Daniel Schindler et al.

Patent Trials and Appeals Board

Aug 11, 2020

14057243 - (D) (P.T.A.B. Aug. 11, 2020)

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.
14/057,243 10/18/2013 Daniel Schindler L0719.70014US02 8416
31904 7590 08/11/2020
REVO BIOLOGICS, INC.
C/O WOLF, GREENFIELD & SACKS, P.C.
600 ATLANTIC AVENUE
BOSTON, MA 02210-2206
EXAMINER
WEN, SHARON X
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
08/11/2020 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):
G0744_eOfficeAction@WolfGreenfield.com
Patents_eOfficeAction@WolfGreenfield.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte DANIEL SCHINDLER, HARRY M. MEADE,
TIMOTHY EDMUNDS, and JOHN MCPHERSON
____________

Appeal 2019-005696
Application 14/057,243
Technology Center 1600
____________

Before DEBORAH KATZ, JOHN G. NEW, and
RYAN H. FLAX, Administrative Patent Judges.

FLAX, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134(a) involving
claims directed to a method for enhancing the binding of the Fc region of an
IgG antibody or antibodies to an FcγRIII receptor. Appellant appeals the
rejection of claims 1–21, 43, and 44 under 35 U.S.C. § 102(e).1 We have
jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 “Appellant” herein refers to the “applicant” as defined by 37 C.F.R.
§ 1.42. Appellant identifies “LFB USA, Inc., which is ultimately a
subsidiary of LFB S.A, and . . . Genzyme Corporation, which is ultimately a
subsidiary of Sanofi S.A.” as the real parties-in-interest. Appeal Br. 3.
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STATEMENT OF THE CASE
The Specification describes that the invention is directed to antibodies
engineered to “have enhanced ADCC [(antibody-dependent cellular
cytotoxicity)] activity and increased binding to CD16 [(FcγRIIIa)] compared
to cell culture-derived material.”2 Spec. 2:32–3:2; see also id. at 1:21–24.
The Specification explains that, “[a]ccording to an aspect of the invention
the binding of the Fc region of IgG1 antibodies is enhanced if the antibody
lacks the core fucose found attached to the Asn297 glycosylation site in the
Fc region (e.g., a fucose linked to the base of the biannetennary structure).
The antibodies of the invention in some aspects lack this core fucose.” Id. at
3:24–26.
The Specification explains that, in some embodiments, the antibody is
an anti-CD137 antibody. Id. at 16:1–32, 19:20–29, 20:10–17. The
Specification describes several embodiments, stating:
In one embodiment at least one chain of the antibodies have been
modified so that it does not contain fucose. In another
embodiment one chain of the antibodies has been modified so
that it does not contain fucose. In still another embodiment the
fucose that at least one chain of the antibodies do not contain is
1,6-fucose. In another embodiment one or at least one chain of
the antibodies have been modified to not contain fucose but the
antibodies have also been modified to contain an oligomannose
or an additional oligomannose. The chain that contains the

