Ex Parte Faulk

Patent Trial and Appeal Board

Oct 21, 2016

12270110 (P.T.A.B. Oct. 21, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/270,110 11113/2008
6449 7590 10/25/2016
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
607 14th Street, N.W.
SUITE 800
WASHINGTON, DC 20005
W. Page FAULK
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.
2932-151 1578
EXAMINER
YAO, LEI
ART UNIT PAPER NUMBER
1642
NOTIFICATION DATE DELIVERY MODE
10/25/2016 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
PTO-PAT-Email@rfem.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte W. PAGE FAULK 1
Appeal2015-0002644
Application 12/270,110
Technology Center 1600
Before JEFFREY N. FRED MAN, RICHARD J. SMITH, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
conjugate of a targeting protein with a bio-affecting molecule that is
substantially free of dimers, trimers and aggregates, which have been
rejected as anticipated. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
"The effectiveness of proteins conjugated with bio-affecting
molecules has been demonstrated[.]" (Spec. 2.) "It has been determined[,]
however, that the efficiency of such conjugates in treating stressed cells,
1 Appellant identifies the Real Party in Interest as Faulk Pharmaceuticals,
Inc. (Br. 2.)
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Application 12/270, 110
such as cancer cells, is reduced by the presence of agglutinated conjugates or
by the presence of conjugates of a bio-affecting molecule with protein
fragments or with two or three protein molecules and is greatly enhanced
when the protein to bio-affecting molecule ratio is closer to 1: 1." (Id.)
Appellant's invention aims "to provide ... a homogeneous conjugate made
by a more efficient method." (Spec. 3.)
Claims 1-5, 8-10, and 13-142 are on appeal. Claim 1 is
representative and reads as follows:
1. A substantially homogeneous material comprising a
targeting protein conjugated with a bioaffecting molecule in a
predetermined ratio of bio-affecting molecules to targeting
protein molecules, wherein said targeting protein is attracted to
receptors on target cells, wherein said substantially
homogeneous material is prepared by a method comprising:
a) adding a solution of said bioaffecting molecule to a solution
of a glutaraldehyde linker material containing DMSO to a final
concentration of a 1: 1 molar ratio ofbioaffecting molecule to
glutaraldehyde resulting in the addition of one bioaffecting
molecule to one glutaraldehyde molecule; and
b) adding the bioaffecting molecule/glutaraldehyde
combination to said targeting protein to produce a substantially
homogeneous conjugate having a predetermined ratio of
bioaffecting molecule to targeting protein;
wherein said targeting protein-bioaffecting molecule conjugate
is substantially free of dimers, trimers and aggregates.
(Br. 25.)
2 Claims 6, 7, 11, and 12 are also pending, but stand withdrawn from
consideration. (Br. 2.)
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The following grounds of rejection by the Examiner are before us on
review:
1. Claims 1-5, 8-10, and 13-14 under 35 U.S.C. § 102(b) as
anticipated over Berczi, 3 as evidenced by Wang4 and Mesh word
search Adriamycin.
2. Claims 1-5, 8-10, and 13-14 under 35 U.S.C. § 102(b) as
anticipated over Page 5 as evidenced by Wang and Lai. 6
DISCUSSION
A. Anticipation by Berczi
The Examiner finds that Berczi teaches a "relatively homogeneous"
conjugate mixture of Adriamycin (also known as Doxorubicin, as evidenced
by the Mesh word search of Adriamycin) linked to transferrin, and that the
conjugate has a molecular weight of 80 kDa. (Ans. 6; Final Action 3.) The
Examiner explains that Wang demonstrates that Adriamycin is an apoptosis
inducing agent. (Ans. 3; Final Action 3.) Regarding the homogeneous
3 Berczi et al., Adriamycin Conjugates of Human Transferrin Bind
Transferrin Receptors and Kill K562 and HL60 Cells, 300(1) Archives of
Biochem and Biophy, 356-63 (1993).
4 Wang et al., Doxorubicin Induces Apoptosis in Normal and Tumor Cells
via Distinctly Different Mechanisms, 279 (24) J. Biological Chem., 25535-
43 (2004).
5 Page et al., U.S. Patent 5,208,323, issued May 1993.
6 Lai et al., Mechanism of action and spectrum of cell lines sensitive to a
doxorubicin-transferrin conjugate, 41 (2) Cancer Chemother. Pharmacol.,
155---60 (1998). The Examiner only referenced the abstract of Lai et al. (See
Final Action 6.)
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Application 12/270, 110
mixture, the Examiner notes that "Berczi states: the spectrophotometric
analysis of peak 2 (fractions 21-27 in figure l[, a column chromatography
analysis ofTRF-ADR conjugates, where fractions 21-27 exhibited a single
peak,]) indicated that the average conjugation numbers of TRF-ADR
conjugates were relatively homogenous (page 358, right col, line 3+)."
