Ex Parte Smith et al

Patent Trial and Appeal Board

Sep 28, 2016

13409855 (P.T.A.B. Sep. 28, 2016)

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.
13/409,855 03/01/2012 HENRY J. SMITH JSMIT-007C3 2863
7663 7590 09/28/2016
STETINA BRUNDA GARRED & BRUCKER
75 ENTERPRISE, SUITE 250
ALISO VIEJO, CA 92656
EXAMINER
SCHWADRON, RONALD B
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
09/28/2016 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)
1
UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________________

Ex parte HENRY J. SMITH and JAMES R. SMITH1
____________________

Appeal 2014-004265
Application 13/409,855
Technology Center 1600
____________________

Before FRANCISCO C. PRATS, RICHARD J. SMITH, and
TAWEN CHANG, Administrative Patent Judges.

CHANG, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of treating rheumatoid arthritis by targeted apheresis, which have
been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
“Rheumatoid arthritis patients have altered IgG in which ‘hidden’
regions of the IgG molecule are exposed.” (Spec. at ¶ 5.) The altered IgG
molecule reacts with rheumatoid factor (RF), an IgM autoantibody, which

1 Appellants identify the Real Party in Interest as the inventors, Henry J.
Smith and James R. Smith. (Appeal Br. 3.)
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can “result in the formation of immune complexes that can deposit in joints,
organs and tissues to cause the symptoms of arthritis.” (Id.)
“Apheresis is a process whereby . . . the patient’s blood is passed
through an extracorporeal device that removes the pathogenic substances
that are causing the disease symptoms.” (Id. at ¶ 4.) According to the
Specification, the conventional method of treating rheumatoid arthritis by
apheresis, which “utilizes an immunosorbent device to remove [the] immune
complexes,” “is inefficient[,] removes native IgG along with the complexed
IgG[, and] does not remove the unbound RF autoantibodies which can still
form immune complexes.” (Id. at ¶ 6.) Further according to the
Specification, the invention “teaches a process of targeted apheresis that
selectively removes the immune complexes and RF autoantibodies involved
in the inflammatory response in rheumatoid arthritis.” (Id. at ¶ 8.)
Claims 1, 3, and 5–7 are on appeal. Claim 1 is representative and
reproduced below:
1. A method of treating rheumatoid arthritis by targeted
apheresis, said method comprising the following steps:
a) providing a device containing heat-denatured
immobilized animal IgG that is conjugated to an insoluble support
matrix, the insoluble support matrix consisting of agarose beads,
wherein the immobilized animal IgG is from a donor not having
rheumatoid arthritis and is heat denatured by heating at 60°C for 15
minutes;
b) extra corporeally circulating blood from a rheumatoid
arthritis patient, wherein said blood contains blood plasma having
rheumatoid factor therein;
c) separating the blood plasma from cellular elements of the
extracorporeally circulating blood obtained in step (b) by differential
centrifugation or a membrane filter; and
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d) selectively removing said rheumatoid factor from said blood
plasma obtained in step (c) by pumping the blood plasma through said
device; and
e) mixing the blood plasma lacking rheumatoid factor obtained
in step d) with the cellular elements from which the blood plasma was
separated in step c ), and returning the blood plasma and the cellular
elements to said patient.
The Examiner rejects claims 1, 3, and 5–7 under 35 U.S.C. § 103(a) as
being unpatentable over Fu,2 Sawada,3 Bernstein,4 Porath,5 and Hallgren.6
(Ans. 2.)
DISCUSSION
Issue
In rejecting the claims, the Examiner finds that Fu teaches “the use of
heat denatured/aggregated immobilized human IgG attached to agar gel to
remove RF from plasma of RA patients.” (Ans. 2.) The Examiner finds that
in Fu the human IgG is not obtained from RA patients. (Id.) While the
Examiner finds that Fu does not specifically teach using agarose beads as the
support matrix to which IgG is conjugated, the Examiner finds that
Bernstein discloses using “cyanogen bromide activated agarose beads to
attach a desired reagent to said beads . . . in targeted apheresis” and further
finds that Porath teaches “the superior properties of agarose over agar gel.”
(Id. at 2–3.) Likewise, while the Examiner finds that in Fu’s method the IgG

