Ex Parte Chang

Board of Patent Appeals and Interferences

Nov 15, 2002

08855744 (B.P.A.I. Nov. 15, 2002)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.

Paper No. 34

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte TSE WEN CHANG
__________

Appeal No. 2001-2497
Application No. 08/855,744
__________

ON BRIEF
__________

Before WILLIAM F. SMITH, SCHENER, and GRIMES, Administrative Patent
Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL

This is a decision on appeal under 35 U.S.C. § 134 from the examiner’s
final rejection of claims 1 and 3, all of the claims in the application. Claim 1 and 3
read as follows:
1. A method of enhancing delivery of a therapeutic agent selected
from the group consisting of tumor necrosis factor and interleukin-1
to a solid tissue site, comprising:

administering to a patient a conjugate consisting of two individual
single chain VH-VL binding molecules which are conjugated with a
hydrophilic peptide linker, one single chain binding molecule having
specificity for a solid tissue antigen and the other for the therapeutic
agent, and waiting until the conjugate concentration in the
Appeal No. 2001-2497 Page 2
Application No. 08/855,744

extravascular space reaches equilibrium between the extravascular
space and the capillaries;

administering a liposome conjugated with antibodies specific for the
conjugate which binds circulating conjugate;

administering the therapeutic agent.
3. The method of claim 1 further including the step of administering
the liposome conjugated with antibodies at least one more time
after time is allowed for the conjugate(s) in the extravascular space
and the blood circulation to reach equilibrium.

The examiner relies on the following references:
Huston et al. (Huston) WO 88/09344 Dec. 1, 1988
Goodwin, “Pharmacokinetics and Antibodies,” The Journal of Nuclear Medicine,
Vol. 28, No. 8, pp. 1358-1362 (1987)

Colcher et al. (Colcher), ”In Vivo Tumor Targeting of a Recombinant Single-
Chain Antigen-Binding Protein,” Journal of the National Cancer Institute, Vol. 82,
No. 14, pp.1191-1197 (1990)

Claims 1 and 3 stand rejected under 35 U.S.C. § 112, first paragraph, for
nonenablement.
Claims 1 and 3 stand rejected under 35 U.S.C. § 103 as obvious in view of
Goodwin combined with either of Huston or Colcher.1
We reverse both rejections.
Background
Immunoconjugates and immunotoxins – monoclonal antibodies
conjugated with a therapeutic agent or toxin – have been investigated for
treatment of cancer. See the specification, pages 1 and 2. These agents,

1 As further discussed infra, we construe the examiner’s rejection under § 103 to be based on
Goodwin combined with either of Huston or Colcher, rather than, as stated in the Examiner’s
Answer, Goodwin combined with Huston and Colcher.
Appeal No. 2001-2497 Page 3
Application No. 08/855,744

however, have proven more effective in treating leukemia or lymphoma than solid
tumors. See id., page 2. “One plausible explanation for this difference in efficacy
is that malignant cells in blood or lymphoid tissues are more accessible than
those in solid tumors. . . . In addition, even where the toxin is in contact with the
target cells, only a very small fraction will actually enter the cell and thus, not all
cells in a solid tumor will be killed.” Id. This problem cannot be solved by
increasing the dosage of immunotoxin, because the immunotoxin is also taken
up by reticuloendothelial cells and phagocytic cells of the liver, and therefore “the
total amount of toxin which can be administered is sever[e]ly limited.” Id.
The specification discloses a method for increasing the amount of
therapeutic agent delivered to a target site such as a tumor, without causing
systemic toxicity. “The invention includes using bifunctional two-domain binding
molecules to recruit a therapeutic agent to a solid tissue target site, where the
binding molecules have one specificity for the target site and the other specificity
for the therapeutic agent.” Specification, page 6. The binding molecules and
therapeutic agent are administered in separate steps. The binding molecules are
administered first and allowed to bind to the target site. Cite specification. A
remover substance (e.g., a liposome conjugated to antibodies against the binding
molecules) is then administered to facilitate clearing of the binding molecules
from the circulation. See id., page 6. After the last administration of remover has
had time to clear from circulation, the therapeutic agent is administered and
bound by the binding molecules bound to the target site. Thus, the toxic effects
Appeal No. 2001-2497 Page 4
Application No. 08/855,744