(Final Action 3--4.) The Examiner finds that "the conjugate in each of lanes
2--4 and 7-8 of Figure 2 of Berczi[, reporting the results of analysis by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of
TRF-ADR conjugates eluted in fractions 21-27 of Figure 1,] is a single
ban[d] at 80 kDa, free of dimers, trimers and aggregates." (Ans. 8; Final
Action 4.) The Examiner notes that there "is no purity of 'substantially
homogeneous"' defined in the Specification; rather, the Specification
"defines the phrase 'substantially homogeneous' as that can be used without
further purification." (Ans. 8.) The Examiner finds that the conjugate of
Berczi "is used in the binding and cytotoxicity assays without further
purification." (Ans. 8.) The Examiner concludes, in light of the foregoing,
that the Berczi TRF-ADR conjugate meets the "structural and functional
limitations of the conjugate recited" by the claims. (Ans. 8.)
We agree with the Examiner's factual findings and conclusion that
Berczi describes the product recited in claim 1. If the product in a product-
by-process claim is the same as a product of the prior art, the claim is
unpatentable even though the prior product was made by a different process
unless "the prior art products do not necessarily or inherently possess the
characteristics of [the] claimed product." In re Thorpe, 777 F.2d 695, 697-
98 (Fed. Cir. 1985).
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Appellant's argument that "the recited method steps result in a
conjugate with specific properties which are different from conjugates made
using Berczi's method" (Br. 8) is not persuasive. Appellant contends that
the SDS-PAGE results set forth in Berczi's Figure 2, and especially lanes 5
and 6 that show "the fractions containing the highest concentration of the
monomer" and "considerable [dark] spots," demonstrate that Berczi' s
process results in the formation of a "significant quantity" of dimers (Br. 8)
and that, in addition to showing dimers in Figure 2, "Berczi mentions the
presence of dimers" (Br. 9). We do not disagree with Appellant that Figure
2 demonstrates dimers in lanes 5 and 6, which correspond to eluted fraction
24 and 25 from the Sepharose column (Berczi 358 (Figs. 1 & 2); Br. 8-10
(discussing why "one skilled in the art would expect dimers to be present
with the monomer in these fractions [containing the highest concentration of
monomer, lanes 5 and 6 of the SDS-P AGE]]"), however, that fact does not
address the material present in fractions 21-23, the results of the SDS-P AGE
being set forth in Berczi's Figure 2, lanes 2--4. As the Examiner notes, each
of lanes 2--4, shows a single band at 80 kDa and thus none demonstrates the
presence of dimers. (Final Action 4; Ans. 8.)
Appellant notes that the declaration of Dr. Klara Barabas, 7 one of the
co-authors of Berczi, "discusses why the gels shown in Berczi cannot be
used to confirm the absence of dimers, trimers and aggregates," including
that "[ t ]he combination of a less sensitive stain [ Coomassie blue] and a
lower protein concentration in lanes 2, 3 and 8 erroneously make it appear as
7 Original Declaration submitted Dec. 30, 2010.
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if these fractions do not include dimers." (Br. 10-11.) However, that
Coomassie blue is less sensitive than silver staining and that the
concentration of protein in lanes 2 and 3 is less than in lanes 5 and 6
(Barabas Deel. i-fi-1 9--11) does not establish the presence of dimers in lanes 2
and 3. Furthermore, we note that lane 4 of Figure 2, appears to have a
significant percentage of monomeric protein given the intensity of the stains
at 80 kDa like lanes 5 and 6, yet Dr. Barabas does not even address the fact
that lane 4, like lanes 2 and 3, and in contrast to lanes 5 and 6, also does not
exhibit a band at 160 kDa. Dr. Barabas does not provide experimental
evidence demonstrating dimers were present after chromatography, in lanes
2 and 3, or a silver stain of the TRF-ADR conjugate produced according to
Berczi which might have demonstrated the presence of dimers in fractions
21 or 22, which correspond to the fractions analyzed in lanes 2 and 3. Thus,
we accord little weight to Dr. Barabas' opinion, which is not grounded in
any experimental proof or compelling scientific reasoning, that dimers were
necessarily present in fractions 21 and 22 (lanes 2 and 3 of the SDS-P AGE
gel), which opinion is in contrast to the experimental evidence provided in
Berczi itself. See Velander v. Garner, 348 F.3d 1359, 1371 (Fed. Cir. 2003)
("In giving more weight to prior publications than to subsequent conclusory
statements by experts, the Board acted well within [its] discretion.").
