Ex Parte Rodeck et al

Patent Trial and Appeal Board

Sep 1, 2016

12633102 (P.T.A.B. Sep. 1, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/633,102 12/08/2009
60612 7590 09/02/2016
MCCARTER & ENGLISH, LLP WILMINGTON
Attn: Patent Department
Renaissance Centre
405 N. King Street, 8th Floor
WILMINGTON, DE 19801
Ulrich Rodeck
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.
119613-00002 5071
EXAMINER
HUYNH, PHUONG N
ART UNIT PAPER NUMBER
1644
MAILDATE DELIVERY MODE
09/02/2016 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 ULRICH RODECK and JOHN WILLIAMS
Appeal2014-006485
Application 12/633,102
Technology Center 1600
Before ERIC B. GRIMES, JEFFREY N. FRED MAN, and
RYAN H. FLAX, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134 involving claims to a
dissociable, bivalent masking ligand. The Examiner rejected the claims as
failing to comply with the written description requirement. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.
1 Appellants identify the Real Party in Interest as Tegopharm Corporation
(see App. Br. 2).
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Application 12/633, 102
Statement of the Case
Background
"Adverse events caused by biologically active compounds
administered with either therapeutic or diagnostic intent remain a significant
problem . . . . Therefore, it is highly desirable to direct pharmacologically
active compounds specifically to disease sites and to reduce reactivity of
these compounds with normal tissue" (Spec. 1 :23-36).
"The invention features masking ligands for reversibly concealing the
antigen-binding site of an antibody. In general, the masking ligands
comprise two copies of the epitope of the antigen to which the antibody
specifically binds and a cleavable polypeptide linker joined to each copy of
the epitope" (Spec. 2:16-19).
The Claims
Claims 1--4, 6, 7, 18-20, 24 and 26-28 are on appeal. 2 Claim 1 is
representative and reads as follows:
1. A dissociable, bivalent masking ligand for
reversibly concealing the antigen-binding sites of an
antibody having a cognate epitope having a known
sequence, comprising two copies of the cognate
epitope to which the antibody specifically binds
joined by a cleavable polypeptide linker, wherein the
masking ligand is capable of forming a non-covalent
complex by binding the antibody, wherein cleavage of
2 Claim 25 was allowed and claim 5 stands objected to (Final Act. 11-12).
Claims 9-17 and 21-23 were withdrawn (Final Act. 2). The Examiner also
indicated that claim 20 was objected to (Final Act. 12), but claim 20 is
included in the rejection on appeal and is specifically addressed (Ans. 2, 12).
The statement that it is objected to, rather than rejected, appears to be in
error.
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the linker reduces the valency of the mask and reduces
the affinity of binding between the masking ligand
and the antibody.
The issue
The Examiner rejected claims 1--4, 6, 7, 18-20, 24, and 26-28 under
35 U.S.C. § 112, first paragraph as failing to comply with the written
description requirement (Final Act. 3-7).
Does the evidence of record support the Examiner's conclusion that
the Specification fails to provide descriptive support for possession of the
claimed genus of "dissociable, bivalent masking ligand for reversibly
concealing the antigen-binding sites of an antibody ... joined by a cleavable
polypeptide linker" where "cleavage of the linker reduces the valency of the
mask and reduces the affinity of binding between the masking ligand and the
antibody," as recited by claim 1?
Findings of Fact
1. The Specification teaches:
The methods and compositions described herein facilitate
molecular interactions between therapeutically active antibodies
or other therapeutic protein molecules and targeted cells at
disease sites, while avoiding activity in normal tissues. To
accomplish this, the therapeutic molecules are "inactivated" by
reversibly concealing their epitope/ligand binding sites and,
thus, blocking antigen recognition and engagement in normal
tissues. However, molecular events that occur predominantly at
disease or target sites are exploited to restore pharmacological
activity to the therapeutic antibody or protein, which then
become free to bind their cognate epitope or ligand.
(Spec. 5:29 to 6:5).
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2. The Specification teaches the "masking ligands can be used on
any type of antibody, and any isotype and idiotype of antibody" (Spec. 8: 1-
2).
3. The Specification teaches:
The epitope can be chemically modified, and the chemical
modifications can decrease the affinity of the antibody for the
epitope in the mask. For polypeptide epitopes, the epitope can
comprise one or more mutations, and the mutations can
decrease or otherwise weaken the affinity of the antibody for
the epitope in the mask, and in tum facilitate dissociation.
(Spec. 8:31-35).
