Ex Parte Ebens et al

Board of Patent Appeals and Interferences

Nov 30, 2010

11141344 (B.P.A.I. Nov. 30, 2010)

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.
11/141,344 05/31/2005 Allen J. Ebens JR. P2094R1 6098
9157 7590 11/30/2010
GENENTECH, INC.
1 DNA WAY
SOUTH SAN FRANCISCO, CA 94080
EXAMINER
FETTEROLF, BRANDON J
ART UNIT PAPER NUMBER
1628
MAIL DATE DELIVERY MODE
11/30/2010 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ALLEN J. EBENS JR., FREDERIC S. JACOBSON,
PAUL POLAKIS, RALPH H. SCHWALL, MARK X. SLIWKOWSKI
and SUSAN D. SPENCER
__________

Appeal 2010-000944
Application 11/141,344
Technology Center 1600
__________

Before DEMETRA J. MILLS, ERIC GRIMES, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

MILLS, Administrative Patent Judge.

DECISION ON APPEAL1

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

Appeal 2010-000944
Application 11/141,344

2
This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for anticipation and obviousness. We have jurisdiction under 35
U.S.C. § 6(b).
STATEMENT OF THE CASE
The following claim is representative and reads as follows:
72. A mixture of antibody-drug conjugate compounds comprising the
structure:

wherein Ab is trastuzumab;
p is selected from 1, 2, 3, and 4; and
the average drug loading is 2 to 4;
produced by a process comprising the steps of:
(a) reacting Ab with about 7.5 to 10 molar equivalents of linker reagent
SMCC to form antibody-linker intermediate Ab-L, and then reacting Ab-
L with a drug moiety DM1 to form the mixture of antibody-drug
conjugate compounds;
(b) measuring the average drug loading by absorbance or mass spectrometry;
(c) measuring anti-tumor efficacy by treating high expressing HER2,
tumor bearing transgenic explant mice with the mixture of antibody-drug
conjugate compounds and determining tumor volume over time; and
(d) measuring toxicity by treating rodents or monkeys with the mixture of
antibody-drug conjugate compounds and determining weight change, serum
chemistry, hematology, or histopathology.
Appeal 2010-000944
Application 11/141,344

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Cited References

The Examiner relies on the following prior art references:

Erickson et al. US 2002/0001587 A1 Jan. 3, 2002
Steeves et al. US 2005/0169933 A1 Aug. 4, 2005

ThermoScientific (Instructions: SMCC and Sulfo-SMCC)

Grounds of Rejection
1. Claims 72-73 are rejected under 35 U.S.C. § 102(e) as being
unpatentable over Steeves as evidenced by Erickson.
2. Claims 72-73 are rejected under 35 U.S.C. § 102(b) or, in the
alternative, 35 U.S.C. §103(a) as being unpatentable over Erickson as
evidenced by ThermoScientific in further view of Steeves.

FINDINGS OF FACT
The findings of fact relevant to all rejections are set forth below.
1. “Steeves et al. teach a cell binding agent maytansinoid conjugate,
wherein one or more maytansinoids is linked to a cell-binding agent via a
non-cleavable linker (paragraph 0022).” (Ans. 4.)
2. “With regards to the cell binding agent, Steeves et al. teach that cell
binding agents include, but are not limited to, polyclonal antibodies,
monoclonal antibodies and binding fragments thereof, single chain
antibodies, chimeric antibodies and domain antibodies (paragraphs 0114-
0119).” (Id.)
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3. “Steeves et al. teach that the antibody is trastuzumab which can be used
to treat breast and other cancer such as prostate and ovarian cancers that
express the Her2 antigen, e.g., ErbB2 receptor (paragraph 00133).” (Id.)
4.
With regards to the maytansinoids, Steeves et al. teach that the
maytansinoids include DM1, which appears to be identical to
the claimed maytansinoid derivative … (Figures 2, wherein R is
S). With regards to the non-cleavable linker, Steeves et al. teach
that noncleavable linkers include, but are not limited to,
succinimidyl-4-(N-maleimidomethyl) cyclohexane-l-
carboxylate, e.g., SMCC, which appears to be identical to the
linker claimed … (paragraph 0153 and Figure 1 and 17).

