Ex Parte Goldenberg

Patent Trial and Appeal Board

Jul 26, 2013

10002211 (P.T.A.B. Jul. 26, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte MILTON D. GOLDENBERG
__________

Appeal 2011-010821
Application 10/002,211
Technology Center 1600
__________

Before LORA M. GREEN, JACQUELINE WRIGHT BONILLA, and
ANNETTE R. REIMERS, Administrative Patent Judges.

BONILLA, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims directed to a
method for ablating cells or treating an immune disease by administering to
a subject a B-cell antibody or fragment thereof.
1
The Examiner has rejected
the claims as lacking adequate written description and enablement, and as
anticipated and obvious. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm.

1
Appellant identifies the Real Party in Interest as Immunomedics, Inc.
(App. Br. 2.) An oral hearing regarding this appeal took place on May 2,
2013.
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STATEMENT OF THE CASE
The Specification describes methods of treating and ablating normal
tissues by parenterally injecting a subject with an antibody or antibody
fragment that binds a tissue, where the antibody or fragment is bound to a
therapeutic and/or ablation agent (Spec. 3-4, 6).
Claims 78-86, 93-108, 114, and 116 are on appeal.
2
Independent
claims 78 and 104 are representative and read as follows:
78. A method of ablating normal cells in a subject, comprising
parenterally administering to a subject a therapeutically effective
amount of a sterile injectable composition comprising a B-cell
antibody or fragment thereof, which specifically binds to a B-cell, in a
pharmaceutically acceptable injection vehicle, thereby to ablate the
normal cells.
104. A method of treating an immune disease in a subject, comprising
parenterally administering to a subject that has been diagnosed with
an immune disease a therapeutically effective amount of a sterile
injectable composition consisting of a B-cell antibody or fragment
thereof, which specifically binds to a B-cell, in a pharmaceutically
acceptable injection vehicle, whereby the immune disease is treated.
The claims stand rejected as follows:
I. Claims 78-86, 93-108, 114, and 116 under 35 U.S.C. § 112, 1st ¶,
for lack of adequate written description;
II. Claims 78-86, 93-108, 114, and 116 under 35 U.S.C. § 112, 1st ¶,
for lack of enablement;
III. Claims 78, 81-86, 102-105, 114, and 116 under 35 U.S.C. § 102(b)
as anticipated by Meyer;
3

2
Appellant has cancelled claims 1-77, 87-92, 109-113, and 115. See
Amendment dated October 8, 2010.
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IV. Claims 78, 79, 81, 93, 96, 102-107, 114, and 116 under 35 U.S.C.
§ 102(b) as anticipated by Bussel,
4
as evidenced by de Grandmont;
5

V. Claims 78, 80, 93, 95-101, 107, and 108 under 35 U.S.C. § 103(a)
obvious over Meyer in view of Sivam;
6
and
VI. Claims 78 and 94 stand rejected under 35 U.S.C. § 103(a) obvious
over Meyer in view of Fishwild;
7

Rejection I – Written Description
The Examiner finds that the “specification does not provide adequate
written description support for the broad genus of antibodies in the method
of ablating normal cell, or a method of treating an immune disease” (Ans. 5).
The Examiner states that the “ablation method do[es] not describe any B-cell
antibody or antibody that is specific to a marker associated with a B cell,”
and does “not disclosed „fully characterized antigen or a marker associated
with a B-cell, either by its structure, formula, chemical name or physical
properties, or by depositing the protein in a public depository‟ for which the
B-cell antibody would bind,” citing Noelle v. Lederman, 355 F.3d 1343,
1349 (Fed. Cir. 2004) (Ans. 5). The Examiner also states that the “single