2 The Specification defines “antibody” as “a glycoprotein comprising at least
two heavy (H) chains and two light (L) chains inter-connected by disulfide
bonds, i.e., covalent heterotetramers comprised of two identical Ig H chains
and two identical L chains that are encoded by different genes,” but also
states that “[t]he term antibodies are meant to encompass antigen-binding
fragments thereof. As used herein, an ‘antigen-binding fragment’ of an
antibody refers to one or more portions of an antibody that retain the ability
to specifically bind to an antigen.” Spec. 17: 1–4, 17:20–22.
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oligomannose can be the same chain that does not contain fucose
but is not necessarily so. In another embodiment the amino acid
sequence of the antibodies have been modified and then
expressed in mammalian mammary epithelial cells. In one
embodiment the amino acid sequence of the antibodies have been
modified. In another embodiment the amino acid sequence of
the antibodies, such as anti-CD137 antibodies, has an amino acid
substitution of Asn297. In a further embodiment the substitution
is with an amino acid that will not be fucosylated. In another
embodiment the Asn297 is substituted with Gln.
Spec. 4:5–18 (emphases added). The Specification describes the above
embodiments as relating to the subject antibodies having a modified
glycosylation pattern. Id. at 3:31–4:2. Such modified glycosylation patterns
can “exhibit a high mannose glycosylation” or “the major carbohydrate is a
non-fucosylated Man5.” Id. at 4:29–5:3.
The Specification further states that, “[i]n another aspect of the
invention the antibodies with enhanced ADCC activity are not in fact
modified by the means provided herein but are antibodies selected for the
above glycosylation patterns.” Id. at 5:14–16. The Specification states that
“glycosylation pattern” refers to the set of carbohydrates that are
present on an individual antibody or on a group of antibodies.
Changes to the glycosylation pattern can be effected by altering
the glycosylation of one antibody or a group of antibodies.
Changing the glycosylation pattern of a composition of
antibodies is intended to encompass instances where the
glycosylation of an individual antibody, a subset of the
antibodies in the compositions or all of the antibodies in the
composition have been changed.
Id. at 13:9–15. Further, the Specification explains that “[g]lycosylation is a
post-translational modification that can produce a variety of final protein
forms in the natural state. IgG molecules are glycosylated at the Asn297
residue of the CH2 domain, within the Fc region.” Id. at 13:30–33.
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The Specification identifies that “one of numerous glycoforms
observed” is an aglycosylated structure, which is “more mobile” than normal
antibodies and “contribute[s] to the immunogenicity of the antibody.” Id. at
13:33–14:7. The Specification also states that “[o]ne embodiment of the
invention pertains to antibodies with increased ADCC activity that do not
have a 1,6-fucose sugar on the heavy chain” and “[i]n one embodiment, the
binding of the Fc region of the antibodies to the FcγRIII receptor found on
monocytes, macrophages and natural killer cells, is enhanced if the antibody
lacks the core fucose found attached to the Asn297 glycosylation site in the
Fc region (e.g., a fucose linked to the base of the bi-antennary structure).”
Id. at 15:5–10. The Specification states that “[t]he antibody can have a
glycosylation pattern as provided anywhere [in the Specification], which
provides or enhances the ADCC activity of the antibody.” Id. at 22:27–29.
The Specification describes that the invention seeks to produce the
aforementioned antibodies in epithelial mammary cells of transgenic animals
to be excreted in milk so they can thereafter be selected. Id. at 8:10–23.
Antibodies can be “selected” based on glycosylation patterns. Id. at 5:14–
