Ex Parte FitzGerald et al

Patent Trial and Appeal Board

Jul 26, 2016

12433737 (P.T.A.B. Jul. 26, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/433,737 0413012009 David J. FitzGerald
45115 7590 07/27/2016
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
8THFLOOR
SAN FRANCISCO, CA 94111
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.
77867-767314 (317200US) 9677
EXAMINER
NATARAJAN, MEERA
ART UNIT PAPER NUMBER
1643
MAILDATE DELIVERY MODE
07/27/2016 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)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DAVID J. FITZGERALD, IRA PAST AN,
ELIZABETH MANSFIELD, and ROBERT KREITMAN 1
Appeal2014-001858
Application 12/433,737
Technology Center 1600
Before MELANIE L. McCOLLUM, JACQUELINE T. HARLOW, and
RICHARD J. SMITH, Administrative Patent Judges.
SMITH, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving a claims to a
recombinant immunoconjugate. We have jurisdiction under 35 U.S.C.
§ 6(b ).
We affirm.
1 According to Appellants, the real party in interest is The Government of
the United States, as represented by the Secretary of the Department of
Health and Human Services. (Br. 3.)
Appeal2014-001858
Application 12/433,737
STATEMENT OF THE CASE
Background
"The present invention provides recombinant antibodies and
immunoconjugates that are highly specific for CD22. 2 An exemplary
molecule employed a Pseudomonas exotoxin (PE) genetically fused to an
anti-CD223 disulfide stabilized antibody, preferably a Fv (dsFV) fragment."
(Spec. 6,11.15-18.)
Claims on Appeal
Claims 1, 3, 4, and 30 are on appeal. 4 (Claims Appendix, Br. 14--15.)
Claim 1 is illustrative and reads as follows:
1. A recombinant immunoconjugate, comprising a Pseudomonas
exotoxin (PE) toxin covalently linked to a recombinant disulfide-stabilized
Fv (dsFv) anti-CD22 antibody, wherein:
the anti-CD22 antibody comprises a variable heavy (VH) chain that
has at least 95% identity to SEQ ID N0:2, comprises the three CDRs of
SEQ ID N0:2, and has a cysteine at position 44; and a variable light chain
(VL) that has at least 95% identity to SEQ ID N0:4, comprises the three
CD Rs of SEQ ID N0:4, and has a cysteine at amino acid position 100; and
the recombinant immunoconjugate retains at least 90% of the binding
affinity of RFB4 IgG5 and is at least 2 to 7-fold more cytotoxic than a
recombinant immunoconjugate comprising the toxin covalently linked to a
recombinant single chain Fv (scFv) anti-CD22 antibody where the scFv has
a VH chain comprising the amino acid sequence of SEQ ID N0:2 and a VL
chain comprising the amino acid sequence set forth in SEQ ID N0:4.
2 "CD22" is an antigen that "is expressed on the surface of many types of
malignant B cells." (Spec. 1, 27-28.)
3 The term "anti-CD22" in reference to an antibody "includes reference to an
antibody which is generated to CD22." (Spec. 15, 11. 5-7.)
4 Claims 8-11, 13-15, and 18 are withdrawn as being drawn to non-elected
inventions. Office Action dated March 2, 2012.
5 "RFB4 IgG is an anti-CD22 monoclonal antibody." (Spec. 2, 1. 3.)
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Appeal2014-001858
Application 12/433,737
Examiner's Rejection
Claims 1, 3, 4, and 30 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over Ghetie, 6 Shen,7 Reiter '94,8 Orlandi,9 Robinson, 10 Ward, 11
and Reiter '96. 12 (Ans. 2.)
Appellants argue claims 1, 3, 4, and 30 as a group, and we therefore
limit our discussion to claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
FINDINGS OF FACT
We adopt as our own the Examiner's findings and analysis concerning
the scope and content of the prior art. The following findings are included
for emphasis and reference convenience.