4. The Specification teaches:
However, a generic method can also be applied to reversibly
conceal antigen binding sites on any monoclonal antibody, even
when the epitope structure is unknown. In some aspects of this
method, ligands can be constructed which recognize the
framework regions that are common to all antibodies of a
particular isotype .... A multivalent, cleavable masking ligand
that binds to these shared framework regions and conceals the
epitope binding site of the mAb is used to form a tetrameric (or
larger) complex in which the CDRs of one mAb are juxtaposed
to the CD Rs of another mAb
(Spec. 10:8-19).
5. The Specification teaches:
The work already accomplished revealed that the
presumably bivalent interaction complex between Cetuximab
and TGP 1 may spontaneously dissociate to some degree. If this
should present a problem in vivo, it can be avoided, in part, by
constructing very stable tretravalent [sic] complexes consisting
of "heteromasks," .... In some aspects, point mutations can be
engineered into the masks which will favor interaction with two
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distinct antibodies, for example Cetuximab and Matuzumab,
rather than one antibody only.
(Spec. 18:18-24).
6. The Examiner finds that "the present application exemplifies
just four masking ligands for reversibly concealing the antigen-binding site
of just two anti-EGFR antibodies, namely cetuximab (C225) and
Matuzumab (425) that bind to just human EGFR" (Ans. 7).
7. Greenspan3 teaches:
What is an epitope, after all? ...
If the epitope is defined, as is often the case in authoritative
sources, in terms of the spatial organization of residues making
contact with ligand, then a structural characterization of the
molecular interface for binding is necessary to define the
boundaries of the epitope. But how informative is this
knowledge? The epitope so defined will likely include residues
that make contacts with ligand but are energetically neutral, or
even destabilizing to binding. In addition, a priori it will not
include any residue that makes no contact with ligand but
whose substitution may profoundly affect ligand recognition
through influence on the stability of the free form of the
macromolecule, or participation in long-range allosteric effects.
Therefore, atoms or larger structural subunits (e.g., amino
acids) should be recognized to have multiple ways of
contributing to a noncovalent interaction, including
contributions to: contact, affinity for a cognate ligand (L'iG), and
affinity of discrimination between two ligands (L'il"iG).
(Greenspan 937, col. 2 (internal citations omitted)).
8. Greenspan teaches:
3 Neil Greenspan and Enrico Di Cera, Defining epitopes: It's not as easy as
it seems, 17 NATURE BIOTECHNOLOGY 936-937 (1999) (hereinafter
"Greenspan").
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The most fundamental causal basis for molecular complex
formation is the free energy change associated with this
process. A number of factors, not primarily related to the
detailed contours of the contact regions of two interacting
molecules, contribute to this free energy change-sometimes
decisively. Consequently, when mutational approaches such as
ASM are used to characterize epitopes, the outcome will not
necessarily coincide with a site characterized on the basis of a
structural analysis of the complex.
(Greenspan 937, col. 3).
9. Dodson 4 teaches that " [ o ]nee a protein structure is known, it is
fairly easy to see the atomic interactions that underpin it. But it is much
harder to take an amino-acid sequence and work out the optimal interactions
that determine how it will fold" (Dodson I 76, col. 2).
I 0. Landry5 teaches that:
Epitope mapping studies and the determination of the structure
to I. 8 A resolution have been carried out for the antigen-
binding fragment MRI in complex with peptide antigen. MRI
is specific for the novel fusion junction of the mutant epidermal
growth factor receptor EGFRvIII and has been reported to have
a high degree of specificity for the mutant EGFRvIII over the
wild-type EGF receptor. The structure of the complex shows
that the peptide antigen residue side-chains found by epitope
mapping studies to be critical for recognition are
accommodated in pockets on the surface of the Fv. However,
the most distinctive portion of the peptide antigen, the novel
4 Eleanor Dodson, Protein Predictions, 450 NATURE I 76-I 77 (2007)
(hereinafter "Dodson").
5 Landry et al., Antibody Recognition of a Conformational Epitope in a
Peptide Antigen: Fv-Peptide Complex of an Antibody Fragment Specific for
the Mutant EGF Receptor, EGFRvJJJ, 308 J. MOLECULAR BIOLOgy 883-893
(200 I) (hereinafter "Landry").
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fusion glycine residue, makes no contact to the Fv and does not
contribute directly to the epitope. The specificity of MRI lies
in the ability of this glycine residue to assume the restricted
conformation needed to form a type II' ~-hairpin tum more
easily, and demonstrates that a peptide antigen can be used to
generate a conformational epitope.
(Landry 883, Abstract).