16; see also id. at 15:14–17 (“antibodies may be selected for the ability to
bind receptors or other proteins, such as those involved in a disease process
and/or ADCC. The antibodies can be directed to any cell marker in which
providing an antibody directed thereto and having ADCC activity would
provide a therapeutic benefit.”).
For example, the Specification describes producing glycosylated and
aglycosylated mAbs in milk, e.g., of transfected goats, and purifying IgG
fractions isolated from pooled milk samples to characterize antibody binding
specificity and affinity. Id. at 28:30–29:2. The Specification further states
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that “[b]oth the glycosylated and aglycosylated chimeric antibody constructs
thereafter were used to generate transgenic goats to express anti-CD137 in
their milk.” Id. at 29:8–10; see also id. at 49:6–28, 55:8–18 (example where
IgG1 antibody is modified by replacing Asn297 with Gln297 by site-specific
mutagenesis to produce glycosylated and aglycosylated heavy chains, which
were used in transient transfection of goats and mice to produce antibodies
with enhanced ADCC properties). The Specification also states, however,
that the aglycosylated Asn297→Gln297 mutated antibodies were used as a
“negative control” because “aglycosylated IgGs are known not to bind to Fc
receptors or to be active in ADCC.” Spec. 56:27–30; 61:13–19.
According to the Specification, a fucose-containing antibody can be
separated from a non-fucosylated antibody by passing the antibodies over a
lectin column (this is the only disclosure in the Specification of any specific
antibody selecting). Id. 64:14–15. The Specification explains that:
Concanavalin A (Con A) is a lectin that binds terminal mannosyl
residues (Goldstein et al., 1965a, Biochim Biophys Acta;
Goldstein et al., 1965b Biochem.). Consistent with our findings
that milk-derived antibody had oligomannose, it bound to
concanavalin A and was eluted with alpha-methylmannoside
(Fig. 4). The major species in cell culture-derived material is
GOF, which has terminal GlcNAc residues, was not expected to
bind to concanavalin A. Fig. 4 shows that transgenic milk-
derived antibody contains oligomannose. In contrast, the
aglycosylated antibody used does not bind in the same
experiment.
Id. at 59:15–21. The Specification further explains that the majority of cell-
culture derived antibodies are fucosylated, but in milk-derived samples (e.g.,
from mice) the antibodies’ major carbohydrate is mostly non-fucosylated
Man5. Id. at 59:26–29.
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Claim 1 is representative and is reproduced below:
1. A method for enhancing the binding of the Fc region of an
IgG antibody or antibodies to an FcγRIII receptor, the method
comprising:
modifying the glycosylation of the IgG antibody or antibodies so
that the binding of the Fc region of the antibody or antibodies to
the FcγRIII receptor is enhanced,
wherein the glycosylation is modified by producing the antibody
or antibodies in mammalian mammary epithelial cells; and
selecting an antibody or antibodies that have enhanced binding
of the Fc region of the antibody or antibodies to the FcγRIII
receptor.
Appeal Br. 21 (Claims Appendix).
The following rejection is appealed:3
Claims 1–21, 43, and 44 stand rejected under 35 U.S.C. § 102(e) as
anticipated by Strome.4
DISCUSSION
“[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting a prima facie case of unpatentability. If
that burden is met, the burden of coming forward with evidence or argument
shifts to the applicant.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
“Anticipation requires that all of the claim elements and their
limitations are shown in a single prior art reference.” In re Skvorecz, 580
F.3d 1262, 1266 (Fed. Cir. 2009). To anticipate “it is not enough that the
prior art reference discloses part of the claimed invention, which an ordinary
artisan might supplement to make the whole, or that it includes multiple,