of the therapeutic agent are confined to the target site and systemic toxicity is
minimized.
Discussion
The claims are directed to a method of treating a patient with either tumor
necrosis factor (TNF) or interleukin-1 (IL-1). In the claimed method, the patient is
first administered a conjugate that consists of two VH-VL binding molecules
connected by a peptide linker. One of the binding molecules in the conjugate
binds specifically to the therapeutic agent (TNF or IL-1) and the other binds to a
target site antigen. After it is administered, the conjugate is allowed to reach
equilibrium between the capillaries and extravascular space. A liposome
conjugated with conjugate-specific antibodies is then administered (one or more
times) to bind circulating conjugate and, finally, the therapeutic agent is
administered.

1. Enablement
The examiner rejected the claims for as nonenabled. The statement of
the rejection in the Examiner’s Answer reads as follows: “Claims 1 and 3 stand
rejected under 35 U.S.C. § 112, first paragraph. . . . This rejection is set forth in
prior Office action, Paper No. 5; please also see the Office action in paper No.
10.” Examiner’s Answer, page 3. Paper No. 5 (mailed July 29, 1992), in turn,
provides the following statement of rejection:
[T]he specification does not provide any probative evidence for the
operability of the claimed methods. . . . [I]t is unclear as to the
operability of the methods since the delivery of the therapeutic
Appeal No. 2001-2497 Page 5
Application No. 08/855,744

agents which are highly toxic occurs after being administered
separately. Furthermore, all of the species being administered
such as the binding molecules, remover substances, and the
therapeutic agents are immunogenic and would appear to hinder
long term administrations. Therefore, in the absence of further
guidelines, it would be undue experimentation to determine the
conditions in which bifunctional binding molecules with which
remover and which therapeutic agents would be operable as
broadly claimed in the instant application.

Paper No. 5, pages 4-5.2 As we understand it, the examiner’s reasoning is that
the claimed method encompasses inoperative embodiments and undue
experimentation would have been required to determine what embodiments
within the scope of the claims are and are not operable.
The examiner bears the initial burden of establishing nonenablement. See
In re Wright, 999 F.2d 1557, 1561-62, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)
(“[T]he PTO bears an initial burden of setting forth a reasonable explanation as to
why it believes that the scope of protection provided by that claim is not
adequately enabled by the description of the invention provided in the
specification of the application; this includes, of course, providing sufficient
reasons for doubting any assertions in the specification as to the scope of
enablement.”).
That burden is not met by a bare assertion that a claimed method has not
been shown to work. “Section 112 does not require that a specification convince
persons skilled in the art that the assertions therein are correct.” In re

2 Paper No. 5 includes an additional basis of nonenablement: “The specification improperly
incorporates the essential material required to make and use the claimed invention.” Page 4,
lines 25-27. This basis, however, was apparently withdrawn in the next Office action. See Paper
No. 10 (mailed Jan. 13, 1993), page 3: “[C]laims 1-3 . . . remain rejected under 35 U.S.C. §112,
Appeal No. 2001-2497 Page 6
Application No. 08/855,744

Armbruster, 512 F.2d 676, 678, 185 USPQ 152, 153 (CCPA 1975). If the
specification “contains a teaching of the manner and process of making and
using the invention in terms which correspond in scope to those used in
describing and defining the subject matter sought to be patented[, it] must be
taken as in compliance with the enabling requirement of the first paragraph of
§ 112 unless there is reason to doubt the objective truth of the statements
contained therein which must be relied on for enabling support.” In re Marzocchi,
439 F.2d 220, 223, 169 USPQ 367, 369 (CCPA 1971), emphasis in original.
Further, a conclusion of nonenablement must be supported by evidence or
scientific reasoning. See Armbruster, 512 F.2d at 677, 185 USPQ at 153 (“[T]he
Patent and Trademark Office must substantiate its rejection for lack of
enablement with reasons.” (emphasis in original)). See also Marzocchi, 439 F.2d
at 224, 169 USPQ at 370 (“[It] is incumbent upon the Patent Office, whenever a
rejection on this basis is made, to explain why it doubts the truth or accuracy of
any statement in a supporting disclosure and to back up assertions of its own
with acceptable evidence or reasoning which is inconsistent with the contested
statement.”).
In this case, the examiner has provided no Wands-based analysis to
support the conclusion of nonenablement and has pointed to no evidence in the
record to support the assertion that the claimed method is likely to be inoperative.
With regard to the asserted requirement for undue experimentation, we note that