Principles of Law
A "generic claim may define the boundaries of a vast genus of
chemical compounds, and yet the question may still remain whether the
specification, including original claim language, demonstrates that the
applicant has invented species sufficient to support a claim to a genus."
Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
When a patent claims a genus using functional language to define a
desired result, "the specification must demonstrate that the applicant has
made a generic invention that achieves the claimed result and do so by
showing that the applicant has invented species sufficient to support a claim
to the functionally-defined genus." Abb Vie Deutsch/and GmbH & Co., KG
v. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir. 2014) (quoting
Ariad, 598 F.3d at 1349).
Analysis
Claim 1 combines the structural elements of two linked ligands with a
functional requirement for the linked ligands to block both antigen binding
sites of a single antibody when linked, but have reduced affinity for the
antibody after the linker is cleaved and the two ligands are no longer joined.
However, while the Specification explains the concept of the
invention (FF 1-5), we agree with the Examiner that the instant
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Specification does not describe a representative number of species for the
claimed genus. In particular, we agree that the Specification lacks specific
design guidance for the genus of ligands that bind antibodies to block the
antigen-binding sites and specific design guidance for the genus of ligands
that bind in bivalent form and dissociate when monovalent (see Ans. 4).
The Examiner has provided evidence that the general guidance in the
Specification (FF 1-5) does not address art recognized concerns regarding
the composition and conformation of cognate epitopes (FF 7, 9, 10) and
issues of whether cognate epitopes can be routinely modified by mutation
(FF 8).
The Federal Circuit confronted comparable facts in Abbvie, where the
claim at issue was drawn to "a class of fully human antibodies that are
defined by their high affinity and neutralizing activity to human IL-12."
Abbvie, 759 F.3d at 1299. Here, claim 1 is drawn to a class of ligands with
sufficiently high affinity to conceal and neutralize antigen-binding sites
when bivalently linked, but with reduced affinity insufficient to conceal and
neutralize antigen-binding sites subsequent to cleavage into monovalent
ligands.
In Abbvie, representative examples were drawn to over two hundred
structurally similar Joe-9 antibodies (id. at 1300), while in the instant case
masking compounds to just two related anti-EGFR antibodies were disclosed
(FF 6). Abbvie noted the need to "describe representative antibodies to
reflect the structural diversity of the claimed genus" and stated that the
binding affinity or "koff rate is merely a desired result, rather than the actual
means for achieving that result." Id. at 1301.
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Similarly, the structural diversity of antibodies to epitopes, even
epitopes of known sequence, is immensely variable (see Ans. 8), and the
functional results of ligands that have the dual properties of concealing
antigen-binding sites when bivalent while revealing them if cleaved to
become monovalent also represents a desired result, without any specific and
detailed guidance on means for routinely achieving the result provided by
the Specification. For example, generic guidance to use chemical
modifications, point mutations, or other known approaches (FF 3, 5) without
more does not provide descriptive support for the full scope of the invention.
Appellants contend that "[b ]y requiring the amino acid sequence of
each claimed masking ligand, the Examiner overlooks the established law
that functional claim language also can meet the written description
requirement when the art has established a correlation between structure and
function" (App. Br. 9).
We find this argument unpersuasive because the Examiner does not
require the amino acid sequence of masking ligands, but rather requires
evidence of a structure-function correlation that is predictable and
determinable, as well as a reasonable number of species, necessary to
demonstrate that "one has truly invented the genus, i.e., that one has
conceived and described sufficient representative species encompassing the
breadth of the genus. Otherwise, one has only a research plan, leaving it to
others to explore the unknown contours of the claimed genus." Abbvie, 759
F.3d at 1300; see also Ariad, 598 F.3d at 1353 (The written description
requirement guards against claims that "merely recite a description of the
problem to be solved while claiming all solutions to it and ... cover any
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compound later actually invented and determined to fall within the claim's
functional boundaries.").
Appellants contend the "amino acid sequence of each epitope is
structurally and functionally defined by the antibody to which it binds. If
the epitope sequence is not already known, a structural biochemist routinely
can determine the epitope sequence of any antibody having the capacity to
bind an antigen" (App. Br. 10). Appellants further note that a "biochemist
skilled in the relevant art also routinely can select the appropriate cleavage
sequence within the linker, based, for example, on proteases expressed in a
target tumor" (App. Br. 11 ). Appellants conclude:
It follows that a structural biochemist routinely can determine
the length and composition of a suitable linker based on the
known or routinely determined distances between epitope
binding sites of any target antibody. From these data, the
biochemist routinely can synthesize an amino acid linker of the
desired length comprising a sequence suitable for cleavage
within the cells or tissues that express the desired cleavage
molecule or protease.