(Id.)
5. “Steeves et al. teach a composition comprising the trastu[zu]mab-SMCC-
DM1 conjugate with an average drug loading of 3.13, wherein the antibody
was first reacted with a 7.5 molar excess of SMCC linker, purified and
conjugated to DM1 (Example 2A, paragraphs 0262-0276 and Table II).”
(Id.)
6.
Steeves et al. teach … a pharmaceutical composition
comprising the conjugate (paragraph 0021, 0219-0220)….
while Steeves et al. does not explicitly teach that p is 1-4, the
claimed limitation does not appear to result in a manipulative
difference because as evidenced by Erickson et al.,
HERCEPTIN ® , e.g., trastuzumab, can be linked to the
maytansinoid at lysine 13 in the light chain, at lysine 32 in the
heavy chain, lysine 26 in the Fab fragments and lysine 38 in the
Fc fragment (paragraph 0198). Thus, p can equal 1 to 4
maytansinoids per 1 antibody.

(Id. at 4-5.)
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7. “Erickson et al. teach an anti-ErbB receptor antibody-maytansinoid
conjugate (abstract).” (Id. at 5.)
8. “With regards to the ErbB receptor, Erickson et al. teach that an ErbB
receptor is a receptor protein tyrosine kinase which belongs to the ErbB
family and includes ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3) and
ErbB4 (HER4) receptors (paragraph 0041).” (Id.)
9. “With regards to the antibodies, Erickson et al. teach that the antibodies
include, but are not limited to, monoclonal antibodies and humanized
antibodies such as … huMAb4D5-8 (HERCEPTIN ®) (paragraph 0077).”
(Id.)
10.
With regards to the maytansinoid, Erickson et al. teach that the
maytansinoid includes DM1, which appears to be identical to
the claimed maytansinoid derivative … (Figures 3, wherein R is
S and Figure 4). Erickson et al. further teach that the antibody
and maytansinoid derivative are conjugated by a bispecific
chemical linker (paragraph 0023). For example, Erickson et al.
teach that the conjugates of the antibody and maytansinoid may
be made by using a variety of bifunctional protein coupling
agents such as succinimidyl-4-(N-maleimidomethyl)
cyclohexane-1-carboxylate,e.g., SMCC, which appears to be
identical to the linker claimed in claims 7-8 and 10 (paragraph
0199) . Moreover, Erickson et al. teach that there are a variety
of possible sites within the antibody molecule for linking the
maytansinoid to the antibody (paragraph 0198). For example,
Erickson et al. teach that in one embodiment HERCEPTIN ®,
e.g., trastuzumab, can be linked to the maytansinoid at lysine 13
in the light chain, at lysine 32 in the heavy chain, lysine 26 in
the Fab fragments and lysine 38 in the Fc fragment, e.g., p=l to
4 maytansinoids per 1 antibody (paragraph 0198).

(Ans. 5-6.)
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11. “Erickson et al. teach that a pharmaceutical composition comprising the
conjugate, wherein the pharmaceutical composition can further comprise and
anti-angiogenic agent such as an antibody which binds to vascular
endothelial growth factor (paragraphs 0201+ and 0228).” (Id. at 6.)
12.
[W]hile Erickson et al. do not specifically teach that the
antibody-maytansinoid conjugate with a SMCC linker has the
structure as shown in claim 10 [sic], the claimed structure does
not appear to result in a patentable difference between the
teachings of the prior art because as evidenced by
ThermoScientific, SMCC is a heterobifunctional cross linker
containing an N-hydroxysuccinimide (NHS) ester and
maleimido group which allows covalent conjugation of amine
and sulfhydrylcontaining molecules (page 1, Introduction). For
example, the instructions provided by ThermoScientific teaches
that conjugates are made by reacting a free amine of an
antibody, e.g., lysine 13 in the light chain, lysine 32 in the
heavy chain, lysine 26 in the Fab fragments and lysine 38 in the
Fc fragment of HERCEPTIN ®, with the succinimidyl group of
SMCC followed by reacting the thiol group, e.g., the thiol
group of DM1, with the maleimido group of SMCC (see page
3, Additional Information). As such, the claimed conjugate
appears to be the same as the prior art.