6 Ghetie et al., Antitumor Activity of Fab' and IgG-anti-CD22 Immunotoxins
in Disseminated Human B Lymphoma Grown in Mice with Severe Combined
Immunodeficiency Disease: Effect on Tumor Cells in Extranodal Sites,
CANCER RESEARCH 51, 587 6-80 (1991) ("Ghetie").
7 Shen et al., Evaluation of Four CD22 Antibodies as Ricin A Chain-
Conatining Immunotoxins for the In Vivo Therapy of Human B-Cell
Leukemias and Lymphomas, INT. J. CANCER 42, 792-97 (1988) ("Shen").
8 Reiter et al., Stabilization of the Fv Fragments in Recombinant
Immunotoxins by Disulfide Bonds Engineered into Conserved Framework
Regions, BIOCHEMISTRY 33, 5451-59 (1994) ("Reiter '94").
9 Orlandi et al., Cloning immunoglobulin variable domains for expression by
the polymerase chain reaction, PROC. NATL. ACAD. SCI. USA 86, 3833-37
(1989) ("Orlandi").
10 Robinson et al., US 5,618,920, issued Apr. 8, 1997 ("Robinson").
11 Ward et al., Binding activities of a repertoire of single immunoglobulin
variable domains secreted from Escherichia coli, NATURE 341, 544--46
(1989) ("Ward").
12 Reiter et al., Antibody Engineering of Recombinant Fv Immunotoxins for
Improved Targeting of Cancer: Disulfide-stabilized Fv Immunotoxins,
CLINICAL CANCER RESEARCH 2, 245-52 (1996) ("Reiter '96").
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Appeal2014-001858
Application 12/433,737
FF 1. The Examiner finds that Ghetie teaches immunotoxins
comprising the RFB4 anti-CD22 antibody conjugated to the toxin ricin A, an
immunoconjugate reported as having "significant antitumor effects." (Ans.
3; Ghetie 5880, left col.)
FF 2. The Examiner finds that Shen teaches the hybridoma that
produces the RFB4 antibody, and that "the superior cytotoxic effect [of the
RFB4 antibody] can be attributed, in part, to higher binding affinity." (Ans.
3--4; Shen 792, 795, right col.)
FF 3. The Examiner finds that Reiter '94 teaches "recombinant
immunotoxins comprising disulfide stabilization with a cysteine at position
44 in the VH and a cysteine at position 100 in the VL" and that "[t]he
antibody is conjugated to a toxin of PE38." (Ans. 4; Reiter '94 5453.)
FF 4. Reiter '94 teaches that "[t]he disulfide-linked toxin is 2-10 fold
more cytotoxic than the scFv-immunotoxin ... depending upon which cell
line was tested" and that "[t]his increased activity could be due to the
enhanced stability of the disulfide-stabilized immunotoxin, which enables
longer exposure time to the cells or better binding of the dsFv-
immunotoxin." (Reiter '94 5456, right col.-5457, left col.)
FF 5. Reiter '94 teaches that "[b ]ecause immunotoxins composed of
disulfide-linked Fv's have cytotoxic activity equal to or better than scFv's
containing a peptide linker, they can be produced more easily than scFv-
immunotoxins, and they are more stable, [and] dsFv-immunotoxins may be
more useful and versatile than scFv-immunotoxins." (Reiter '94 5458, right
col.)
FF 6. Reiter '96 teaches that
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Appeal2014-001858
Application 12/433,737
some [ scFvs] show a reduced binding affinity when compared to
whole antibody ... The reason for the reduced affinity can be
due to interference of the peptide linker with antigen binding or
because the linker distorts or does not sufficiently stabilize the
Fv structure. []To overcome these problems ... [ o ]ur choice was
to introduce disulfide bonds between the two domains to mimic
the whole antibody molecule which is stabilized with disulfide
bonds between heavy and light chains.
(Reiter '96 246, right col.)