Moreover, while Dr. Barabas asserts that after centrifugation, but
before chromatography, smaller aggregates as well as dimers and trimers
remained in solution (Barabas Deel. i1 5), even if it were true, that fact does
not establish that any of eluted fractions 21-23 include dimers. Nor does the
fact that Berczi indicates "a small percentage of dimeric forms was found"
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(Berczi 358). (Barabas Deel. i-f 12.) Berczi's disclosure that only a "small
percentage of dimeric forms was found" could reasonably be understood to
mean the small percentage was found in the conjugated material eluted as a
whole from the Sepharose CL-4B chromatography column, not each
individual fraction collected. (Berczi 358.) That interpretation is consistent
with lanes 2--4, which correspond to eluted fractions 21-23, only showing a
single band at 80 kDa, representing monomeric TRF-ADR. (Berczi 358
(Fig. 2).) Even Dr. Barabas agrees that lanes 2 and 3, which are
compositions arising after chromatography, have an "apparent absence of a
stain indicative of transferrin: transferrin dimers" (Barabas Deel. i-f 9.)
For the foregoing reasons, and contrary to the opinion of Dr. Barabas
(Barabas Deel. i-f 12), we find insufficient evidence leading to a conclusion
that the small percentage of dimeric forms noted by Berczi to have been
"found" was found in each fraction eluted from the chromatography column.
Moreover, even if we were to accept that some undetectable amount
of dimer were present in fractions 21 and 22 (or even 23) (Barabas Deel. i-f
10), the claims require only that the conjugate be substantially free of dimer,
trimer, or aggregates. There is no specific level of purity required by the
claim or set forth by definition in the specification. We conclude that an
"undetectable" amount that may be present in the eluted fractions 21, 22,
and 23 is within the claim requirement of "substantially free."
In light of the foregoing, we agree with the Examiner that Berczi
discloses a product, specifically the product found in the tubes of eluted
fractions 21, 22, and 23, that is a substantially homogeneous material
comprising TRF-ADR conjugate monomer substantially free of dimers,
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trimers, or other aggregates. The fact that dimers may be detectably found
in other fractions does not negate the foregoing.
Appellant's argument that the definition of "substantially
homogeneous conjugate" provided in the Specification "excludes prior art
conjugates which require gel filtration to remove the aggregates and thus the
amount of dimers in figures 1 and 2 of Berczi would not meet the limitation
of 'substantially free' or 'substantially homogenous' as recited in the present
claims" (Br. 13-14) is also not persuasive. Initially, we note that claim 1
does not recite "substantially homogeneous conjugate," which is the phrase
defined in paragraph 52 of the Specification to mean "that the conjugates
can be used without further purification to remove protein dimers, polymers
or aggregates." And, in any event, as just discussed, Berczi teaches
obtaining fractions 21, 22, and 23, each of which are materials that are
substantially homogeneous compositions of a TRF-ADR monomer
substantially free of dimers. Appellant does not argue that, nor do we
discern any reason why, the conjugates obtained in fractions 21, 22, and 23
could not "be used without further purification to remove protein dimers,
polymers or aggregates." (Spec. i-f 52.)
We find that, based on the disclosure in Berczi of the relative
homogeneity of the conjugate produced, the Examiner has met his burden of
establishing the microhomogeneity aspect of the claimed product is inherent
to Berczi. Appellant asserts that Berczi' s process would result in a mixture
of conjugates with different ratios of ADR to TRF because Berczi does not
include DMSO in the glutaraldehyde solution when adding doxorubicin.
(Br. 12.) However, simply asserting that Berczi does not employ the same
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process as Appellant is not probative of whether Berczi's product does or
does not have the claimed homogeneity of a predetermined ratio of TRF-
ADR. Thus, we find that Appellant has not met its burden demonstrating
that Berczi does not have the claimed microheterogeneity. See In re Best,
562 F.2d 1252, 1255 (CCPA 1977) (holding that after a prima facie case is
made out, the burden shifts to the applicant to prove a difference between
the prior art compounds and the claimed compound).
For the foregoing reasons, we agree with the Examiner that Berczi's
conjugate in fractions 21, 22, and 23, would meet both structural and
functional limitations of the conjugate recited in claim 1 and defined in the
application.