(Id.)
13. “[A]lthough Erickson et al. do not specifically teach that the average
drug loading of the Herceptin-SMCC-DM1 composition is 3.1, the claimed
limitation does not appear to result in a manipulative difference between the
prior art because as evidenced by Steeves et al., conjugation of Trastuzumab
containing a SMCC crosslinker with DM1 results in a composition
comprising an average drug loading of 3.13 (paragraph 0276). As such, the
claimed composition appears to be identical to the prior art.” (Id.)
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ISSUE
The Examiner concludes that “Steeves et al. teach a composition
comprising the trastu[zu]mab-SMCC-DM1 conjugate with an average drug
loading of 3.13, wherein the antibody was first reacted with a 7.5 molar
excess of SMCC linker, purified and conjugated to DM1 (Example 2A,
paragraphs 0262-0276 and Table II).” (Ans. 7.)
Appellants argue that “Steeves does not teach the limitation of a
mixture of antibody conjugates with 1, 2, 3, or 4 DM1 drug moieties
attached to one antibody, the pending claims are not anticipated and the
rejection is overcome.” (App. Br. 15.) “In the instant application, use of a
product by process claim is justified given the special circumstances and
complexity of the product mixture. The antibody drug ratio (p) and the
average drug loading features are keys to the special and unexpected
properties of the product mixture of antibody drug conjugates of claim
72.” (Id. at 13.)
The issue is: Do the cited references teach the mixture of antibody-
drug conjugate compounds claimed?

PRINCIPLES OF LAW
In order for a prior art reference to serve as an anticipatory reference,
it must disclose every limitation of the claimed invention, either explicitly or
inherently. See In re Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997).
Where … the claimed and prior art products are identical
or substantially identical, or are produced by identical or
substantially identical processes, 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.
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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).
“Where a product-by-process claim is rejected over a prior art product
that appears to be identical, although produced by a different process, the
burden is upon the applicants to come forward with evidence establishing an
unobvious difference between the claimed product and the prior art
product.” In re Marosi, 710 F.2d 799, 803 (Fed. Cir. 1983).
“[W]hen unexpected results are used as evidence of nonobviousness,
the results must be shown to be unexpected compared with the closest prior
art.” In re Baxter-Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991).
“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 (Fed.
Cir. 1993) (citations omitted). In order to determine whether a prima facie
case of obviousness has been established, we consider the factors set forth in
Graham v. John Deere Co., 383 U.S. 1, 17 (1966): (1) the scope and content
of the prior art; (2) the differences between the prior art and the claims at
issue; (3) the level of ordinary skill in the relevant art; and (4) objective
evidence of nonobviousness, if present.

Appeal 2010-000944
Application 11/141,344

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ANALYSIS
We agree with the Examiner’s fact finding, statement of the rejection
and responses to Appellants’ arguments and adopt them as our own. In
particular, we agree with the Examiner and do not find that Appellants have
provided sufficient evidence to show that the antibody conjugate of Steeves
having a drug loading of 3.13 is not the same as that claimed.

CONCLUSION OF LAW
Upon review of the evidence before us, we conclude that the cited
reference supports the Examiner’s anticipation rejection.

2. Claims 72-73 are rejected under 35 U.S.C. §102(b) or, in the alternative,
35 U.S.C. §103(a) as being unpatentable over Erickson as evidenced by
ThermoScientific and Steeves.
We agree with the Examiner’s fact finding, statement of the rejection
and responses to Appellants’ arguments and adopt them as our own. We
provide the following additional comment. With respect to the anticipation
rejection over Erickson, we agree with the Examiner and do not find that the
Appellants have provided sufficient evidence to show that the antibody
conjugate of Erickson is not the same as that made by the claimed product
by process language. With respect to the rejection of the claims for
obviousness, we are not persuaded by Appellants’ evidence of unexpected
results because Appellants have failed to compare the claimed antibody
conjugate with that of the closest prior art to show unexpected results in
view of the prior art product.
Appeal 2010-000944
Application 11/141,344

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CONCLUSION OF LAW
Upon review of the evidence before us, we conclude that the cited
reference supports the Examiner’s anticipation and obviousness rejections.

TIME PERIOD
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

alw

GENENTECH, INC.
1 DNA WAY
SOUTH SAN FRANCISCO, CA 94080