3 The Examiner withdrew a second, anticipation rejection. Answer 5.
4 US 2006/0182744 A1 (published Aug. 17, 2006) (“Strome”).
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distinct teachings that the artisan might somehow combine to achieve the
claimed invention.” Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359,
1371 (Fed. Cir. 2008). “In order to anticipate the claimed invention, a prior
art reference must ‘disclose all elements of the claim within the four corners
of the document,’ and it must ‘disclose those elements ‘arranged as in the
claim.’” Microsoft Corp. v. Biscotti, Inc., 878 F.3d 1052, 1068 (Fed. Cir.
2017)).
With these standards of law in mind, we analyze the Examiner’s
rejection and Appellant’s arguments regarding anticipation below.
Appellant has argued the claims as a group, focusing only on claim 1.
Therefore, we similarly address the issues on appeal and all claims stand or
fall with claim 1. In re Kaslow, 707 F.2d 1366, 1376 (Fed. Cir. 1983).
The Examiner determined:
Strome et al. taught a method of enhancing the binding of
the Fc region of an anti-CD137 antibody to FcγRIII by:
1) mutating the Asn 297 residue in the Fe thereby modifying the
glycosylation of the Fc region of the antibody (see, e.g.,
paragraphs [0122], [0126]-[0127]; claims 1 and 4);
2) producing the antibody in mammary epithelial cells of
transgenic mice and goats and expressing the antibody in their
milk (see paragraphs [0142]-[0144]; claims 12, 17-19); and
3) selecting the antibody with modified glycosylation by passing
the antibodies over a Con A lectin column (see, e.g., paragraph
[0268] and Figures 24a-b).
Strome’s antibodies are full length antibodies of IgGl or
IgG2 isotype (paragraph [0110], [0235]) or antibody fragments
(paragraph [0098]), chimeric, humanized, or fully human
(paragraphs [0162], [0237], claims 20-23); and exhibit high
mannose wherein at least 30% of the carbohydrates are non-
fucosylated Man 5 and fucose-containing (paragraph [0262] and
figure 23). Given that Strome et al. taught the same or nearly the
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same method of modifying glycosylation of Fc (i.e., altering the
fucose attachment site by altering residue Asn297), the prior art
antibody would have the same carbohydrate profiles as recited in
the present claims.
. . . In the instant case, by performing the steps 1-3 which
are same as those recited in claim 1, one would necessarily
produce antibodies with enhanced binding of the Fc region to
FcγRIII receptor as evidenced by the present claims.
Moreover, Strome’s teaching of passing the antibodies
over a Con A lectin column (step 3 above) reads on “selecting an
antibody or antibodies that have enhanced binding of the Fc
region of the antibody or antibodies to the FcγRIII receptor”
under the broadest reasonable interpretation in view of the instant
disclosure wherein Appellant contemplated selecting fucose-
containing antibody by separating it from the non-fucosylated
antibody by passing the antibody mixture over a lectin column
(see instant specification page 64, lines 14-15).
Answer 3–4; see also Final Action 4–6.
Appellant concedes that Strome teaches mutating the same antibody
in the same way as claimed and as disclosed in the Specification, and
producing the antibody in epithelial cells of mammaries so that it is present
in mammalian milk, but argues that the sole limitation of the claims missing
from Strome’s disclosure is selecting for the subpopulation of antibodies that
are non-fucose containing and, therefore, specifically have enhanced Fc site
binding to an FcγRIII receptor. See Hr’g Tr. 6:26–7:7 (Appellant
confirming that, compared to the invention, Strome starts with the same
antibodies, provides the same mutation, and produced the antibodies in the
epithelial cells of mammaries of mammals). Thus, although other arguments
were made in the Appeal Brief, Appellant clarifies that the sole question
here is whether Strome teaches the claimed “selecting an antibody or
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antibodies that have enhanced binding of the Fc region of the antibody or
antibodies to the FcγRIII receptor.” See Appeal Br. 13–21.
Appellant argues that the claimed “selecting” act means “separating
out a specific subpopulation of antibodies from the population of antibodies
that were obtained growing them in the mammalian mammary epithelial
cells.” Hr’g Tr. 7:13–14; Appeal Br. 15 (“The principle of ‘selecting’ results
in a subpopulation of antibodies”), 16 (Strome’s disclosure of a genus of
milk-produced antibodies, some of which inherently have enhanced binding
of the Fc region to the FcγRIII receptor is insufficient). We are not
persuaded by Appellant’s argument.
As explained in Appellant’s Specification, modified antibodies within
the scope of the invention include those that do not contain fucose, those
where one chain does not contain fucose, those where at least one chain
lacks 1,6-fucose, and those where one chain lacks fucose but contains
oligomannose. See, e.g., Spec. 4:5–18. However, it is apparent from the
disclosure and the claims, particularly dependent claim 12, that the total
omission of fucose-containing antibodies from a population of selected
enhanced antibodies is not a requirement. See, e.g., Spec. 4:23–25 (“In a
further embodiment the antibodies have been modified so that less than