(App. Br. 12).
We find this argument unpersuasive because the Examiner does not
challenge the enablement of claim 1, but rather whether claim 1 has
descriptive support. Ariad recognized that "requiring a written description
of the invention plays a vital role in curtailing claims that do not require
undue experimentation to make and use, and thus satisfy enablement, but
that have not been invented, and thus cannot be described." Ariad, 598 F.3d
at 1352. Ariad further noted that "written description requirement also
ensures that when a patent claims a genus by its function or result, the
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specification recites sufficient materials to accomplish that function." Id. at
1353.
Claim 1 broadly claims reversible bivalent masking ligands for
antibodies, describing a "problem to be solved while claiming all solutions
to it and ... cover[ing] any compound later actually invented and
determined to fall within the claim's functional boundaries-leaving it to the
pharmaceutical industry to complete an unfinished invention." Id. Thus,
irrespective of whether the prior art enables claim 1, an issue not addressed
by the Examiner, we agree with the Examiner's written description analysis
that:
the instant disclosure does not provide sufficient description of
a representative number of species of masking ligands by actual
reduction to practice, reduction to drawings, or by disclosure of
relevant, identifying characteristics shared by members of the
genus of cognate epitopes to which the genus of antibodies
bind, sufficient to show the applicant was in possession of the
claimed genus of bivalent masking ligands comprising two
copies of epitopes heaving [sic] any mutation joined by any
cleavable polypeptide linker that could reversibly conceal[] the
antigens-binding sites of all antibodies.
(Ans. 5).
Appellants contend the "point of novelty, analogous to the solvate of
[Ex parte] Chem, is not the amino acid sequence of the masking ligand, but
instead is the claimed generic structure summarily described as a masking
ligand comprising a cleavable linker that connects two cognate epitopes that
noncovalently bind a target antibody until the linker is cleaved" (App. Br.
14).
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Application 12/633, 102
We find this argument unpersuasive because, unlike in Chern, where
the claims were drawn to solvates of the very specific chemical structure N6-
( 4-hydroxybenzyl) adenosine and limited to solvate forms of that chemical
structure, the instant claims recite no specific definition by structure,
formula, chemical name, physical properties or a representative number of
species for all bivalent compounds that conceal epitopes of an antibody until
cleaved to monovalent form. See Ex Parte Chern, 2011 WL 5080233 (BP AI
2011).
Appellants contend "disclosure of a representative number of amino
acid sequences of epitopes that bind a target antibody is not required because
binding of an antibody to its cognate epitope satisfies the written description
requirement as a matter of law" (Reply Br. 3).
We find this argument unpersuasive because the claims are not limited
to cognate epitopes, but rather to cognate epitopes whose binding to the
antibody is not dissociable when linked in bivalent form, but whose binding
is dissociable when monovalent, and also cognate epitopes that function to
conceal the antibody-binding sites rather than compete with naturally
occurring epitopes. Thus, even if there were a per se rule that sequences and
representative numbers of species are not required for cognate epitopes of
antibodies generally, the specific situation of claim 1 is drawn to cognate
epitopes that function in a very particular fashion. It is the breadth of that
function, unconstrained by structure or representative species, which
underlies the Examiner's written description rejection. See Regents of the
University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir.
1997) ("[N]aming a type of material generally known to exist, in the absence
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of knowledge as to what that material consists of, is not a description of that
material.")
We think this situation is similar to that found in In re '318, where the
Court found in the enablement context that, "[t]hus, at the end of the day, the
specification, even read in the light of the knowledge of those skilled in the
art, does no more than state a hypothesis and propose testing to determine
the accuracy of that hypothesis. That is not sufficient." In re '318 Patent
Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009). We agree
with the Examiner that the instant disclosure is insufficient to satisfy the
written description requirement.
Conclusion of Law
The evidence of record supports the Examiner's conclusion that the
Specification fails to provide descriptive support for possession of the
claimed genus of "dissociable, bivalent masking ligand for reversibly
concealing the antigen-binding sites of an antibody ... joined by a cleavable
polypeptide linker" where "cleavage of the linker reduces the valency of the
mask and reduces the affinity of binding between the masking ligand and the
antibody" as recited by claim 1.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. § 112,
first paragraph as failing to comply with the written description requirement.
Claims 2--4, 6, 7, 18-20, 24 and 26-28 fall with claim 1. 37 C.F.R.
§ 41.37(c)(l)(iv).
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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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