Ex Parte Rosenblum et al

Board of Patent Appeals and Interferences

Oct 23, 2009

10964195 (B.P.A.I. Oct. 23, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte MICHAEL ROSENBLUM and LAURA K. SHAWYER
____________

Appeal 2009-008350
Application 10/964,195
Technology Center 1600
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Decided: October 23, 2009
____________

Before TONI R. SCHEINER, DONALD E. ADAMS, and
DEMETRA J. MILLS, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claim 24. The Examiner
has indicated that pending claims 3-10, 23, and 25 are allowable
(App. Br. 3). We have jurisdiction under 35 U.S.C. § 6(b).

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STATEMENT OF THE CASE
The claims are directed to an antibody-toxin conjugate composition.
Claims 7, 23, and 24 are reproduced below:
7. (Allowed) A composition comprising a conjugate of an antibody
exhibiting binding specificity for an extracellular epitope of c-erbB-2 protein
and a plant derived toxin, wherein said toxin is pharmacologically effective
against neoplastic cells and is selected from the group consisting of gelonin,
full length recombinant gelonin and functional gelonin fragments, wherein
said conjugate is a fusion protein between said antibody and said toxin.

23. (Allowed) The composition of claim 7, wherein the antibody is a
portion of a full length antibody.

24. (Under Appeal) The composition of claim 23, wherein the antibody
portion is an antibody fragment selected from the group consisting of Fab;
F(ab’)2; a CDR; a VL or a VH.

The Examiner relies on the following evidence:
Rudikoff, et al., Single amino acid substitution altering antigen-binding
specificity, 79 Proc. Natl. Acad. Sci. USA 1979-1983 (1982).

MaCallum, et. al., Antibody-antigen Interactions: Contact Analysis and
Binding Site Topography, Journal of Molecular Biology, Vol. 262, 732-745
(1996).

De Pascalis et al.,[hereinafter Pascalis] Grafting of “Abbreviated”
Complementarity-Determining Regions Containing Specificity-Determining
Residues Essential for Ligand Contact to Engineer a Less Immunogenic
Humanized Monoclonal Antibody, The Journal of Immunology, Vol. 320,
415-428 (2002).

Holm et al., Functional mapping and single chain construction of the anti-
cytokeratin 8 monoclonal antibody TS 1, Molecular Immunology, Vol. 44,
1075-1084 (2007).

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Chen et al., Selection and Analysis of an Optimized Anti-VEGF Antibody:
Crystal Structure of an Affinity-matured Fab in Complex with Antigen,
Journal of Molecular Biology, Vol. 293, 865-881 (1999).

Wu et al., Humanization of a Murine Monoclonal Antibody by Simultaneous
Optimization of Framework and CDR Residues Journal of Molecular
Biology, Vol. 294, 151-162 (1999).

Casset et al., A peptide mimetic of an anti-CD4 monoclonal antibody by
rational design, Biochemical and Biophysical Research Communications,
2003, Vol. 307, 198-205 (2003).

Appellants rely on the following evidence:
Michael G. Rosenblum and Laura K. Shawver Declaration, executed June 6
and 18, 2007.

The rejection presented by the Examiner is as follows:
Claim 24 stands rejected under the enablement provision of
35 U.S.C. § 112, first paragraph.
We affirm.

ISSUE

Have Appellants established error in the Examiner’s conclusion that
Appellants’ Specification fails to provide an enabling disclosure
commensurate in scope with the claimed invention?

FINDINGS OF FACT
FF 1. The Examiner finds that the composition of claim 24 encompasses,
inter alia, an antibody portion that is a “Fab, [F](ab’)[2], a CDR, a VL or a
VH (Ans. 4).
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FF 2. The Examiner finds that while Appellants’ Specification provides an
enabling disclosure of “an antibody portion which is a Fab or F(ab’)2
fragment, [it] does not reasonably provide enablement for an antibody
portion which is a CDR, VL or VH” (id.).
FF 3. The Examiner finds that Rudikoff “teaches that the formation of an
intact antigen-binding site generally requires the association of the complete
heavy and light chain variable regions of a given antibody, each of which
consists of three CDRs which provide the majority of the contact residues
for the binding of the antibody to its target epitope” (id.).
FF 4. The Examiner finds that “a ‘CDR’ can be any one of the constant
regions (CH1-3), and the art recognizes that the different CDR domains do
not contribute equally to epitope binding, and that less than a full antibody
paratope results in a dramatically decreased affinity for any given antigen”
(Ans. 5).
FF 5. The Examiner finds that MaCallum, Pascalis, Casset, Vajdos, Holm,
Chen, and Wu teach that the conformation of the “CDRs as well as
framework residues influence binding” (Ans. 5-6).

PRINCIPLES OF LAW
“[T]o be enabling, the specification of a patent must teach those
skilled in the art how to make and use the full scope of the claimed invention
without ‘undue experimentation.’” Genentech, Inc. v. Novo Nordisk, A/S,
108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557,
1561 (Fed. Cir. 1993)).

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ANALYSIS
We adopt the Examiner's reasoning as our own in sustaining the
rejections of record, and we add the following for emphasis only.
Appellants contend that “[m]erely showing differences exist between
what Pascalis, Caseet [sic] and Chen report compared to what Appellant
claims does not indicate that Appellant’s Claim is not enabled” (App. Br. 8;
Reply Br. 3-5). Similarly, Appellants contend that:
The same applies to Holm . . .; that residues from both CDR2
and 3 were involved in binding in Holm does not indicate
unpredictability or support an enablement rejection. . . . The
Examiner also admits that Wu . . . successfully identified
important residues that were sought. Thus, the totality of the
evidence the Examiner cites does not indicate unpredictability,
but rather weighs in favor of enablement.

(App. Br. 8.) We are not persuaded.
Claim 24 reads on an antibody-toxin conjugate composition wherein
the antibody component of the conjugate is a single CDR. Contrary to
Appellants’ contentions, the evidence on this record supports the Examiner’s
conclusion that at the time the invention was made an “antibody portion
which consists of less than the antibody paratope as defined by the three
hypervariable regions of an antibody in the appropriate three dimensional
shape would not be expected to exhibit binding specificity for an
extracellular epitope of c-erbB2” (Ans. 4; FF 3-5).
We are not persuaded by Appellants’ intimation that since the
references do not discuss an antibody directed against c-erbB2 they are not
pertinent to the invention of claim 24. Appellants failed to identify the
unique features or properties of an antibody – c-erbB2 interaction that
exempt this specific interaction from the antibody-antigen interaction
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dynamics taught by the prior art relied upon by the Examiner (see e.g., Ans.
7 (Rudikoff, Pascalis, Casset, Chen, and Holm are cited for “teaching the
complexity of the interaction between an[ ] antibody and an antigen and
therefore the unpredictability of alterations of a known antibody with respect
to retention of antigen-binding.”)).
In addition, we recognize Appellants’ contention that “Figure 9
specifically discloses the functional CDRs . . . of an exemplary antibody.
The Specification also provides a description of CDRs and provides outside
references to the manipulation of functional CDRs” (App. Br. 8 (emphasis
added)). Conspicuous by its absence is a statement from Appellants
regarding a disclosure or teaching in their Specification or the prior art of
record that a person of ordinary skill in the art, at the time the invention was
made, would have expected a single CDR to exhibit “binding specificity for
an extracellular epitope of c-erbB2” (Ans. 4).
We recognize Appellants’ intimation that their disclosure of
Fab or F(ab’)2 fragments is representative and sufficient to support the
full scope of claim 24 (App. Br. 9; Reply Br. 5-6). We are not
persuaded. “[T]o be enabling, the specification of a patent must teach
those skilled in the art how to make and use the full scope of the
claimed invention without ‘undue experimentation.’” Genentech, Inc.
v. Novo Nordisk, A/S, 108 F.3d at 1365 (emphasis added).
The Examiner has established an evidentiary basis to support the
conclusion that CDRs (plural), in addition to their associated framework
regions are responsible for antigen binding specificity (FF 3-5). An intact
antibody, Fab, and F(ab’)2 each contain CDRs (plural) and associated
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framework regions. Therefore, the Examiner has found that Appellants’
Specification provides an enabling disclosure of these reagents.
In contrast, a single CDR, for example, does not have a complete set
of CDRs or associated framework regions. Cf. FF 5 (“CDRs [(plural)] as
well as framework residues influence binding”). Accordingly, based on the
evidence relied upon by the Examiner, the Examiner has found that a single
CDR, for example, would not be expected to exhibit “binding specificity for
an extracellular epitope of c-erbB2” (Ans. 4). We find no error in the
Examiner’s conclusion on this record. For the foregoing reasons, we
disagree with Appellants’ contention that a disclosure of a Fab and/or
F(ab’)2 is sufficient on this record to support a conclusion that a single CDR
would be expected to exhibit binding specificity for an extracellular epitope
of c-erbB2 as required by Appellants’ claim 24.
For the foregoing reasons we are not persuaded by Appellants’
contentions regarding the Rosenblum and Shawver Declaration (App. Br. 10
and Declaration). Appellants have not identified and we do not find a
discussion of the ability of a single CDR to exhibit binding specificity for an
extracellular epitope of c-erbB2 in this Declaration.

CONCLUSION OF LAW
Appellants failed to establish error in the Examiner’s conclusion that
Appellants’ Specification fails to provide an enabling disclosure
commensurate in scope with the claimed invention.
The rejection of claim 24 under the enablement provision of
35 U.S.C. § 112, first paragraph is affirmed.

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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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