3
Meyer, Jr. et al., U.S. Pat. No. 4,861,579, issued Aug. 29, 1989.
4
Bussel et al., Maintenance Treatment of Adults With Chronic Refractory
Immune Thrombocytopenic Purpura Using Repeated Intravenous Infusions
of Gammaglobulin, 72 BLOOD, 121-127 (1988).
5
de Grandmont et al., Intravenous immunoglobulins induce the in vitro
differentiation of human B lymphocytes and the secretion of IgG, 101 BLOOD
3065-3073 (2003).
6
Sivam et al., U.S. Pat. No. 5,116,944, issued May 26, 1992.
7
Fishwild et al. High-avidity human IgGк monoclonal antibodies from a
novel strain of minilocus transgenic mice, 14 NATURE BIOTECHNOLOGY 845
-851 (1996).
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monoclonal antibody LL2” described in the Specification at page 12 “is
insufficient to represent the genus of the monoclonal antibodies required to
practice the claimed ablation method in a subject” (id. at 5-6).
In addition, the Examiner states that the Specification does not
adequately support the phrase “B-cell immune disease,” recited in dependent
claims 102 and 105 (Ans. 8-9). According to the Examiner, such a disease
“is not recognized as a class of disorders by one of skill in the art,” and the
“specification only disclose „an immune disease, lymphoma or other
disease‟” (Ans. 8 (citing Spec. 12, ll. 34-35)). Likewise, the Examiner finds
that the Specification fails to adequately support the phrase “a marker
associated with a B cell,” as recited in claims 114 and 116 (id. at 9-10).
According to the Examiner, the Specification fails to set “forth the relevant
identifying characteristics of the marker associated with a B-cell (e.g.
structural elements of the antibody or B-cell marker)” (id. at 10).
Appellant offers evidence that claim phrases “B-cell antibody,” “B-
cell immune disease,” and “marker associated with a B cell” represented a
number of antibodies, diseases and markers that were well known and
understood in the art. (App. Br. 4-16, citing, e.g., Declarations by Drs. Foon
and Dörner; see also Reply Br. 1-5). We find Appellant‟s argument and
evidence persuasive regarding the written description rejections.
When evaluating claims for written description, a specification must
be viewed from the perspective of a person of skill in the art, who is deemed
to “come[] to the patent with the knowledge of what has come before.”
LizardTech, Inc. v. Earth Res. Mapping, Inc., 424 F.3d 1336, 1345 (Fed. Cir.
2005). Thus, a specification need not spell out every detail of the invention,
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but “enough must be included to convince a person of skill in the art that the
inventor possessed the invention” at the time the application was filed. Id.
Here, Appellant persuades us that, in view of what an ordinary artisan would
have known about a number of B-cell antibodies, diseases, and markers at
the time of filing, the Specification provides adequate written description
support of the claim phrases identified by the Examiner.
Rejection II – Enablement
The Examiner states the Specification fails to enable one of skill in the
art how to make and use the subject matter recited in method claims 78-86,
93-108, 114, and 116 (Ans. 10-13).
To be enabling, a specification must “teach those skilled in the art
how to make and use the full scope of the claimed invention without „undue
experimentation.‟” ALZA Corp. v. Andrx Pharm., LLC, 603 F.3d 935, 940
(Fed. Cir. 2010) (citations omitted). Whether undue experimentation is
required “is not a single, simple factual determination, but rather is a
conclusion reached by weighing many factual considerations.” ALZA, 603
F.3d at 940 (citing In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988)). In
Wands, the Federal Circuit set forth the following factors to consider when
determining whether a disclosure requires undue experimentation:
(1) the quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of
working examples, (4) the nature of the invention, (5) the state
of the prior art, (6) the relative skill of those in the art, (7) the
predictability or unpredictability of the art, and (8) the breadth
of the claims.
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Wands, 858 F.2d at 737. It is not necessary to review all the Wands factors
to find a disclosure enabling; “[t]hey are illustrative, not mandatory.”
Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1213 (Fed. Cir. 1991).
Here, the Wand factors weigh in favor of concluding that undue
experimentation would have been necessary to practice the claimed methods
at the time of filing. First, as the Examiner notes, “the claimed B cell
antibody would encompass any or all antibody that binds cell surface as well
as intracellular proteins not exclusive to B cells” (Ans. 11, 30). In other
words, the pending claims are very broad in scope. See, e.g., independent
claims 78 and 93 (directed to ablating any normal cells using any B-cell
antibody or fragment); claim 104 (directed to treating any immune disease
using any B-cell antibody or fragment). Such claims encompass large
genuses. As just one example, the claims encompass the use of any
“fragment thereof” in relation to a generically recited B-cell antibody. The
Specification, on the other hand, describes only one B-cell antibody (LL2
monoclonal antibody) (Spec. 12) in particular, and provides no examples or
experimental results regarding ablation of any normal cells or the treatment
of any immune disease in relation to a B-cell antibody (see Ans. 11-12).
In addition, it is generally the case that “[p]harmaceutical therapies in
the absence of in vivo clinical data are unpredictable,” for the reasons stated
by the Examiner, among others (id. at 12). Likewise, as noted by the
Examiner, “it is unpredictable whether all of the B-cell antibodies . . . can be
administered alone or conjugated to „therapeutic agent‟ and/or „a drug‟
and/or „a cytokine‟ to treat immune disease as broadly claimed” (id.).
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In response, Appellant argues that “[a] skilled artisan does not
understand the term „B-cell antibody‟ in applicant's claims to include HLA-
DR antibodies such as Lym-1 and Lym-2,” described in the Meyer reference
(App. Br. 17). In the Reply Brief, Appellant further responds to the
Examiner‟s concerns about therapies being unpredictable in the absence of
in vivo clinical data. Appellant argues that:
many of the examiner‟s concerns, e.g., proteolytic degradation,
inability to cross the mucosa or absorption by fluids cells and
tissues where the protein has no effect, are not particularly
applicable in the context of an antibody administered
parenterally by sterile injection to bind with B-cells, a large
percentage of which are in the bloodstream.
(Reply Br. 6). Appellant also states that Dr. Foon‟s Declaration counters
such concerns when explaining that “B-cell antibodies were disclosed prior
to 1992 for therapy of B-cell cancers, where they would experience these
same alleged problems,” citing certain studies using a handful of B cells
antibodies to affect cancer progression (id.).
Weighing the Wand factors here, we conclude that the Examiner
establishes by a preponderance of the evidence that the Specification does
not sufficiently enable the pending claims. Specifically, one skilled in the
art would have needed to engage in undue experiment to practice the
claimed methods, especially without more disclosure in the Specification
regarding the characteristics of the B-cell antibodies or fragments, agents,
drugs, and/or cytokines, as they relate to an ability to ablate normal cells
and/or treat an immune disease in a subject (see Ans. 13, 31). Appellant‟s
arguments and evidence regarding a subset of “concerns” and declaration
evidence regarding some B-cell antibodies used to treat cancer are
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insufficient to persuade us otherwise in light of the broad claim scope at
issue, particularly as it relates to an unpredictable field.
Rejection III – Anticipation by Meyer
The Examiner rejects claims 78, 81-86, 102-105, 114, and 116 as
anticipated by Meyer (Ans. 13-14). The Examiner finds that Meyer teaches
a method of treating immune diseases by administering an anti-B antibody
or fragment thereof that suppresses the response of B-lymphocytes (id.).
The Examiner states that “although the reference is silent about the ablation
of normal cells, the claim language or limitation of ablating normal cell does
not result in a manipulative difference in the method steps when compared
to the prior art disclosure” (id. at 14). Thus, according to the Examiner, the
methods described in Meyer inherently encompass the ablation of normal
cells in a subject (id. at 14, 34-35).
Appellant argues that “according to Meyer the side effects arising
from the treatment of autoimmune diseases using antibodies may be treated
using an antibody against the B-lymphocytes,” and therefore Meyer does not
teach using B-cell antibodies to ablate normal cells, as recited in
independent claims 78 and 93, or to treat an immune disease, as recited in
independent claim 104 (App. Br. 18; Reply Br. 8). Appellant also contends
that those skilled in the art would not consider Meyer‟s Lym-1 and Lym-2
antibodies to be B-cell antibodies. According to Appellant, these antibodies
preferentially bind to HLD-DR (a MHC class II cell surface receptor)
present on malignant B cells, but bind only at low levels on normal cells (id.
at 19). In other words, as stated by the Examiner, Appellant has “not
disagreed that HLA-DR antigen expressed on B-cell surface,” but instead
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argues that because HLD-DR “is expressed at low level” on normal B cells,
“antibodies specific to HLA-DR are not considered B-cell antibodies” (Ans.
34).
“[D]uring examination proceedings, claims are given their broadest
reasonable interpretation consistent with the specification.” In re Hyatt, 211
F.3d 1367, 1372 (Fed. Cir. 2000). In this case, the Specification does not
define “B-cell antibody.” At most, it refers to “antibodies against bone
marrow cells” or “B-cells” generally (Spec. 9, 12), and refers to one example
when it states that “[a]ntibodies that target the spleen well include the LL2
(also known as EPB-2) monoclonal antibody … which is directed against
normal and malignant B-cells” (id. at 12). Thus, the Specification does not
define a “B-cell antibody” to be something narrower than its ordinary
meaning, i.e., an antibody that binds a B-cell with any measurable level of
specificity. Thus, we are not persuaded by Appellant‟s argument that the
recited “B-cell antibody” does not encompass Lym-1 and Lym-2 antibodies
described in Meyer, especially when Appellant concedes that these
antibodies bind to both malignant and normal B-cells (albeit the binding to
normal B-cells is less than that to malignant B-cells).
In addition, Meyer does not merely describe using B-cell antibodies to
treat side effects arising from the treatment of autoimmune diseases using
antibodies. Meyer also describes administering B-cell antibodies, such as
the Lym antibodies, to humans to treat B-lymphocyte lymphoma (Meyer,
col. 2, ll. 59-65 (stating that “[a]ntibodies to malignant B-lymphocytes,
useful for the treatment of B-lymphocyte lymphoma, are often cross-reactive
with normal B-lymphocytes”); see also id. at col. 3, ll. 37-46). Thus, Meyer
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teaches using B-cell antibodies to treat a cancer involving B-cells, and
indicates that such antibodies also bind to normal B-cells. Meyer further
teaches administering B-cell antibodies to “elicit antibody mediated or cell
mediated cytotoxicity” (id. at col. 1, ll. 59-65).
As the Examiner and Appellant both agree, however, Meyer does not
expressly disclose ablating cells, as recited in claims 78 and 93. The
Examiner states that ablating cells (removing cells from a tissue) inherently
or necessarily occurs when administering B-cells to treat B-cell lymphoma
as described in Meyer because the steps in Meyer are otherwise the same as
those recited in claims 78 and 93.
An examiner has the burden of providing reasonable proof that a
claim limitation is an inherent characteristic of the prior art. In re Best, 562
F.2d 1252, 1254-55 (CCPA 1977). The Examiner meets this “burden of
production by „adequately explaining the shortcomings it perceives so that
the applicant is properly notified and able to respond.‟” In re Jung, 637 F.3d
1356, 1362 (Fed. Cir. 2011) (quoting Hyatt v. Dudas, 492 F.3d 1365, 1370
(Fed. Cir. 2007)). The burden of proof then shifts to Appellant “to prove
that the subject matter shown to be in the prior art does not possess the
characteristic relied on.” Best, 562 F.2d at 1254-55; In re Schreiber, 128
F.3d 1473, 1478 (Fed. Cir. 1997) (holding that once the Examiner
established a prima facie case of anticipation, the burden of proof was
properly shifted to the inventor to rebut the finding of inherency).
As stated by the Examiner:
Given that Meyer et al. recognize that antibodies to
malignant B-lymphocytes are often cross-reactive with normal
B-lymphocytes (see entire document, particularly lines 59-62
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on column 2), the prior art method of administering such
antibodies to malignant B-lymphocytes cross-reactive with
normal B-lymphocyte would inherently result in ablating
normal cells including spleen B cells in a subject. It is
reasonable to conclude that the same patient population is being
administered with the same active agent of B-cell antibody by
the same mode of administration in both the instant claims and
the prior art reference.
(Ans. 34.) Thus, the Examiner provides a reasonable basis for finding that
Meyer inherently discloses ablating cells because the method in Meyer and
the method recited in claims 78 and 93 similarly involve administering B-
cell antibodies to a subject. Moreover, it is reasonable to presume that
Meyer‟s methods for treating B-cell lymphoma and/or eliciting antibody-
mediated or cell-mediated cytotoxicity necessarily involve ablating both
malignant and normal cells to which the antibody binds.
The burden therefore shifts to Appellant to show that ablating cells
does not necessarily occur when one follows the method disclosed in Meyer.
Appellant provides no evidence or argument establishing how/if one would
not necessarily ablate cells when administering B-cell antibodies to treat B-
cell lymphoma. The Examiner therefore makes a prima facie case of
anticipation of claims reciting a method of ablating normal cells, and
Appellant does not persuade us to the contrary.
Claim 104 recites a method of treating “an immune disease.” While it
is a close call whether a B-cell lymphoma qualifies as “an immune disease,”
we must consider what the Specification teaches. The Specification does not
define “immune disease” per se, but describes a treatment involving
“ablation of certain normal organs and tissues for other therapeutic purposes,
such as the spleen in patients with immune disease or lymphomas….” (Spec.
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6-7) (emphasis added). The Specification also refers to “cytotoxic ablation
of the spleen in patients with lymphoma or certain immune diseases, such as
immune thrombocytopenic purpura, etc” (id. at 9) (emphasis added).
Likewise, the Specification describes “treating normal spleen cells in
patients with immune diseases, lymphoma, and other diseases” (id. at 12).
Thus, the Specification distinguishes between an immune disease and a
lymphoma, such as B-cell lymphoma described in Meyer. Thus, we agree
with Appellant that Meyer does not expressly or inherently (i.e., necessarily)
disclose the use of a B-cell antibody to treat “an immune disease” as we
interpret that phrase based on a broadest reasonable interpretation consistent
with the Specification.
We conclude that the Examiner establishes by a preponderance of the
evidence that Meyer anticipates claims 78, 81-86, 114, and 116, but not
claims 102-105.
Rejection IV – Anticipation by Bussel
The Examiner rejects claims 78, 79, 81, 93, 96, 102-107, 114, and 116
as anticipated by Bussel, as evidenced by de Grandmont (Ans. 14-15). The
Examiner states that Bussel teaches “a method of treating immune
thrombocytopenic purpura by administering intravenous immunoglobulins
(IVIG)” (id. at 14). The Examiner relies on de Grandmont to establish that
IVIGs “contain antibodies reacting against a large repertoire of antigens,
including those on B lymphocytes, e.g. CD40” (id. at 15). Thus, according
to the Examiner, Bussel inherently teaches administering B-cell antibodies,
including antibodies specific for a marker associated with a B-cell (such as
CD40), to treat immune thrombocytopenic purpura (id.).
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Appellant argues, and we agree, that de Grandmont does not disclose
or establish that the IVIGs disclosed in Bussel comprise B cell antibodies in
a sufficient amount or kind to ablate normal cells or treat an immune
disease. The arguments and evidence cited by Appellant (App. Br. 20-21;
Reply Br. 8-9) persuade us that the Examiner fails to establish anticipation
of pending claims by Bussel.
Rejection V – Obviousness over Meyer in view of Sivam
The Examiner rejects claims 78, 80, 93, 95-101, 107, and 108 as
obvious over Meyer in view of Sivam (Ans. 15-16). The Examiner finds
that “Sivam et al. teach antibody and its fragments such as Fv, single chain
antibody, Fab, Fab‟, F(ab‟)2 and chimeric antibody can be conjugated to
cytokines to improve characteristic[s],” such as half-life, stability and up-
take (id. at 16). In response, Appellant argues that Sivam “fails to overcome
Meyer‟s failure to teach treatment of an immune disease with a B-cell
antibody” (App. Br. 22; Reply Br. 10).
Appellant points may be well taken regarding pending claims reciting
a method of treating an “immune disease.” That said, as discussed in
Section III above, the Examiner sufficiently establishes that Meyer
inherently discloses a method of “ablating normal cells” by administering a
B-cell antibody to a subject, as recited in claims 78, 80, 93, 95-101, 107, and
108. Thus, the Examiner establishes a prima facie case of obviousness of
these claims, and Appellant‟s arguments do not persuade us otherwise. We
conclude that the Examiner establishes by a preponderance of the evidence
that claims 78, 80, 93, 95-101, 107, and 108 are obvious over Meyer in view
of Sivam.
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Rejection VI – Obviousness over Meyer in view of Fishwild
The Examiner rejects claims 78 and 94 as obvious over Meyer in view
of Fishwild (Ans. 17-18). The Examiner finds that Fishwild teaches
methods of making human monoclonal antibodies (id. at 17). Appellant
argues that Fishman “fails to overcome Meyer‟s failure to teach treatment of
an immune disease with a B-cell antibody” (App. Br. 22; Reply Br. 10).
As discussed in Section III above, the Examiner sufficiently
establishes that Meyer inherently discloses a method of “ablating normal
cells” by administering a B-cell antibody to a subject, as recited in claims 78
and 94. Thus, the Examiner establishes a prima facie case of obviousness of
these two claims, and Appellant‟s arguments do not persuade us otherwise.
We conclude that the Examiner establishes by a preponderance of the
evidence that claims 78 and 94 are obvious over Meyer in view of Fishwild.
SUMMARY
We reverse the rejection of pending claims for lack of adequate
written description. We affirm, however, the rejection of pending claims for
lack of enablement. In addition, we affirm the rejection of claims 78, 81-86,
114, and 116 as anticipated by Meyer, but reverse the same rejection
regarding claims 102-105. We reverse the rejection of claims 78, 79, 81, 93,
96, 102-107, 114, and 116 as anticipated by Bussel. We affirm the
rejections of claims 78, 80, 93, 95-101, 107, and 108 as obvious over Meyer
in view of Sivam, and claims 78 and 94 as obvious over Meyer in view of
Fishwild.
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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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