first paragraph, for the reasons previously set forth on page 4, line 28 to page 5 of [Paper No. 5]”
(emphasis added).
Appeal No. 2001-2497 Page 7
Application No. 08/855,744

the claims as they presently stand encompass only two therapeutic agents (TNF
and IL-1) in combination with a single remover substance (liposomes). In short,
the examiner has not carried the initial burden of showing a prima facie case of
nonenablement. The rejection under 35 U.S.C. § 112, first paragraph, is
reversed.
2. Obviousness
The examiner also rejected the claims as obvious over the prior art. The
statement of the rejection in the Examiner’s Answer reads as follows: “Claims 1
and 3 stand rejected . . . under 35 USC 103 over Goodwin in view of Huston et
al, and Colcher et al. This rejection is set forth in prior Office action, Paper No. 5;
please also see the Office action in paper No. 10.” Examiner’s Answer, page 3.
This statement of rejection leaves us somewhat at a loss, since neither of
Paper No. 5 or Paper No. 10 contains a rejection based on Goodwin, Huston,
and Colcher. The § 103 rejection in Paper No. 5 is based on “Goodwin (1987) in
view of Huston et al.,” while Paper No. 10 contains two rejections under § 103,
one being the Goodwin-and-Huston rejection from Paper No. 5, and the other
based on “Goodwin (1987) in view of Huston et al . . . or Colcher et al (1990) and
further in view of Glennie . . . and Chang et al.” We also note that in the next
Office action, the latter rejection morphed one based on “Goodwin (1987) in view
of Huston et al . . . or Colcher et al (1990) essentially for the reasons of record.”
See Paper No. 16, mailed June 17, 1993.
Thus, other than the Examiner’s Answer, the record nowhere contains a
rejection under § 103 based on Goodwin, Huston, and Colcher. Thus, the
Appeal No. 2001-2497 Page 8
Application No. 08/855,744

rejection as stated in the Examiner’s Answer would constitute a new ground of
rejection that could not be raised for the first time on appeal; the examiner would
have had to reopen prosecution.
Since the examiner expressly referred to prior Office actions, however, we
assume the examiner intended to state the rejection as it had been set out in
previous Office actions, i.e., a rejection under 35 U.S.C. § 103 based on
Goodwin in combination with either Huston or Colcher. Our review of the
rejection is based on this understanding of its basis.
Goodwin discloses a method of detecting cancers “in which the antibody
and the radiolabel are administered separately.” Page 1361. Goodwin describes
the method as follows:
Nonradioactive antibody is given first (pretargeted) and allowed
time to reach maximum tumor concentration, usually at least one
day. At the time of maximum tumor concentration of nonradioactive
antibody, the blood is quickly cleared of excess circulating
nonradioactive antibody using a special intravenous “chase”.
Shortly after (30-60 min) the radiolabel is given and images made
in 1-3 hr.

Id.
Goodwin also teaches that “[a]n obvious improvement in this system is the
development of bifunctional antibodies that could bind both a chelate and a tumor
antigen. . . . Either hybrid antibodies or antibody conjugates could be used for
this application.” Id.
Huston and Colcher both disclose single-chain VH-VL molecules with
potential diagnostic and/or therapeutic applications. Huston describes the
molecule as a “multifunctional protein” having affinity for a preselected antigen.
Appeal No. 2001-2497 Page 9
Application No. 08/855,744