FF 7. Reiter '96 teaches the relative cytotoxicities of four dsFv
immunoconjugates and their scFv counterparts, and binding affinities of the
immunoconjugates in comparison to the starting IgG antibodies, and that an
Anti-Tac dsFv immunoconjugate construct had a binding affinity that was
about the same as the parent IgG antibody and cytotoxicity that is a little
over 2 fold that of the counterpart scFv. (Reiter '96 250, Table 4; Br. 10.)
Issue
Whether a preponderance of evidence of record supports the
Examiner's conclusion of obviousness under 35 U.S.C. § 103(a).
Analysis
The Examiner concluded that it would have been prima facie obvious
to one of ordinary skill in the art to produce the recombinant
immunoconjugate comprising the anti-CD22 RFB4 antibody conjugated to
PE by using the RFB4 antibody and hybridoma taught by Ghetie and Shen,
and obtaining the DNA and protein sequence of the VH and VL chains from
the RFB4 hybridoma, using the methods taught by Orlandi, Robinson, and
Ward, to produce a disulfide stabilized anti-CD22 antibody conjugate of
RFB4 which retains at least 90% affinity and increased cytotoxicity as
taught by Reiter '94 and Reiter '96. (Ans. 6.) Furthermore, according to the
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Application 12/433,737
Examiner, one of ordinary skill in the art would have been motivated to do
so, and have had a reasonable expectation of success, because ( 1) Ghetie
teaches that the RFB4 conjugates inhibited protein synthesis and extended
the mean survival time in mice with tumors, and (2) Reiter '94 and Reiter
'96 teach a general method of stabilizing Fv' s with increased cytotoxicity by
insertion of cysteine residues in the conserved framework residues. (Id. at
6-7.)
We find that the Examiner has satisfied the burden of showing "some
articulated reasoning with some rational underpinning to support the legal
conclusion of obviousness." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,
418 (2007). Moreover, the Examiner has established a prima facie case of
obviousness and, as discussed below, Appellants have not overcome that
prima facie case.
Reasonable Expectation of Success
Appellants argue that "[t]he rejection provides no proper evidence
that, prior to the invention, one of skill would have reasonably expected that
the properties of an RFB4 dsFV [immunoconjugate] were predictable." (Br.
9.) Furthermore, according to Appellants, "one of skill would not be able to
reasonably predict the cytotoxicity, relative to the counterpart scFv; and
binding properties, relative to the parent IgG, of an immunoconjugate." (Id.)
Appellants support this argument by reference to a statement in Reiter '96
(sentence quoted here in full) that "[t]he dsFvs are a new class of molecules
and as such it is currently impossible to predict the properties of a given
dsFv prior to producing it." (Id. at 10; Reiter '96 251.)
We are not persuaded. A reasonable expectation of success does not
refer to the reasonable expectation of predictability, but rather "to the
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likelihood of success in combining references to meet the limitations of the
claimed invention." Intelligent Bio-Systems, Inc. v. Illumina Cambridge
Ltd., 821F.3d1359, 1367 (Fed. Cir. 2016). Here, given the teachings of
Reiter '96 that one of four immunoconjugates had the cytotoxicity and
binding properties of claim 1 (FF 7), the similar teachings of Reiter '94 (FF
3-5), and the teachings of Ghetie and Shen (FF 1, 2), we agree with the
Examiner's finding that a person of ordinary skill in the art would have had
a reasonable expectation of success in combining the references to meet the
limitations of claim 1. (Ans. 6-7.) See also KSR, 550 U.S. at 421 ("A
person of ordinary skill is also a person of ordinary creativity, not an
automaton."); In re Sovish, 769 F.2d 738, 743 (Fed. Cir. 1985) (skill is
presumed on the part of one of ordinary skill in the art).
Moreover, we do not agree that a reasonable expectation of success
requires an expectation that the combination has the specific properties
recited in claim 1. Instead, it merely requires a reasonable expectation that
the combination would provide a successful immunoconjugate. In the
absence of adequate evidence of unexpectedly superior results, the specific
properties achieved are merely inherent properties of the combination.
We are similarly unpersuaded by Appellants' related arguments that
the teachings of Reiter '94 and Reiter '96 reflect unpredictability regarding
the cytotoxicity and binding affinity of the disclosed immunoconjugates.
(Br. 8-10.) However, "obviousness cannot be avoided simply by a showing
of some degree of unpredictability in the art so long as there was a
reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1364 (Fed. Cir. 2007). Here, a reasonably probability of success is
established (see above), and Appellants' contentions regarding
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Application 12/433,737
unpredictability are thus unpersuasive. Moreover, Appellants reference to
the statement in Reiter '96 that it is "currently impossible to predict the
properties of a given dsFv prior to producing it" (emphasis added) is
similarly unpersuasive in overcoming the prima facie case of obviousness.
See In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988) ("Obviousness does
not require absolute predictability of success. Indeed, for many inventions
that seem quite obvious, there is no absolute predictability of success until
the invention is reduced to practice.").
Hindsight
Appellants argue that "[i]n alleging that it was predictable to make
immunoconjugates having the recited properties, the Examiner is engaging
in improper hindsight reconstruction based on Appellants' disclosure." (Br.
11.) We are not persuaded. The issue of predictability is addressed above.
Moreover, rather than using hindsight) the Examiner points to specific
disclosures in the prior mi that describe the limitations of Appellants'
claimed invention. (Ans. 2-12.) \Ne therefore find that the Exmniner's
obviousness conclusion is based on sufficiently articulated reasoning that
overcomes any concerns about hindsight bias. 13 See KSR, 550 U.S. at 418.
Variants within the Scope of Claimed Genus
Appellants argue that "[ o ]ne of skill can make variants having the
structural features set forth in the claims that would reasonably be expected
13 We also note Appellants' argument regarding claim 7 and the Examiner's
alleged acknowledgment about predictability of cytotoxicity and binding
properties. (Br. 11.) However, as Appellants acknowledge, claim 7 is not
before us on appeal. (Id. at 6.) Moreover, on the record that is before us, we
are not persuaded of any error on the part of the Examiner.
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Application 12/433,737
to retain the binding and cytotoxic properties of the construct of claim 7."
(Br. 11.) That is, according to Appellants, the scope of the "claimed genus"
is proper because "as of the effective filing date ... one of skill could
reasonably expect to be able to predictably identify variants with the scope
of the claimed genus based on the teachings in [the] specification taken
together with teachings in the prior art." (Id.) Appellants conclude this line
of argument by stating
Here, the rejection fails to establish that one of skill could not
have reasonably expected to generate variant immunoconjugates
that retain functional properties once an [immunoconjugate] with
superior binding affinity and cytotoxicity becomes known. Thus,
the rejection of the full scope of the claims remains improper,
regardless of whether the species represented by claim 7
demonstrates unexpected results. Therefore, the full scope of the
claims should be deemed allowable.
(Id. at 12.)
We are not persuaded. We understand Appellants argument to
essentially be that if claim 7 is allowable, then claim 1 should allowable.
However, neither claim 7 nor any evidence of unexpected results are before
us on appeal, nor have Appellants provided an adequate explanation as to
how any evidence presented during prosecution is sufficient to demonstrate
unexpected results, particularly with regard to the full scope of claim 1.
Moreover, the establishment of a prima facie case of obviousness, as the
Examiner has done here, shifts the burden of producing contrary evidence or
arguments to Appellants. See In re Best, 562 F.2d 1252, 1254--55 (CCPA
1977); In re Oetiker, 977 F.2d 1443, 1445--46 (Fed. Cir. 1992). Thus, it is
Appellants' burden to produce evidence or arguments as to why the claims
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Application 12/433,737
before us are nonobvious over the art of record. On this record, Appellants
have not persuaded us that claim 1 is nonobvious.
Conclusion of Law
A preponderance of evidence of record supports the Examiner's
conclusion that claim 1 is obvious under 35 U.S.C. § 103(a). Claims 3, 4,
and 30 were not argued separately and fall with claim 1.
SUMMARY
We affirm the rejection of all claims on appeal.
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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