2 Chun-Xiao Fu et al., Heat-Aggregated Human IgG as Immunosorbent for
Rheumatoid Arthritis, 16 ARTIFICIAL CELLS, BLOOD SUBSTITUTES, AND
IMMOBILIZATION BIOTECHNOLOGY 367 (1998).
3 Sawada et al., US 6,713,252 B2, issued Mar. 30, 2004.
4 Bernstein et al., US 4,863,611, issued Sep. 5, 1989.
5 Porath et al., US 3,959,251, issued May 25, 1976.
6 Hällgren et al., US 4,153,417, issued May 8, 1979.
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is heated at 63 ºC for 20 minutes rather than at 60 ºC for 15 minutes as
recited in the claims, the Examiner finds that Hällgren discloses that “IgG
that is heat denatured/aggregated at 60 degree[s] C can also effectively bind
RF,” and “routine experimentation would have yielded the particular time to
use at said temperature.” (Id.) The Examiner further cites Sawada for its
disclosure of the general procedure for apheresis. (Id. at 2.) The Examiner
concludes that a skilled artisan would have had reason to combine or modify
the prior art to arrive at the claimed invention because
the particular steps used by Sawada et al. are art recognized
procedures for apheresis[;] Fu et al. teach the use of heat denatured
immobilized human IgG attached to agarose beads to remove RF from
plasma of RA patients[;] H[ä]llgren et al. disclose that IgG that is heat
denatured at 60 degree[s] C can also effectively bind RF[;] Porath et
al. teach the superior properties of agarose over agar gel[;] and
Bernstein et al. disclose use of cyanogen bromide activated agarose
beads to attach a desired reagent to said beads wherein the beads are
used in targeted apheresis.
(Id. at 3–4.)
Appellants contend that the prior art teaches “heat-aggregated” IgG,
rather than “heat-denatured” IgG, as the immunosorbent and thus does not
disclose the limitation of “wherein the . . . IgG . . . is heat denatured.”
(Appeal Br. 6–7.) Appellants contend that the claims are not obvious
because Hällgren discloses reacting IgG with RF after removing monomeric
IgG, whereas the Appellants’ invention omits the step of monomer removal
but still retain the function of allowing IgG to react with RF. (Id. at 10.)
Appellants contend that Hällgren and Fu teach away from the invention by
“advocating the use of aggregated IgG and rejecting the use of monomeric
(unaggregated) IgG.” (Id.) Appellants also contend that there is no
teaching, suggestion, or motivation to combine the elements found in the
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cited prior art references. (Id. at 11–12.) Finally, Appellants argue that the
claims are not obvious because there are objective indicia of nonobviousness
including teaching away, industry skepticism, and fulfillment of a long-felt
need. (Id. at 12.)
Appellants do not separately argue the claims. (Id. at 5.)
Accordingly, we limit our analysis to claim 1. The issue with respect to this
rejection is thus (1) whether the evidence of record supports the Examiner’s
conclusion that claim 1 is obvious over the combination of Fu, Sawada,
Bernstein, Porath, and Hallgren, and, if so, (2) whether Appellants have
submitted evidence of objective indicia of non-obviousness that, when
weighed with the evidence of obviousness, render claim 1 non-obvious.
Findings of Fact
1. Fu teaches “immobilizing heat-aggregated human IgG . . . on
. . . agar gel” “[i]n order to selectively remove pathogenic rheumatoid factors
(RF) from plasma of rheumatoid arthritis (RA) patients.” (Fu Abstract.) Fu
further suggests the use of the disclosed immunosorbent in hemoperfusion.
(Id. at 374.)
2. Fu discloses obtaining gamma globulins from The Academy of
Medicine of China and teaches heating IgG monomers “at 63 ºC at 20
minutes to yield soluble aggregates.” (Id. at 368.)
3. Fu teaches that