See the abstract. The proteins are disclosed to bind the target antigen via a
“biosynthetic antibody binding site” and are disclosed to optionally “include other
polypeptide sequences which function, e.g., as an enzyme, toxin, binding site, or
site for attachment to an immobilization medi[um] or radioactive atom.” Id. Thus,
Huston’s multifunctional proteins comprise separate domains that (1) bind to the
target antigen and (2) carry out enzymatic or toxic reactions.
Colcher discloses “in vivo targeting of tumors with a single-chain antigen-
binding protein.” Abstract. The disclosed protein was “composed of a variable
light-chain (VL), amino acid sequence of an immunoglobulin tethered to a
variable heavy-chain (VH) sequence by a designed peptide.” Id. This protein
was disclosed to bind to the appropriate tumor antigen. See id. Colcher
suggests that “it may be possible, for more efficient therapeutic and/or diagnostic
applications, . . . to add drugs or specific combining sites for drugs and
radionuclides (i.e., bifunctional chelates).” Page 1196.
The examiner concluded that
It would have been prima facie obvious to one of ordinary skill in
the art at the time the invention was made to apply the method of
pretargeted radiolabel of Goodwin using the functionally equivalent
bifunctional antibodies . . . which can be made as single chain as
taught by Huston et al[.] or Colcher et al[.] since Goodwin teaches
the use of bifunctional antibodies . . . and since Huston et al[.] and
Colcher et al[.] teach the advantages of having single chain
chimeric antibodies over the antibody fragment conjugates . . . with
the expected benefit of reduced immunogenicity and increased
bioavailability. See Page 3, the last paragraph of Huston et al[.]
and page 1196 of Colcher et al.

Paper No. 10, page 8.
Appeal No. 2001-2497 Page 10
Application No. 08/855,744

“In rejecting claims under 35 U.S.C. § 103, the examiner bears the initial
burden of presenting a prima facie case of obviousness. Only if that burden is
met, does the burden of coming forward with evidence or argument shift to the
applicant.” In re Rijckaert, 9 F.3d 1531, 1532, 28 USPQ2d 1955, 1956 (Fed. Cir.
1993).
In this case, the examiner has not made out a prima facie case of
obviousness. One obvious defect in the examiner’s rejection is that it fails to
account for several of the limitations of the claims. In addition to a conjugate
made up of two VH-VL binding molecules, the claims require the use of either
TNF or IL-1 as the therapeutic agent, in combination with liposomes conjugated
with antibodies specific for the conjugate. The examiner’s rejection, however,
does not explain why it would have been obvious to use TNF or IL-1 as the
therapeutic agent, nor why it would have been obvious to use antibody-
conjugated liposomes. Obviousness is determined based on the claimed
“subject matter as a whole.” 35 U.S.C. § 103. Express limitations of the claims
cannot be ignored. See General Foods Corp. v. Studiengesellschaft Kohle mbH,
972 F.2d 1272, 1275, 23 USPQ2d 1839, 1840 (Fed. Cir. 1992) (“[E]ach claim is
an entity which must be considered as a whole.” (emphasis in original)).
In addition, the examiner has not adequately explained how the
combination of the reference disclosures would have suggested the claimed
method. In the imaging method disclosed by Goodwin, a tumor-binding molecule
is administered and allowed to bind its target, then the blood is cleared of excess
binding molecule, and finally, a radiolabel is administered. Since Goodwin’s
Appeal No. 2001-2497 Page 11
Application No. 08/855,744

method depends on the tumor-binding activity and the effector activity (radiolabel
for imaging, toxin for therapy) being administered at different times, it is essential
that those activities be carried out by different molecules.
Colcher and Huston, however, disclose or suggest multifunctional proteins
that both bind to an antigen and carry out the effector function. Since both
functions reside in the same protein, it would appear that the proteins disclosed
by Colcher and Huston could not be used in the multistep procedure of Goodwin,
since there would be no way to administer the tumor-binding part of the protein
separately from the effector part of the protein. The examiner has not explained
how the multifunctional proteins disclosed by Colcher and Huston could be
combined with Goodwin’s method in such a way as to yield the instantly claimed
invention.
Appeal No. 2001-2497 Page 12
Application No. 08/855,744

Summary
The examiner has not carried the initial burden of supporting a prima facie
case of nonenablement or obviousness. We therefore reverse the rejections
under 35 U.S.C. § 112, first paragraph, and 35 U.S.C. § 103.

REVERSED

WILLIAM F. SMITH )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
TONI R. SCHEINER )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
ERIC GRIMES )
Administrative Patent Judge )
Appeal No. 2001-2497 Page 13
Application No. 08/855,744

ERIC MIRABEL
TANOX BIOSYSTEMS
10301 STELLA LINK ROAD
HOUSTON, TX 77025

EG/jlb