50%, 40%, 30%, 20%, 10%, or fewer of the antibodies do not contain fucose
on one or at least one chain.”), 4:29–5:6 (modified antibodies of the
invention have a high-mannose glycosylation pattern and less than, e.g.,
30% carbohydrates with fucose); Appeal Br. 22. Claim 12, for example,
depends from claim 1 and requires that “less than 40% of the carbohydrates
of the antibody contain fucose.” Appeal Br. 22. Thus, Appellant’s
argument that the claimed “selecting” requires separating out some sub-
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population of modified antibodies entirely lacking fucose is not supported by
the record.
As further explained in Appellant’s Specification, there is a distinction
between modified antibodies produced in transgenic animal milk when one
subpopulation is glycosylated and one subpopulation is aglycosylated (not
glycosylated). Spec. 12:24–28, 56:26–30, Fig. 13. As opposed to milk-
produced, glycosylated, anti-CD137 antibodies, aglycosylated anti-CD137
antibodies do not bind to Fc receptors and are not active in ADCC. Id. The
glycosylated and the aglycosylated samples from pooled, milk-derived
antibodies are two subsets or subpopulations of antibodies that can be
separated using Concanavalin A (Con A) lectin, which binds mannosyl
residues (because glycosylated antibodies have mannose and aglycosylated
antibodies do not). See id. at 28:30–29:10; 55:8–18, 59:7–21. The milk-
derived glycosylated sample will express enhanced ADCC activity and
FcγRIII binding and the milk-derived aglycosylated antibodies, which do not
bind Fc receptors, will not. See id. at 61:13–62:20. Thus, dividing such a
population of milk-derived antibodies in this way selects for “an antibody or
antibodies that have enhanced binding of the Fc region of the antibody or
antibodies to the FcγRIII receptor,” as claimed.
Strome is directed to and discloses “the development and methods of
use of a recombinant agonistic antibody anti-human CD137, and
glycosylation variants thereof,” where “the recombinant antibodies of [its]
invention were produced in and purified from the milk of transgenic
animals.” Strome, Abstract. Strome teaches characterizing milk-derived
anti-CD137 antibodies by purifying milk-derived IgG fractions and
comparing its glycosylated and aglycosylated chimeric samples to one
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another and to original monoclonal antibodies and wild antibodies. Id.
¶¶ 142, 147. Strome states that:
After the purification of sufficient quantities of antibody from
milk to test the bioactivity it was found that though they were
essentially produced at identical levels, the activity profiles of
the two forms differed. More importantly their activity against
given specific types of cancers varied with each version offering
a variable level of activity vis-a-vis the other form.
Id. ¶ 142. As an initial matter and as noted above, Appellant concedes that
these Strome antibodies are the same as those of the claimed invention on
appeal. Thus, as Strome discloses that such milk-derived antibodies, having
modified (post-translational) glycosylation are separated into glycosylated
and aglycosylated samples, this act necessarily requires selecting the
glycosylated variant, which would have the enhanced binding of the Fc
region to the FcγRIII receptor, as claimed. Such a comparison could not be
accomplished without having made such a selection.
Strome also explains how to select for the glycosylated, modified
antibodies. Strome teaches that such antibodies’ oligosaccharides were “a
mixture of high mannose, hybrid and complex type oligosaccharides with or
without fucose.” Id. ¶ 249. Strome teaches, however, that in the anti-
CD137 antibodies expressed, the major oligosaccharide was Man5 without
fucose, as opposed to the wild type that contained mainly fucosylated
oligosaccharides. Id. ¶ 262. Strome teaches that the majority of transgenic
glycosylated antibodies bind to Con A – a lectin specific for high mannose
type carbohydrates (just as described in Appellant’s Specification). Id.
Strome teaches that, while glycosylated transgenic antibodies bind to Con A,
most of non-glycosylated anti-CD137 antibodies and antibodies without any
high mannose oligosaccharides do not bind to Con A. Id. ¶¶ 262–268.
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Strome discloses that its “FIG. 24(a)-(b) [s]how[ ] chromatographs of
glycosylated and non-glycosylated transgenic antibodies on Con A column,”
and its “FIG. 25(a)-(b) [s]how[ ] the use of a Lentil lectin column used to
determine the presence of core fucose” in milk-derived antibodies. Id.
¶¶ 38–39. Further, “[b]oth glycosylated and non-glycosylated transgenic
antibodies were applied to a Lentil lectin column, respectively. The bound
protein was eluted by a-methylmannoside.” Id. ¶ 39. Thus, Strome
discloses and illustrates selecting for antibodies with enhanced binding of
the Fc region, to FcγRIII receptor, as claimed.
Strome discloses the same method as claimed. For the reasons above,
we conclude that the Examiner did not err in determining that Strome
anticipates the rejected claims.
CONCLUSION
In summary:
Claims
Rejected 35 U.S.C. § Reference Affirmed Reversed
1–21, 43, 44 102(e) Strome 1–21, 43, 44
Overall
Outcome 1–21, 43, 44

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED