Minh Diem. Vu et al.

Patent Trials and Appeals Board

Nov 25, 2019

14783775 - (D) (P.T.A.B. Nov. 25, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/783,775 10/09/2015
3705 7590 11/27/2019
ECKERT SEAMANS CHERIN & MELLOTT LLC
U.S. Steel Tower
600 Grant Street, 44th Floor
Pittsburgh, PA 15219
Minh Diem VU
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.
298068-00170(ENG0009-US) 4900
EXAMINER
ROARK, JESSICA HOPE
ART UNIT PAPER NUMBER
1643
NOTIFICATION DATE DELIVERY MODE
11/27/2019 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):
ipmail@eckertseamans.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MINH DIEM VU, KLAUS STREIN, EKKEHARD MOESSNER,
RALF HOSSE, OLIVER AST, ANNE FREIMOSER-GRUNDSCHOBER,
TANJA FAUTI, RAMONA MURR, CHRISTIAN KLEIN,
PABLO UMANA, and SAMUEL MOSER
Appeal2018-008737
Application 14/783,775
Technology Center 1600
Before JOHN G. NEW, RYAN H. FLAX, and JAMIE T. WISZ,
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 to a method of treating an RORI-positive hematological malignancy
or a plasma cell disorder. Appellant appeals the Examiner's rejection of
claims 18-21 under 35 U.S.C. § 103. 1,2,3 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 itself, "ENGMAB SARL," as the real party-in-interest.
Appeal Br. 1.
2 Oral argument was heard on November 1, 2019; a transcript of the hearing
will be made a part of the record in due course.
3 The Final Action also includes two maintained obviousness-type double
patenting rejections of claim s 18-22; however, Appellant has not appealed
these rejections. Final Action 11-12; Appeal Br. 5; Answer 10-12.
Appeal2018-008737
Application 14/783,775
STATEMENT OF THE CASE
Independent claim 18, reproduced below, is representative of the
claims on appeal:
18. A method of treating an RORI-positive
hematological malignancy comprising[:]
administering a trivalent bispecific antibody which
specifically binds human CD3E (CD3) and the extracellular
domain of human RORI (RORI), wherein the antibody
comprises RORI Fab-Fc-CD3 Fab-RORI Fab (FIG.1(1)), to a
subject in need thereof,
wherein the RORI-positive hematological malignancy is
selected from the group consisting of: chronic lymphocytic
leukemia (CLL), hairy cell leukemia (HCL), acute lymphoblastic
leukemia (ALL), acute myeloid leukemia (AML), chronic
myeloid leukemia (CML), mantle cell lymphoma (MCL),
marginal zone lymphoma (MZL ), diffuse large B cell lymphoma
(DLBCL), multiple myeloma (MM), and follicular lymphoma
(FL).
Appeal Br. 22 (Claims Appendix) (formatting added for readability). Claim
18, and also independent claim 20, recite the antibody structure illustrated in
the Specification at Figure 1.1, which is reproduced below:
Fe hole
LALA/PO
crossfab
fc knob
~- LALA/PG
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Figure 1 (1 ), above, shows a trivalent, bispecific antibody structure having
the following components or fragments: Fab RORI-Fc-Fab CD3-Fab
RORI. See Spec. 12:31-32; Fig. 1.1.
The Specification defines "RORI" as "humanRORl (synonyms:
tyrosine-protein kinase transmembrane receptor RORI, EC=2.7.I0.1,
neurotrophic tyrosine kinase, receptor-related 1, UniPrtKB QOI973) which
is a tyrosine-protein kinase receptor" and "CD3" as "human CD3E described
under UniProt P07766 (CD3E_human." Spec. 15: 11-25. The Specification
further states, "RORI is significantly and uniformly expressed on the cell
surface of the[] [claimed] various blood cancers." Id. at 11:3-12. The
Specification further defines the claim language "' [b ]ispecific antibody
specifically binding to CD3 and RORI' ... [as] refer[ing] to a respective
definition for binding to both targets." Id. at 16: 15-17.
The Specification states that "[ t ]he present invention relates to novel
bispecific antibodies against CD3E and RORI." Spec. 1 :3--4. The
Specification explains, "[p ]referably the bispecific antibody according to the
invention is characterized in being trivalent and comprising a bivalent anti-
RORI antibody specifically binding to RORI, and a monovalent Fab
fragment of an antibody specifically binding to CD3," thus, by trivalent, the
claims refer to three antigen-binding sites on the antibody molecule: two for
RORI and one for CD3. Id. at 5:10-12.
The antibody structure shown in the Specification's Figure 1.1, above,
and claimed, includes a crossfab portion at the CD3 fragment. The
Specification explains this means, "in the light chain and heavy chain of the
CD3 Fab the variable domains VL and VH or the constant domains CL and
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CHI are replaced by each other (CD3 crossFab)." Id. at 5:13-14; see also
id. at 19:10-20:3 (describing Fab fragments and preferred CD3 Fab
crossFab ). Figure 1.1, above, illustrates this configuration with white-
speckled and gray shading at the CD3 fragment.
The following rejection is on appeal:
Claims 18-21 stand rejected under 35 U.S.C. § 103 over Rader4 and
Ast. 5 Final Action 4--10; Answer 4--9; see also Office Action dated Apr. 26,
2017, at 6-9 ("Non-Final Action").
Although, as noted supra at n.3, the Examiner's final rejection of the
claims included a first provisional obviousness-type double patenting
rejection of claims 18-21 over U.S. Patent Application No. 13/590,866 and
Rader, and another over U.S. Patent Application No. 15/517,296, Appellant
opens its briefing by stating, "[t]he only issue in this appeal is whether
claims 18-21 are non-obvious under 35 U.S.C. § I03(a) over
WO 2012075158 (Rader) in view of U.S. 2013/0078249 (Ast)," and presents
no argument over these double patenting rejections. See Final Action 11-
12; Appeal Br. 5; see also Answer 10-12 (maintaining these two double
patenting rejections and withdrawing a third of claim 22). Therefore, we
summarily affirm these two maintained double patenting rejections.
FINDINGS OF FACT
We agree with and adopt the Examiner's findings of fact and rationale
for obviousness as set forth in the Final Action and Answer, as well as in the
4 WO 2012/075158 Al (published June 7, 2012) ("Rader").
5 US 2013/0078249 Al (published Mar. 28, 2013) ("Ast").
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Non-Final Action. See Final Action 4--10; Answer 3-9, 12-22; Non-Final
Action 6-10. The following findings of fact (FF) highlight certain evidence:
FF 1. Ast discloses and "generally relates to novel bispecific
antigen binding molecules for T cell activation and re-direction to
specific target cells ... [ and] further relates to methods for producing
the bispecific antigen binding molecules of the invention, and to
methods of using these bispecific antigen binding molecules in the
treatment of disease." Ast, Abstract.
FF2. Further to the preceding finding of fact, Ast discloses that
such a T cell activating molecule is capable of binding CD3 and tumor
cell antigens, and that such molecules can be provided in
pharmaceutical compositions for use as a medicament to treat cancer
upon administration of a therapeutically effective amount. Ast ,r,r 21,
25-27.
FF3. Ast discloses 13 "[ e ]xemplary configurations of the T cell
activating bispecific antigen binding molecules of the invention,"
including the following two antibody molecules:
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Ast Figs. l(G), l(L). Fig. l(G), above-left, is an "[i]llustration of the
'2+ 1 IgG Crossfab' molecule with alternative order of Crossfab and
Fab components ('inverted')" and Fig. 1 (L ), above-right, is an
"[i]llustration of the '2+ 1 IgG Crossfab, inverted, linked light chain'
molecule." Ast ,r 28. Each of Figs. l(G) and l(L) shows a trivalent,
bispecific antibody molecule having a crossfab CD3 fragment fused to
other fragments at the Fab region. Id. ,r 149.
FF4. Ast discloses that:
it will be advantageous to have a T cell activating bispecific
antigen binding molecule comprising two or more antigen
binding moieties specific for a target cell antigen (see examples
in shown in FIG. IC, IF, IG, 1J or IL), for example to optimize
targeting to the target site or to allow crosslinking of target cell
antigens.
Ast ,r 159. And, further, "in certain embodiments, the T cell
activating bispecific antigen binding molecule of the invention further
comprises a third antigen binding moiety which is a Fab molecule
capable of specific binding to a target cell antigen." Id. ,r 160.
FF5. Further to the preceding finding of fact, Ast discloses, "[i]n
a particular embodiment according to the invention, the T cell
activating bispecific antigen binding molecule is capable of
simultaneous binding to a target cell antigen, particularly a tumor cell
antigen, and an activating T cell antigen," and "[i]n a particular
embodiment the activating T cell antigen is CD3, particularly human
CD3," particularly CD3E. Ast ,r,r 199, 203, 206.
FF6. Further to the preceding finding of fact, Ast further
discloses "[i]n certain embodiments the target cell antigen binding
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moiety is directed to an antigen associated with a pathological
condition, such as an antigen presented on a tumor cell or on a virus-
infected cell. Suitable antigens are cell surface antigens, for example,
but not limited to, cell surface receptors." Ast ,r 207.
FF7. Ast teaches using the above-noted antibody molecules in
therapeutically effective amounts to treat a variety of cancers,
including, inter alia, breast cancer, colorectal cancer, blood cancer,
and proliferation disorders of the lymphatic system. Ast ,r,r 259--265.
FF8. Ast discloses several working examples where a "2+ 1 IgG
Crossfab" antibody molecule construct, like illustrated at Figures 1 (G)
and 1 (L ), was particularly effective at re-directing T cell cytotoxicity
in tumor cells and inducing apoptosis therein, "via binding of the
antigen binding moieties to their respective target antigens on cells."
Ast ,r,r 340-377 (Example 6: "the '2+ 1 IgG Crossfab' construct is the
most potent molecule in this assay").
FF9. Rader is directed to and discloses "antibodies having
specificity for human RORI, compositions thereof; and methods for
using such antibodies, including in the diagnosis and treatment of
disorders associated with aberrant RORI expression." Rader,
Abstract.
FFIO. Further to the preceding finding of fact and FF5 and FF6,
Rader discloses "[t]he invention provides an isolated antibody with
specificity for the extracellular domain of receptor tyrosine kinase-like
orphan receptor 1 (ROR 1 ), which is selectively expressed on the
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surface of malignant cells, including B-cell tumors and other cancers."
Rader ,r 6; see also id. ,r,r 60-61.
FFI 1. Rader discloses:
In some embodiments, the antibody can also have
specificity for one or more antigens in addition to RORI. For
example, the antibody of the invention can be engineered ( e.g.,
as a bivalent diabody or a conjugated Fab dimer or trimer) to
have specificity for RORI and another tumor antigen, e.g., an
antigen associated with B-CLL, MCL, Burkitt lymphoma, renal
cell carcinoma, colon cancer ( e.g., colon adenocarcinoma), or
breast cancer ( e.g., breast adenocarcinoma). The antibody can
be engineered to have specificity for RORI and an antigen that
promotes activation or targeting of cytotoxic effector cells.
Rader ,r 58 (emphasis added); compare with FF4-FF7 (Ast is directed
to an overlapping set of cancers to be treated with a bispecific
antibody).
FFI2. Further to the preceding finding of fact, Rader discloses
that an anti-RORI antibody, IgG 1 RI2, demonstrated strong and
homogenous (superior) binding at relatively low concentrations,
recognizing cell surface human RORI, including selective binding to
CLL cells, but not normal B cells. Rader ,r,r 101-104. And,
furthermore, this RI2 antibody had high binding activity, had some,
albeit weak antibody-dependent cellular cytotoxicity (ADCC) activity
(it is slow to internalize), and had no effect on apoptosis. Id. ,r,r 113,
130.
FFI3. Rader discloses that "[t]he antibody of the invention can be
produced by any suitable technique, for example, using any suitable
eukaryotic or non-eukaryotic expression system," "[b ]acterial
expression systems can be used to produce [antibody] fragments,"
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[t]echniques for altering DNA coding sequences to produce such
fragments are known in the art," and "[t]he antibody of the invention
can be conjugated to a synthetic molecule using any type of suitable
conjugation" where "it will be understood that the synthetic molecule
can also be a protein (e.g., an antibody)." Rader ,r 52-54.
FF14. Further to the preceding finding of fact, Ast similarly
discloses that "[ m ]ethods to produce polyclonal antibodies and
monoclonal antibodies are well known in the art," "[a] humanized or
fully human form of the antibody can also be prepared in accordance
with methods well known in the art," and "[h ]uman antibodies and
human variable regions can be produced using various techniques
known in the art." Ast ,r,r 239, 240. Furthermore, "T cell activating
bispecific antigen binding molecules prepared as described herein
may be purified by art-known techniques" and, similarly, the
preparation of a pharmaceutical composition containing the T cell
activating bispecific antigen binding molecule would also be
accomplished by known techniques. Id. ,r,r 242, 252.
DISCUSSION
I. LEGAL STANDARDS
"[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting aprimafacie case ofunpatentability.
[Once] ... 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). Arguments made by Appellant in the Appeal Brief and
properly presented in the Reply Brief have been considered; arguments not
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so-presented are waived. See 37 C.F.R. § 4I.37(c)(l)(iv) (2017); see also Ex
parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) ("Any
bases for asserting error, whether factual or legal, that are not raised in the
principal brief are waived.").
"The combination of familiar elements [ or steps] according to known
methods is likely to be obvious when it does no more than yield predictable
results." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007). "[W]here
a rejection is predicated on two references each containing pertinent
disclosure ... we deem it to be of no significance, but merely a matter of
exposition, that the rejection is stated to be on A in view of B instead of on
B in view of A, or to term one reference primary and the other secondary."
