Ex Parte Govindan et al

Patent Trial and Appeal Board

Apr 24, 2017

13774526 (P.T.A.B. Apr. 24, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
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Alexandria, Virginia 22313-1450
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/774,526 02/22/2013 Serengulam V. Govindan IMMU-0031US2 7799
37013 7590 04/26/2017
Rossi, Kimms & McDowell LLP
20609 Gordon Park Square
Suite 150
Ashburn, VA 20147
EXAMINER
MOSELEY II, NELSON B
ART UNIT PAPER NUMBER
1642
NOTIFICATION DATE DELIVERY MODE
04/26/2017 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
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SERENGULAM V. GOVINDAN
and DAVID M. GOLDENBERG1
Appeal 2017-004473
Application 13/774,526
Technology Center 1600
Before MELANIE L. McCOLLUM, ULRIKE W. JENKS, and DAVID
COTTA, Administrative Patent Judges.
McCOLLUM, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an
autoimmune disease treatment method. The Examiner has rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The Specification “concerns compositions and methods of use of
immunoconjugates, comprising one or more camptothecin moieties attached
to an anti-CD22 antibody or antigen-binding fragment thereof’ (Spec. 3).
1 Appellants identify the real party in interest as Immunomedics, Inc. (App.
Br. 2).
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Application 13/774,526
The Specification discloses that, “[preferably, the anti-CD22 antibody is
epratuzumab [(also known as hLL2)] and the camptothecin is SN-38” (id.
3 & 25). The Specification also discloses that the “immunoconjugate is
of use to treat B cell diseases, such as . . . autoimmune disease,” and that
“[ijmmune diseases may include . . . systemic lupus erythematosus (SLE)”
(id. 113 & 197).
Claims 1, 2, 5—10, 15, 16, 18—30, 33, 36, 37, and 39-46 are on appeal
(App. Br. 3 & 16—18).2 Claim 1 is representative and reads as follows:
1. A method of treating an autoimmune disease comprising
administering to an individual with an autoimmune disease that is mediated
by CD22-expressing B cells, an immunoconjugate consisting of (i) an anti-
CD22 antibody or antigen binding fragment thereof; and (ii) at least one
therapeutic agent attached by a linker to the anti-CD22 antibody or fragment
thereof, wherein the therapeutic agent is a camptothecin.
Claims 1, 5-8, 15, 16, 18, 19, 22, 23, 29, 33, 36, 37, 39, 40, 43, and 44
stand rejected under 35 U.S.C. § 103(a) as obvious over Goldenberg3 in
view of Abrams4 and Allen5 (Final Act.6 3).
Claims 2 and 30 stand rejected under 35 U.S.C. § 103(a) as obvious
over Goldenberg in view of Abrams, Allen, and Leung7 (id.).
2 Claims 3, 4, 31, and 32 are also pending but have been withdrawn from
consideration (11/5/15 Amend. 2 & 6 & 3/27/2014 Final Act. 1).
3 Goldenberg et al., WO 00/74718 Al, Dec. 14, 2000.
4 Abrams, US 4,867,962, Sep. 19, 1989.
5 Allen et al., US 6,056,973, May 2, 2000.
6 “Final Act.” refers to the Final Office Action dated May 5, 2015.
7 Shui-on Leung et al., Construction and Characterization of a Humanized,
Internalizing, B-cell (CD22)-Specific, Leukemia/Lymphoma Antibody, LL2,
32 Molecular Immunology 1413—27 (1995).
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Claims 9 and 10 stand rejected under 35 U.S.C. § 103(a) as obvious
over Goldenberg in view of Abrams, Allen, and Hansen8 (id. at 4).
Claims 20 and 41 stand rejected under 35 U.S.C. § 103(a) as obvious
over Goldenberg in view of Abrams, Allen, and Sakaguchi9 (id. ).
Claims 21 and 42 stand rejected under 35 U.S.C. § 103(a) as obvious
over Goldenberg in view of Abrams, Allen, and Charlotte10 (id.).
Claims 24—28 stand rejected under 35 U.S.C. § 103(a) as obvious over
Goldenberg in view of Abrams, Allen, and Root* 11 (id. at 4—5).
Claims 45 and 46 stand rejected under 35 U.S.C. § 103(a) as obvious
over Goldenberg in view of Abrams, Allen, and Nepom12 (id. at 5).
The Examiner relies on Goldenberg for teaching “a method for
treating autoimmune disorders by administering antibodies that bind to a B
cell antigen, such as the CD22 antigen, conjugated to a drug” (Ans. 4). The
Examiner finds that Goldenberg teaches “that anti-B cell antibodies suitable
for use in the invention may be an LL2 antibody” and “that SLE is among
the autoimmune disorders that can be treated by the disclosed therapeutic
composition” (id.). However, the Examiner finds that Goldenberg does “not
8 Hansen et al., US 2003/0219433 Al, Nov. 27, 2003.
9 Nahoko Sakaguchi et al., Reactive Oxygen Species and Intracellular Ca2+,
Common Signals for Apoptosis Induced by Gallic Acid, 55 Biochemical
Pharmacology 1973—81 (1998).
10 Charlotte Magdelaine-Beuzelin et al., IgGl Heavy Chain-Coding Gene
Polymorphism (Glm Allotypes) and Development of Antibodies-to-
Infliximab, 19 Pharmacogenetics & Genomics 383—87 (2009).
11 Root et al., US 4,200,690, Apr. 29, 1980.
12 Gerald T. Nepom, Therapy of Autoimmune Diseases: Clinical Trials &
New Biologies, 14 Current Opinion Immunology 812—15 (2002).
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teach that an antibody and therapeutic agent can be conjugated via a linker,
nor ... the camptothecin, SN-38, as a therapeutic agent” (id. at 5).
The Examiner relies on Abrams for teaching “that for some
immunoconjugates that comprise antibodies linked to therapeutic
compounds, the biological activity of the compound may be reduced if the
compound is attached to the antibody” and that, “[tjherefore,
immunoconjugates comprising linkages which are cleavable in the vicinity
of the target site may be used” (id.). In view of Abrams, the Examiner
concludes that it would have been obvious “to prepare [Goldenberg’s]
immunoconjugates comprising an antibody and a therapeutic agent that are
conjugated via a linker” (id. at 6).
The Examiner relies on Allen for teaching “that the camptothecin
analogue SN-38 is a cytotoxic agent that has a deleterious or toxic effect on
cells” (id. at 5). The Examiner concludes:
One of ordinary skill in the art would have been motivated to
arrive at the claimed invention, because by administering an
immunoconjugate consisting of an anti-CD22 antibody
conjugated to SN-38 to patients with SLE, said immuno­
conjugate would bring B cells responsible for producing
autoantibodies into contact with SN-38, and the SN-38 would be
expected to have a deleterious or toxic effect on the
autoantibody-producing B cells.
(Id. at 6.)
ISSUE
Appellants traverse the rejection over Goldenberg in view of Abrams
and Allen (App. Br. 3—16). With regard to the other obviousness rejections,
Appellants merely argue that the additionally applied references do not
overcome the deficiencies of Goldenberg, Abrams, and Allen (id. at 16—18).
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Thus, the following issue is dispositive for all of the rejections on appeal:
Does the evidence supports the Examiner’s conclusion that the combination
of Goldenberg, Abrams, and Allen suggest the method of representative
claim 1?
ANALYSIS
Goldenberg states that “[ajutoimmune diseases are a class of diseases
associated with a B-cell disorder” and that the “most common treatments are
corticosteroids and cytotoxic drugs” (Goldenberg 2: 6—10). Goldenberg
“relates to immunotherapeutic methods for treating autoimmune disorders
... by administering antibodies that bind to a B-cell antigen, such as the
CD22 . . . antigen” (id. at 1: 11—14). Goldenberg discloses that the
antibodies “may be naked or conjugated to a drug, toxin or therapeutic
radioisotope” (id. at 1: 15—16). Goldenberg also discloses that “[djrugs
which are known to act on B-cells, plasma cells and/or T-cells are
particularly useful in accordance with the present invention, whether
conjugated to a B-cell antibody, or administered as a separate component in
combination with a naked or conjugated B-cell antibody” (id. at 16: 31 to
17: 2).
Abrams discloses that a “problem associated with some methods of
linking certain therapeutic compounds to antibodies is that the biological
activity of the compound (e.g., drug, toxin, etc.) may be reduced when the
compound is attached to the antibody” (Abrams, col. 6,11. 55—59). Abrams
therefore discloses “immunoconjugates comprising linkages which are
cleavable in the vicinity of the target site” (id. at col. 6,11. 63—65).
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Allen discloses that cytotoxic agents include “a topoisomerase I
inhibitor, such as camptothecin and its analogues, including SN-38” (Allen,
col. 8,11. 50-52). In view of the teachings of Goldenberg, Abrams, and
Allen, we conclude that the Examiner has set forth a prima facie case of
obviousness (Ans. 4—6).
Appellants argue, however, that it “would not have been prima facie
obvious to conjugate a camptothecin such as SN-38 to an antibody for
delivery” (App. Br. 6). In particular, Appellants argue:
The fact that techniques in which SN-38 and other camptothecin
derivatives are formulated attached to delivery agents such as
polymers, polymeric micelles, or liposomes as carriers failed to
show antitumor activity in clinical studies contravenes any
conclusion by the examiner that it would have been obvious to
attach SN-39 [sic, SN-38] to an antibody for delivery.
{Id. at 7 (emphasis omitted).) We are not persuaded.
Appellants have submitted a Declaration of one of the inventors,
Dr. Goldenberg,13 which states:
Several approaches have been reported making use of polymers,
polymeric micelles, or liposomes as carriers of SN-38 and other
camptothecin derivatives for protracted release of the active drug
or for passive targeting to tumor sites. So far, those conjugated
with SN-38, such as polyethylene glycol (PEG), have failed to
show antitumor activity in clinical studies.
(Decl. 15.) However, we do not agree with Appellants that this statement
suggests that the claimed conjugate would not have been expected to work.
In fact, the Declaration states, based on the above-mentioned failure, that
13 Declaration under 37 C.F.R § 1.132 of Dr. David M. Goldenberg, signed
September 23, 2014 (filed September 29, 2014).
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“targeting by attachment to an anticancer antibody appears to be a preferred
approach” {id.).
Appellants also argue that “there is data of record showing that the
results for ADCs [(antibody-drug conjugates)] comprising SN-38 are
unexpected as compared to results with unconjugated irinotecan,” which is
the parent of SN-38 (App. Br. 7—8 & 10). In support of this position,
Appellants point to the Goldenberg Declaration, as well as Examples 14 and
15 of the present Specification and Sharkey14 {id. at 9). We are not
persuaded.
Sharkey discloses “the efficacy of SN-38 conjugates prepared with
epratuzumab [(Emab)] . . . , humanized anti-CD22 . . ., was examined for
the treatment of B-cell malignancies” (Sharkey, Abstract). Sharkey also
discloses that “Emab—SN-38 is active in lymphoma and leukemia at doses
well below toxic levels” {id.). In addition, Sharkey discloses that “[c]ross-
linked, unconjugated epratuzumab had no effect on cell viability, but Emab—
SN-38 killed 100% of the cells at approximately 1 to 10 nmol/L” {id. at
226). Similarly, the Specification states that “[hjumanized anti-CD22 MAb
(epratuzumab) conjugated with SN-38 . . . shows potent efficacy for therapy
of hematologic tumors” (Spec. 87).
The Declaration states that it “is surprising . . . that conjugation of
Emab to SN-38 does not increase the toxicity, since it has a different
detoxification mechanism, with reduced production of glucuronidated
14 Robert M. Sharkey et al., Epratuzumab—SN-38: A New Antibody-Drug
Conjugate for the Therapy of Hematologic Malignancies, 11 Molecular
Cancer Therapeutics 224—34 (2011).
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SN-38, thus mitigating side effects, such as neutropenia and diarrhea,
usually associated with SN-38 released from irinotecan or Camptosar”
(Decl. 111). The Declaration also states that it “was completely unexpected
that the negative side effects of the camptothecins could be mitigated by
administering them as a conjugate, and that a much lower dose of the
camptothecin could be administered without loss of efficacy” {id. 113).
However, as noted by the Examiner (Ans. 22), “[tjumor-directed
therapy has the potential to improve efficacy, by increasing the intratumoral
concentration of the targeted agent, and to minimize toxicity by reducing
systemic exposure” (Trail15 584). Thus, we agree with the Examiner that
Appellants have not adequately explained why
the invention of Goldenberg et al. would [not] be expected to
more effectively deliver a therapeutic agent, such as a
camptothecin, to a CD22-expressing autoimmune cell when
compared to the delivery of an unconjugated camptothecin,
because the conjugate of Goldenberg et al. would be expected to
deliver a therapeutic agent directly to the cells that are mediating
autoimmune disease.
(Ans. 18.)
We note Appellants’ arguments that “even [cancer] patients who had
failed prior therapy with irinotecan or Camptosar, both topoisomerase-1
inhibitors, responded to IMMU-132,” which targets the TROP-2 antigen,
and that
since many of the patients had failed therapy with unconjugated
irinotecan, it is entirely unexpected that the approach of
15 Pamela A. Trail & Albert B. Bianchi, Monoclonal Antibody Drug
Conjugates in the Treatment of Cancer, 11 Current Opinion Immunology
584—88 (1999).
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conjugating to an antibody would have led to any response at all,
and certainly not to a disease control rate of 82%, which included
patients for whom irinotecan or Camptosar was not efficacious!
(App. Br. 7—8 (emphasis omitted); see also Decl. 1 8.)
However, we agree with the Examiner that Appellants have not
adequately explained why this data is sufficient to demonstrate unexpected
results for the use of an anti-CD22 antibody drug conjugate in the treatment
of an autoimmune disease (Ans. 26 (“Appellants’] allegedly unexpected
results, which are concerned with treating solid tumors, do not predict the
efficacy of treating a B cell-mediated autoimmune disease with an anti-
CD22/camptothecin conjugate.”)). In addition, we note that Appellants’
data does not provide a comparison to the closest prior art, which teaches the
use of an anti-CD22 antibody drug conjugate in the treatment of an
autoimmune disease.
In this regard, we recognize that the Declaration states that, “since
CD22+ B cells are a proven therapeutic target for the therapy of autoimmune
diseases (as evidenced by published results of epratuzumab in patients with
moderate/severe systemic lupus erythematosus and Sjogren’s disease), [Dr.
Goldenberg] fmd[s] these data persuasive of success in treating autoimmune
disease” (Decl. 112). However, we do not agree with Appellants that
evidence of an expectation of success is sufficient to demonstrate
unexpected results.
In addition, we understand Appellants’ position that reduced side
effects “would not turn on the difference in the target cells, i.e., tumor versus
autoimmune,” and “[therefore the results with tumors can be extended to
autoimmune disease” (App. Br. 12). However, this reasoning would not
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apply to the data demonstrating efficacy. Additionally, we conclude that
Appellants have not clearly pointed to sufficient data to support the position
that the claimed method provides unexpectedly reduced side effects.
We also note that the issue to be decided by the Board is not “whether
an overall disease control rate of 82% with an SN-38 conjugate, in a study
where 8 out of 22 patients had failed prior therapies with irinotecan or
Camptosar, is ‘expected.’” {Id. at 8.) Instead, given that Appellants have
the burden of demonstrating unexpected results, the issue is whether
Appellants have sufficiently demonstrated that the results are unexpected
and relevant to the present claims, which recite the use of an anti-CD22
antibody drug conjugate in a method of treating an autoimmune disease. We
conclude that they have not.
Appellants also argue that the “fact that the SN-38 from the ADC
concentrates 120-fold over that from irinotecan is a result that could not
have been predicted by the skilled artisan” {id. at 9). We are not persuaded.
The Declaration does state that “studies clearly show that the SN-38
derived from the ADC concentrates by a factor of about 120-fold over that
derived from irinotecan, proving the selectively increased delivery of the
cytotoxic drug, SN-38, by the ADC without increasing host toxicity” and
that the “improved therapeutic index is also confirmed in the clinical
experience, where repeated cycles of 8-10 mg/kg given on days 1 and 8 of a
21-day therapy cycle have shown objective antitumor responses in patients
with advanced, relapsed/refractory cancers” (Decl. 111). However, it is not
clear that these studies are relevant to claims directed to the use of an anti-
CD22 antibody drug conjugate in the treatment of an autoimmune disease
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and, even if we assume that they are, Appellants have not presented the
underlying data that supports these conclusory statements, nor have they
provided sufficient evidence that the selectivity and improved therapeutic
index would have been unexpected in view of Goldenberg.
We note Appellants’ argument that ‘“the magnitude of the therapeutic
effect achieved by conjugation is entirely unexpected. ’ Two logs in vitro
and 120-fold in the clinic, are certainly not modest or expected results.”
(Reply Br. 5.) However, “Attorney’s argument in a brief cannot take the
place of evidence.” In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974).
In addition, Appellants argue that they have “provided additional
publications showing unexpected results achieved when anti-CD22
antibodies are used to treat autoimmune diseases” (App. Br. 13). We are not
persuaded.
Appellants have pointed to several references {id. at 13—14).
However, we agree with the Examiner that Appellants have not adequately
explained how these references demonstrate that the claimed method
provides an unexpectedly superior result (Ans. 26—27).
Appellants also argue that “Cardillo el al.16 and Govindan et al.17
counter the examiner’s conclusion that a skilled artisan can expect and/or
16 Thomas M. Cardillo et al., Humanized Anti-Trop-2 IgG-SN-38 Conjugate
for Effective Treatment of Diverse Epithelial Cancers: Preclinical Studies in
Human Cancer Xenograft Models and Monkeys, 17 Clinical Cancer Res.
3157-69 (2011).
17 Serengulam V. Govindan et al., Milaluzumah SN-38 Conjugates for the
Treatment of CD74+ Cancers, 12 Molecular Cancer Therapeutics 968—78
(2013).
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predict the effect of administering any ADC” (Reply Br. 3). We are not
persuaded.
As noted by Appellants (id. at 2—3), Cardillo teaches:
We reported the preparation of antibody—drug conjugates (ADC)
using an anti-CEACAM5 (CD66e) IgG coupled to several
derivatives of SN-38, a topoisomerase-1 inhibitor that is the
active component of irinotecan, or CPT-11 . . . . The derivatives
varied in their in vitro serum stability properties, and in vivo
studies found 1 form (designated CL2) to be more effective in
preventing or arresting the growth of human colonic and
pancreatic cancer xenografts than other linkages with more or
less stability. Importantly, these effects occurred at nontoxic
doses, with initial testing failing to determine a dose-limiting
toxicity .... These results were encouraging, but also surprising,
because the CEACAM5 antibody does not internalize, a property
thought to be critical to the success of an ADC. We speculated
that the therapeutic activity of the anti-CEACAM5-SN-38
conjugate might be related to the slow release of SN-38 within
the tumor after the antibody localized.
(Cardillo 3157—58.) However, as with the data discussed above, this
teaching does not relate to an anti-CD22 antibody or the treatment of an
autoimmune disease. In addition, Cardillo states that the results were
“surprising[] because the CEACAM5 antibody does not internalize” (id. at
3158). Appellants have not adequately explained how this would be
relevant to the present claims.
As also noted by Appellants (Reply Br. 3), Govindan teaches that
“[pjrior studies indicated a preference for a linker (CL2A) that allowed
SN-38 to dissociate from the conjugate in serum with a half-life of
approximately 1 day, rather than other linkers that were either more or less
stable in serum” (Govindan 969). Govindan also teaches:
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When the CL2E-linked conjugate was found to be much less
potent in the solid tumor cell lines than the CL2A conjugate, this
suggested that the lower surface expression of CD74 on the solid
tumor cell lines reduced the internalization of SN-38 via
milatuzumab binding. However, when in vivo studies in Raji
also showed the milatuzumab-CL2A-SN-38 was superior to the
CL2E conjugate, other factors had to be affecting CL2E-based
conjugate’s efficacy.
{Id. at 976.) However, the present claims are not directed to a particular
linker. Thus, it is not clear how Govindan demonstrates that the present
claims provide an unexpectedly superior property. In particular, we do not
agree with Appellants’ implication that the inventors’ “surprise” over
various results is sufficient to demonstrate that the present method provides
an unexpectedly superior result.
CONCLUSION
The evidence supports the Examiner’s conclusion that the
combination of Goldenberg, Abrams, and Allen suggest the method of
representative claim 1. We therefore affirm the obviousness rejection over
Goldenberg, Abrams, and Allen of claim 1. Claims 5—8, 15, 16, 18, 19, 22,
23, 29, 33, 36, 37, 39, 40, 43, and 44 have not been argued separately and
therefore fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
Because they are not separately argued, we also affirm the
obviousness rejections of: claims 2 and 30 over Goldenberg in view of
Abrams, Allen, and Leung; claims 9 and 10 over Goldenberg in view of
Abrams, Allen, and Hansen; claims 20 and 41 over Goldenberg in view of
Abrams, Allen, and Sakaguchi; claims 21 and 42 over Goldenberg in view
of Abrams, Allen, and Charlotte; claims 24—28 over Goldenberg in view of
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Abrams, Allen, and Root; and claims 45 and 46 over Goldenberg in view of
Abrams, Allen, and Nepom.
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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