It was previously established that heating gamma globulin at 62 to 65
ºC a strong reaction with rheumatoid serum occurred. The increased
reactivity was due to aggregates of gamma globulin . . . . Henney and
Stanworth suggested that the heating processes responsible for
effecting the reactivity of human IgG with RF brought about the
rupture of inter-chain disulfide bonds in Fc portion of the molecules
which took part in intermolecular bridging, leading to aggregate
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formation and unmasking of new determinant groups which was
unavailable in native IgG molecules . . . .
(Id. at 369, 373.)
4. Sawada teaches that “[a]pheresis has recently been employed
for the purpose of treating various diseases.” (Sawada 1:18–19.)
5. Sawada generally teaches an apheresis apparatus and method
whereby blood is drawn from the vein of a patient and passed through the
column containing an adsorptive carrier before being returned to the patient.
(Id. at 5:7–63, Figs. 1, 2; see also id. at 4:31–35 (plasma separated from
other blood components before being contacted with adsorptive carrier and
treated plasma or blood returned to the patient), claims 3, 10.)
6. Bernstein teaches generally
[a]n apparatus for removing material from a biological solution
consisting of a reactor chamber having an inlet and an outlet, a
bioactive compound immobilized on particular supports within the
reactor, means for retaining the particular supports within the reactor,
means for recirculating the solution and the supports at a high flow
rate within the reactor, and means for agitating or dispersing the
recirculating solution-support mixture throughout the reactor chamber
so as to prevent packing of the supports while not subjecting the
solution to excessive or damaging forces.
(Bernstein Abstract; see also id. at 2:19–27, 2:34–41, 3:58–65, 5:5–8
(bioactive compound useful in invention include antibodies), claim 10.)
7. Bernstein teaches using crosslinked agarose as the porous
particular supports on which bioactive compounds are immobilized and
further teaches using spherical particles. (See, e.g., id. at 2:62–65
(crosslinked agarose particles), 3:17–20 (spherical particles), 3:26–30
(crosslinked agarose particles), 3:35–37 (porous spherical support); 4:21–24
(suggested materials for support include agarose among others, preferably in
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the form of porous spheres), 8:9–24 (example using 8% agarose porous
spherical particles), claims 5, 14 (crosslinked agarose beads as particulate
supports).)
8. In particular, Bernstein teaches that, for the porous particular
supports,
[t]he preferred material is agarose, a naturally occurring hydrophilic
polymer. A beaded gel with a porosity of from 90-96% is formed by
varying the percentage of agarose. The molecular weight of the gel
ranges from 0.5 million for 10% agarose to 20 million for 4% agarose.
Particle diameters ranging from 20 to 200 microns are commercially
available.
(Id. at 4:37–43.)
9. Bernstein teaches a preferred method for binding an exemplary
bioactive compound (heparinase) to agarose beads by cyanogen bromide
coupling. (Id. at 5:20–22.)
10. Porath relates to “agar products for separation purposes.”
(Porath Abstract.) Porath states that “[t]he same properties which
characterize the ideal molecular sieve are also desirable when the gel is to be
used as a source material for preparing . . . adsorption agents and for
preparing enzymes chemically bonded to a gel.” (Id. at 2:6–13.)
11. Porath teaches that
[t]he ideal molecular sieve ought to fill certain demands. For
example, it ought not contain charged groups and it should be
insoluble and chemically resistant. Common agar is markedly
deficient in these respects.

It has now been discovered that agar contains a fraction, agarose,
which has a significantly lower content of charged groups than the
source material. Therefore, this fraction has found use as a molecular
sieve and has better properties than agar. Agarose has also replaced
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agar in other fields where it is essential for the gel not to contain large
amounts of charged groups chemically bonded in the gel substance.

An additionally improved product phase is obtained according to the
patent specification No. 3,507,851 which describes cross-linking
agarose with epichlorohydrin. In this way, cross-linked agarose is less
soluble than the natural agarose and is also more resistant to alkali.
(Id. at 1:47–65.)
12. Porath teaches that
[a]gar also has ionogenic groups. However agarose, one of the
polysaccharide components in agar, has a lower concentration of
ionogenic groups and is therefore more suitable as a matrix for
polymer-bonded proteins.
(Id. at 8:60–64.)
13. Hällgren discloses a method of indicating the presence of RF in
a sample by reacting the sample with labeled, soluble, aggregated
immunoglobulin to form aggregates between RF and the aggregated, labeled
immunoglobulin. (Hällgren Abstract.)
14. Hällgren teaches preparing aggregated human IgG by heating
2% human IgG solution for 20 minutes at 60 ºC. (Id. at 2:42–46; see also id.
at 1:51–52.)
15. Hällgren teaches that reacting serum from rheumatoid arthritis
patients with labeled aggregated human IgG result in measurement values
indicating presence of RF. (Id. at 3:6–4:10.)
Analysis
We find that the evidence of record supports the Examiner’s
conclusion that claim 1 is obvious in light of the prior art.
As evidenced by Sawada, the general procedure of apheresis is known
in the art. (FF4, FF5, Spec. ¶ 23 (“The overall procedure for targeted
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apheresis is the same as that used in conventional apheresis.”.) Fu
specifically teaches selective removal of RF from the plasma of rheumatoid
arthritis patients using immobilized heat-treated human IgG and suggests the
use of this method in hemoperfusion. (FF1.) With respect to the heat-
treated human IgG, Fu discloses obtaining gamma globulins from The
Academy of Medicine of China and heating the IgG monomers “at 63 ºC at
20 minutes” (FF2). Likewise, Hällgren teaches that aggregated human IgG
prepared by heating IgG solution for 20 minutes at 60 ºC are able to bind to
RF. (FF13–FF15.)
Fu teaches immobilizing IgG on agar gel rather than on agarose beads
as recited in claim 1. (FF1.) However, Bernstein teaches immobilizing
bioactive compounds (e.g., antibodies) on crosslinked agarose beads for
purposes of removing material from a biological solution. (FF6–FF9.) In
addition, Porath teaches that agarose is more suitable than agar as a matrix
for polymer-bonded proteins. (FF10–FF12.)
We find that a skilled artisan would have found it obvious to combine
the cited art, because Fu suggests using apheresis to treat rheumatoid
arthritis by removing RF from patients’ blood, and Hällgren relates to
bioactive compounds that can bind to RF, while Sawada, Bernstein, and
Porath all relate to methods or devices directly or reasonably pertinent to
apheresis. Furthermore, given the teaching in Bernstein of using crosslinked
agarose beads as support for immobilizing bioactive compounds, and given
Porath’s disclosure of the superiority of agarose to agar in that regard, a
skilled artisan would have had reason and reasonable expectation of success
in replacing agar gel with agarose beads as support in Fu’s method.
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Appellants contend that the prior art teaches “heat-aggregated” IgG,
rather than “heat-denatured” IgG, as the immunosorbent and thus does not
disclose the limitation of “wherein the . . . IgG . . . is heat denatured.”
(Appeal Br. 6–7.) We are not convinced because both Fu and Hällgren teach
heating the human IgG under substantially similar conditions as those
claimed. (FF2 (Fu, 63 ºC for 20 minutes), FF14 (Hällgren, 60 ºC for 20
minutes), claim 1 (60 ºC for 15 minutes).) Both Fu and Hällgren also
disclose that the treated IgG binds RF. Accordingly, the Examiner has
established a reasonable basis that Fu and Hällgren disclosed heat-denatured
IgG, and Appellants have provided no evidence that the IgG disclosed in Fu
and Hällgren are not denatured.7 “Where . . . the claimed and prior art
products are identical or substantially identical . . . the PTO can require an
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.” In re Best, 562 F.2d
1252, 1255 (CCPA 1977) (citations and footnote omitted).
Appellants contend that the claims are not obvious because Hällgren
discloses reacting IgG with RF after removing monomeric IgG, whereas the

7 Indeed, Fu cites art suggesting that heating may effectuate the reactivity of
human IgG with RF by rupturing molecular bonds in the antibody (i.e.,
denaturing the antibody), leading to “unmasking of new determinant groups
which was unavailable in native IgG molecules” as well as aggregate
formation. (FF3.)

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Appellants’ invention omits the step of monomer removal but still retain the
function of allowing IgG to react with RF. (Appeal Br. at 10.) Appellants
also contend that Hällgren and Fu teaches away from the invention by
“advocating the use of aggregated IgG and rejecting the use of monomeric
(unaggregated) IgG.” (Id.) These arguments are not persuasive. Claim 1
uses the open transitional phrase “comprising.” Thus, it does not preclude
additional steps such as removal of monomers or further purification.
Neither does the claim require the use of monomeric rather than aggregated
IgG.
Appellants further contend that there is no teaching, suggestion, or
motivation to combine the elements found in the cited prior art references.
(Id. at 11–12.) We are not persuaded for the reasons already discussed
above.
Finally, Appellants contend that the claims are not obvious because
there are objective indicia of nonobviousness including teaching away,
industry skepticism, and fulfillment of a long-felt need. (Id. at 12.) As
discussed above, we find that the prior art does not teach away from the
claimed invention. Neither are we convinced by Appellants’ contentions
regarding industry skepticism or fulfillment of a long-felt need. Appellants
support their contentions through attorney argument. However,
“[a]ttorneys’ argument is no substitute for evidence.” Johnston v. IVAC
Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989).
Accordingly, we affirm the Examiner’s rejection of claim 1. Claims 3
and 5–7 fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv).
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SUMMARY
For the reasons above, we affirm the Examiner’s decision rejecting
claims 1, 3, and 5–7.
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