Claims 2-5, 8-10, and 13-14 have not been argued separately and
therefore fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
B. Anticipation by Page
The Examiner finds that Page teaches a method of making a
homogeneous conjugate comprising transferrin linked to doxorubicin,
wherein the conjugate is denoted R-glutaraldehyde-M, where R is transferrin
and Mis doxorubicin. (Final Action 4, 6; Ans. 9.) The Examiner further
finds that Page teaches the conjugate made by this process "does not have a
tendency to polymerize," which meets the limitation of "free of dimers,
trimers, and aggregates." (Id.) The Examiner further finds that Page teaches
a range for the ratio of R-M in the conjugate that can be as desired, including
5: 1 to 7: 1, as well as 1: 1. (Final Action 6.) The Examiner notes that Lai
evidences that "transferrin binds and is attracted to the receptor expressed on
[a] tumor cell." (Final Action 4; Ans. 6.) The Examiner further notes that
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Page "teaches a method of using the conjugate in a cytotoxicity assay
without further purification." (Ans. 10.) In view of the foregoing, the
Examiner concludes that the Page TRF-ADR conjugate anticipates the
claimed product-by-process. (Final Action 4, 1 O; Ans. 6.)
We agree with the Examiner's factual findings regarding the
conjugate of Page and conclusion that Page anticipates the claimed
conjugate.
Appellant argues that the process by which Page's doxorubicin-
glutaraldehyde is produced is different from the process used to produce the
claimed product, that Page "does not recognize the necessity of proper
electrostatical balance" between DMSO and glutaraldehyde in forming the
DOX-GLU complex, and that Page does not teach or suggest any methods
for preventing the formation of dimers, trimers or aggregates. (Br. 15-1 7.)
Appellant contends that "[ t ]he molar excess [of glutaraldehyde] used in Page
results in the addition of more than one glutaraldehyde molecule to some
molecules of doxorubicin which results in a mixture of conjugates with
different ratios of DOX to TRF as well as dimers, trimers and aggregates."
(Br. 18.) We do not find Appellant's arguments persuasive.
While Appellant posits that polymerization occurs because a molar
excess of glutaraldehyde to doxorubicin is used in Page and because "prior
to the present invention, it was difficult to control the degree of conjugation"
(Br. 21 (citing Faulk Declaration8)), Appellant provides no experimental
evidence to support its assertion that Page's process results in "different
8 Declaration of Dr. W. Page Faulk submitted with response filed Oct. 30,
2013.
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Application 12/270, 110
ratios of DOX to TRF as well as dimers, trimers and aggregates" (Br. 18).
Page, on the other hand, teaches that the improved coupling method, which
involves an intermediate glutaraldehyde activated doxorubicin derivative
being coupled to TRF in DMSO, results in conjugates that "do not have a
tendency to polymerize" (Page 3:65--4:23), as well as that are in a DOX:TRF
ratio as desired (Page 6:25-30.) Page indicates that this lack of
polymerization is the result of a method that produces conjugates that are
"substantially pure." (Page 2: 63---65).
The opinion testimony of an interested party, such as Dr. Faulk, is of
little or no probative value in establishing that Page's teaching that the
process produces a conjugate that does not have a tendency to polymerize, in
fact, results in the production of dimers, trimers, and/or aggregates. Cf
Perring B. V. v. Barr Laboratories, Inc., 437 F.3d 1181, 1188 (Fed. Cir.
2006) ("A witness's interest is always pertinent to his credibility and to the
weight to be given to his testimony ... "). Moreover, Dr. Faulk's testimony
does not address the particular procedure set forth in Page, but rather is a
generic statement that "before the present invention, it was difficult to
control the degree of conjugation." (Faulk Dec. i-f 4.) That assertion is not
meaningful in demonstrating that Page's process results in dimers, trimers,
and/or aggregates.
Furthermore, it is well settled that mere lawyer's arguments and
conclusory statements, which are unsupported by factual evidence, are
entitled to little probative value. See, e.g., In re Geisler, 116 F .3d 1465,
1470 (Fed. Cir. 1997). The only "factual evidence" provided to support the
argument in Appellant's brief that Page's conjugates polymerize despite
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Page's contrary teaching, or that a mixture of conjugates with different ratios
ofDOX to TRF is produced is the Declaration by Faulk, an interested party,
and the bald unsupported statement in the brief, that the molar excess of
glutraldehyde necessarily "results in the addition of more than one
glutaraldehyde molecule to some molecules of doxorubicin which results in
a mixture of conjugates with different ratios of DOX to TRF as well as
dimers, timers and aggregates." (Br. 21.) We find Appellant's argument
lacks sufficient factual basis to demonstrate the conjugate in Page is not
substantially free of dimers, trimers, or aggregates or that the conjugate
contains a predetermined ratio ofbio-affecting molecule to targeting protein.
See In re Best, 562 F.2d at 1255.
Claims 2-5, 8-10, and 13-14 have not been argued separately and
therefore fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm the rejection of claims 1-5, 8-10, and 13-14 under 35
U.S.C. § 102(b) as anticipated over Berczi, as evidenced by Wang and Mesh
word search Adriamycin.
We affirm the rejection of claims 1-5, 8-10, and 13-14 under 35
U.S.C. § 102(b) as anticipated over Page, as evidenced by Wang and Lai.
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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