
Huang
HI. Huang teaches expression of three plasmids coding for human
fibrinogen alpha chain, beta chain and gamma chain, respectively, each
under the control of the rice glutelin promoter Gtl. Huang 134. “These
plasmids, including a plasmid (not shown) containing the hygromycin
selectable marker, were bombarded into embryogenic rice callus to create
transgenic rice plants expressing these three genes in mature rice seeds.” Id.
H2.
FIG. 3 shows the simultaneous expression of the three
fibrinogen polypeptide chains (a, P and y) in transgenic rice
seeds and analyzed via Western blot analysis. Fibrinogen
polypeptides and protein aggregates were detected using
antibody recognizing all three chains.
Id. 136.
H3. Fig. 3B is reproduced below:
H4.
FIG. 3B indicates total protein extracted from rice seeds in 2%
SDS, 1 M urea, 1% pMe and PBS pH 7.4, and run on SDS-
PAGE. Lane 1, positive control, native human fibrinogen
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(obtained from the Red Cross) showing all three polypeptide
chains; Lane 2, molecular weight standards; Lanes 3-5, three
independent transgenic rice lines expressing all three fibrinigen
[sic, fibrinogen] polypeptides.
Id.
H5.
A purified blood protein recombinantly produced in a plant cell,
preferably substantially free of contaminants of the host plant
cell, and preferably comprising at least one plant glycosyl
group is also provided by the invention. The plant glycosyl
groups, while identifying that the blood protein was produced
in a plant, does not significantly impair the biological activity
of the blood protein in any of the applied therapeutic contexts
(preferably less than 25% loss of activity, more preferably less
than 10% loss of activity, as compared to a corresponding non­
recombinant human blood protein).
Id. 192.
H6. Huang teaches that the recombinant rice express and extracted
human fibrinogen can be used as fibrin sealant/bandage. Id. 1133. Huang
teaches that fibrin sealants are “effective hemostatic agents,” “a means for
achieving tissue adhesion, preventing fluid accumulation and promotion of
wound healing.” Id. “Fibrin sealants can also be used as a means of slowly
releasing medications, including antibiotics, growth factors and other
agents.” Id.
Roy (1991)
Rl. Roy (1991) describe stable transfection of COS-1 cells with three
vectors, coding for Aa, Bp, and y chains, respectively, of human fibrinogen.
Roy (1991) 4758.
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R2. Fig. 4B, lane 1, shows fibrinogen-related proteins in cell lysates
from COS-a,P,y cells (recombinant COS cells which transfected with
express the a, P, and y chains of fibrinogen).
R3. Fig. 5, reproduced below, shows secretion of expressed
fibrinogen chains.
R4. Fig. 5A shows “the immunoprecipitable proteins in the
incubation medium were separated under reducing conditions.” Lane 8
shows expressed protein secreted into the medium from COS-a,P,y cells.
COS a,P,y cells secreted the expressed proteins into the
medium (Fig. 5A). When analyzed under nonreducing
conditions the secreted fibrinogen chains were components of a
high molecular weight disulfide-linked complex, with an
apparent M, of 340,000 which is similar to that of plasma
fibrinogen. This M, 340,000 complex accounts for 99.4% of the
immunoprecipitable protein radioactivity secreted. No free
fibrinogen chains, nor intermediate products of assembly were
detected in the medium (Fig. 5B). A small amount of protein
radioactivity (less than 1 %) was sometimes noted at about 130
kDa and this may be due to leakage from the cell or may be a
degradative product of fibrinogen.
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Id. at 4761.
R5.
Clotting of Recombinant Fibrinogen—To determine whether
secreted recombinant fibrinogen is capable of clotting, the
incubation medium of control (nontransfected) and COS-a,P,y
cells, incubated for 24 h with L-[35S]methionine, was mixed
with human plasma fibrinogen and induced to clot by the
addition of thrombin . . . clots formed in the presence of
radiolabeled media from COS-a,P,y cells . . . had 30 to 45 times
background levels of radioactivity associated with the clot.
Id. at 4762.
R6.
COS cells containing all three fibrinogen chain cDNAs express,
assemble, and secrete the chains in a form which is capable of
forming a thrombin-induced clot.
Id.
REJECTIONS
The rejections are based on one of three different publications —
Matsuyama, Huang, and Roy (1991) — cited for the same teaching of a tissue
culture cell expressing DNA coding for the a, P, and y chains of fibrinogen
and the expression by the cell of recombinant fibrinogen comprising the
three specific chains. The Examiner found the fibrinogen in each
publication was homogenous because each fibrinogen molecule was made
from the same three specific chains, as required by the term “homogenous”
(see Claim Interpretation supra at p.5—6). The Examiner also found more
than 85% of the fibrinogent was intact based on gels showing three discrete
bands (M6, M8, H2—H4, R3, R4). Based on statements that the fibrinogen
was active (M10, H6) and working examples in which activity was
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demonstrated (R5, R6), the Examiner found that the recombinant fibrinogen
was biologically active as recited by claim 15.
Appellants, without providing objective evidence, contend that the
Examiner’s findings about homogeneity, intactness, and biological activity
are erroneous. Specifically, Appellants contend that the Examiner made
“conclusory” statements, remarks (Reply Br. 9, 10, 14), and assumptions (id.
at 9), and complained about the lack of proof (id. at 10, 14, 16 (only
prophetic statements)) and the absence of data in the cited publications (id.
at 12, 14).
Appellants have misconstrued the standard necessary for the
Examiner to establish the claims prima facie anticipated or obvious based on
Matsuyama, Huang, and Roy (1991).
[Even] though product-by-process claims are limited by and
defined by the process, determination of patentability is based
on the product itself. The patentability of a product does not
depend on its method of production. If the product in the
product-by-process claim is the same as or obvious from a
product of the prior art, the claim is unpatentable even though
the prior product was made by a different process. MPEP §
2113 (8th ed., Rev. 2, May 2004) (quoting In re Thorpe, 111
F.2d at 698).
SmithKline Beecham Corp., 439 F.3d at 1317. The PTO has the initial
burden of providing a rationale to show that the product described by the
prior art is the same product which is claimed. In re Marosi, 710 F.2d 799,
802 (Fed. Cir. 1983).
As held in In re Best, 562 F.2d 1252, 1255 (CCPA 1977):
Where, as here, the claimed and prior art products are identical
or substantially identical, or are produced by identical or
substantially identical processes, the PTO can require an
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applicant to prove that the prior art products do not necessarily
or inherently possess the characteristics of his claimed product.
Whether the rejection is based on “inherency” under 35 U.S.C.
§ 102, on “prima facie obviousness” under 35 U.S.C. § 103,
jointly or alternatively, the burden of proof is the same, and its
fairness is evidenced by the PTO’s inability to manufacture
products or to obtain and compare prior art products.
Once “the PTO shows sound basis for believing that the products of the
applicant and the prior art are the same, the applicant has the burden of
showing that they are not.” In re Spada, 911 F.2d 705, 708 (Fed. Cir. 1990).
Thus, upon establishing a prima facie case, the burden shifts to Appellants
“to prove that the prior art products do not necessarily or inherently possess
the characteristics of [their] claimed product.” In re Fitzgerald, 619 F.2d 67,
70 (CCPA 1980); Best, 562 F.2d at 1255.
The Examiner cited specific disclosure in each of Matsuyama (Final
Act. 3—4, 5), Huang (id. at 10-11, 13), and Roy (1991) (id. at 16, 19) as
factual evidence the disclosed recombinant fibrinogen anticipated or
rendered obvious the recombinant fibrinogen of claim 15. The findings are
summarized above in the “Findings of Fact.” Appellants’ contentions that
the Examiner has made conclusory statements misapprehends the
Examiner’s findings and burden necessary to have made the prima facie
rejection.
First, the Examiner cited facts in each publication (M6, H3, R3) that
showed the same three chains present in all fibrinogen molecules produced
by the cell culture system constituting homogenous fibrinogen because each
molecule was made of the same a, P, and y chains.
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Secondly, based on this evidence as well as prophetic statements and
actual working examples, the Examiner reasonably inferred that the
molecules were biologically active, namely, fibrinogen that polymerizes into
fibrin in the presence of thrombin (see Claim Interpretation supra at p. 6).
The Examiner’s inference is reasonable because in each publication such
activity is asserted (M10, H5, H6, R5 (activity is demonstrated in working
example)) and a fully reconstituted fibrinogen is made. Thus, the Examiner
had adequate factual basis to shift the burden to Appellants to prove that the
fibrinogen was either not homogenous or not biologically active. Appellants
did not provide adequate rebuttal arguments or objective evidence to prove
that the Examiner erred.
Homogenous
Appellants contend that neither Matsuyama nor Roy (1991) describes
a “homogenous” fibrinogen preparation. Reply Br. 7.
Appellants state that “Matsuyama does not teach or suggest a
homogeneous fibrinogen preparation because Matsuyama employs mixed
and combined genes.” Reply Br. 8. Appellants state that Matsuyama
“combines an expression vector having a gene encoding an alpha chain and
a gamma chain and an expression vector having a gene encoding a beta
chain and a gamma chain at an equal amount.” Id. Appellants also state that
“Matsuyama teaches that the number of a gamma chain gene is an equal
amount or more relative to a total number of an alpha chain gene and a beta
chain gene,” making it “reasonable to expect that Matsuyama's method
produces excess gamma chain products in the final fibrinogen preparation.”
Id.
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Matsuyama used only one a, one P, and one y chain. M2.
Accordingly, any fibrinogen made from the three chains would be
“homogenous” as that word is properly interpreted (see Claim Interpretation
supra at p. 5—6). Matsuyama shows that the fibrinogen secreted into the
culture medium is made of the same three fibrinogen chains. M4—M8.
There is no discussion in Matsuyama that excess y chain is present in the
reconstituted fibrinogen. Appellants have not guided us to factual grounds
upon which this speculation is based. Furthermore, Matsuyama does not
require an excess of y chain. M3. Thus, even were excess y chain a
concern, not all embodiments described by Matsuyama require an excess.
Id.
Appellants also contend that Roy (1991) does not describe a
homogenous fibrinogen preparation. Reply Br. 9. As evidence, Appellants
point to Fig. 4 of Roy (1991). This argument is not persuasive. Fig. 4
shows fibrinogen-related proteins in cell lysates from transfected COS-a,P,y
cells. R2. However, Roy (1991) also collected fibrinogen secreted into
incubation medium. R3, R4. Roy (1991) teaches that the secreted
fibrinogen molecular weight “340,000 complex [that] accounts for 99.4% of
the immunoprecipitable protein radioactivity secreted. No free fibrinogen
chains, nor intermediate products of assembly were detected in the
medium.” R4. Thus, the secreted fibrinogen is homogenous because it is
only comprised of three specific chains.
Intact
Appellants contend that fibrinogen described in Matsuyama is not
intact. Reply Br. 9. Appellants contend that Fig. 2 shows “faint bands in
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addition to each of the main alpha, beta and gamma bands in Fig. 2,
suggesting a number of chain lengths for each of chain.” Id. at 13.
Matsuyama shows a Western blot with three discrete bands and
characterizes them as having discrete weights. M6—M8. While Appellants
contend there are “faint bands” in Fig. 2, there is no mention of the bands or
partial protein segments in Matsuyama, nor have Appellants pointed to
“faint bands” in Fig. 2. To the contrary, Matsuyama states there were “three
bands [shown in Fig. 2] . . . coincident with molecular weigh[t]s of the
known respective fibrinogen chains: a chain; 66kDa, P chain; 52kDa, y
chain; 46.5kDa.” M8.
Moreover, even were there faint bands present in Fig. 2, Appellants
have not met their burden to show that such bands constitute more than 15%
of the total amount of protein and less than the “85% of the recombinant
human fibrinogen is in an intact form” as required by claim 15.
In sum, based on the express disclosure in Matsuyama, the Examiner
had reasonable factual basis to insert that “more than 85% of the
recombinant human fibrinogen is in an intact form, as measured by an SDS-
PAGE or Western blotting analysis.” Appellants have not provided
adequate rebuttal arguments or evidence that would dispel this reasonable
fact-based conclusion.
Appellants made the same contention about Huang (Reply Br. 10, 16),
but have similarly failed to address the evidence in Huang of three discrete
polypeptide chains shown on a Western blot is less than 85% intact human
fibrinogen. H2—H4.
Biologically active
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The claims require the recombinant fibrinogen to be “biologically
active.” Biological activity is defined in the Specification: “fibrinogen
which polymerizes into fibrin in the presence of thrombin.” Spec. 7:18—19
(see Claim Interpretation supra.). Matsuyama and Huang each teach such
activity. M10, H5,H6. Roy (1991) has a working example demonstrating
this activity. R5, R6.
Because the fibrinogen of Matsuyama and Huang is made up of all
three chains present in native fibrinogen, the Examiner had a reasonable
basis to conclude that it possessed the stated activity.
Appellants improperly put the burden on the Examiner to prove that
the fibrinogen of each of Matsuyama and Huang possesses the recited
activity. Reply Br. 10, 14, 16, and 17. The Examiner does not have the
burden to prove it; the Examiner must have a reasonable factual basis to
make the assertion. Marosi, 710 F.2d at 802; Spada, 911 F.2d at 708;
Fitzgerald, 619 F.2d at 70. The Examiner met this burden at least based on
the statements in Matsuyama and Huang that the recombinant fibrinogens
were biologically active and contained all three chains present in the native
form, thus shifting the burden to Appellants to prove that the fibrinogens
lacked biological activity. This burden was not met.
Do process steps impart distinct structural characteristics?
Appellants contend that the claimed process steps impart distinct
structural characteristics, such as the absence of cis-acting sites. Reply Br.
6, 14. Appellants contend such characteristics include the recited
“homogenous,” “intact form,” and “biological activity” (id. at 14), but a
preponderance of the evidence as discussed above, supports the Examiner’s
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conclusion that such features are characteristics of the cited Matsuyama,
Huang, and Roy (1991) publications.
Appellants further contend that the plant glycosyl groups present in
Huang structurally distinguish their fibrinogen from the fibrinogen of the
claims. Reply Br. 10.
Appellants have not properly interpreted the breadth of the claim. The
claim recites “culturing a cell” without specifying the type of cell (see Claim
Interpretation supra at p. 6—7). Huang introduced its plasmids into rice
callus (HI) which comprises rice cells. The claim does not exclude rice
cells from its scope. Consequently, the claimed fibrinogen could be
produced as in the Huang publication and therefore would be
indistinguishable from it.
SUMMARY
For the forgoing reasons, we affirm the rejection of claim 15 as
anticipated and obvious as set forth in Grounds of Rejections 1—7. Claims
18, 27, 29, and 38^11 fall with claim 15. 37 C.F.R. § 41.37(c)(l)(iv).
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv).
AFFIRMED
19