In re Bush, 296 F.2d 491,496 (CCPA 1961). The test for obviousness is
"whether the teachings of the prior art, taken as a whole, would have made
obvious the claimed invention." In re Gorman, 933 F.2d 982, 986 (Fed. Cir.
1991). "What matters is the objective reach of the claim. If the claim
extends to what is obvious, it is invalid under§ 103." KSR, 550 U.S. at 419.
"[A] presumption arises that both the claimed and unclaimed
disclosures in a prior art patent are enabled." Amgen, Inc. v. Hoechst
Marion Roussel, Inc., 314 F.3d 1313, 1355 (Fed. Cir. 2003). Furthermore,
"a reference is not limited to the disclosure of specific working examples."
In re Mills, 470 F.2d 649, 651 (CCPA 1972)). That the prior art "discloses a
multitude of effective combinations does not render any particular
formulation less obvious. This is especially true [when] the claimed
composition is used for the identical purpose taught by the prior art." Merck
& Co. Inc. v. Biocraft Labs. Inc., 874 F.2d 804, 807 (Fed. Cir. 1989).
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The "case law is clear that obviousness cannot be avoided simply by a
showing of some degree of unpredictability in the art so long as there was a
reasonable probability of success .... [T]he proper standard [is that] the
expectation of success need only be reasonable, not absolute." Pfizer, Inc. v.
Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007); see also In re O'Farrell,
853 F.2d 894, 903---04 (Fed. Cir. 1988) (reasonable expectation of success,
not absolute predictability, is required). "[T]he question is whether there is
something in the prior art as a whole to suggest the desirability, and thus the
obviousness, of making the combination, not whether there is something in
the prior art as a whole to suggest that the combination is the most desirable
combination available." In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004)
( citation omitted). "It is prima facie obvious to combine two compositions
each of which is taught by the prior art to be useful for the same purpose, in
order to form a third composition which is to be used for the very same
purpose. . . . [T]he idea of combining them flows logically from their
having been individually taught in the prior art." In re Kerkhoven, 626 F.2d
846, 850 (CCPA 1980).
"One way for a patent applicant to rebut a prima facie case of
obviousness is to make a showing of 'unexpected results,' i.e., to show that
the claimed invention exhibits some superior property or advantage that a
person of ordinary skill in the relevant art would have found surprising or
unexpected." In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). "To be
particularly probative, evidence of unexpected results must establish that
there is a difference between the results obtained and those of the closest
prior art, and that the difference would not have been expected by one of
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ordinary skill in the art at the time of the invention." Bristol-Myers Squibb
Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014); see also
In re Baxter Travenol Labs., 952 F.2d 388,392 (Fed. Cir. 1991) ("[W]hen
unexpected results are used as evidence of nonobviousness, the results must
be shown to be unexpected compared with the closest prior art."). Also,
"[ m Jere improvement in properties does not always suffice to show
unexpected results. In our view, however, when an applicant demonstrates
substantially improved results ... and states that the results were
unexpected, this should suffice to establish unexpected results in the absence
of evidence to the contrary." In re Soni, 54 F.3d at 751 (emphasis original).
However, "'differences in degree' of a known and expected property are not
as persuasive in rebutting obviousness as differences in 'kind'-i.e., a new
property dissimilar to the known property." Bristol-Myers, 752 F.3d at 977.
With these standards in mind and in view of the Findings of Facts set
forth supra and as presented by the Examiner, we address the Examiner's
rejection and Appellant's arguments there-over.
IL ANALYSIS
The Examiner determined the appealed claims would have been
obvious over the combination of Rader and Ast. See Final Action 4--10,
Answer 3-9, 12-22, and Non-Final Action 6-10 (collectively citing Rader in
its entirety, but specifically at Abstract, ,r,r 6, 58, 60, 61, 103, 104, 112-113,
118-119, 128-132, Figure 2; Ast in its entirety, but specifically at Abstract,
,r,r11, 12, 16,21,25-28, 159, 199-208,217,241,259-265,300,340-377,
Figures 1 ( G), 1 (L ). To summarize the Examiner's position, Ast discloses a
T cell-activating/re-directing, bispecific antibody structure having a CD3
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binding, 2+ 1 IgG Crossfab, portion that binds to CD3 and tumor cell
antigens, thereby targeting cancer cells, including cells of blood cancers,
breast cancers, colorectal cancers, and lymphatic cancers, thereby treating
such cancers. See FFI-FF3, FF5-FF8. Further, Ast discloses that it would
be advantageous to provide such an antibody structure with two or more
antigen binding moieties, that is, make it bispecific, to optimize targeting to
cell antigens, particularly on the cancer cells' surface. FF5, FF6; see also
FFIO (Rader's RORI is just such a surface antigen). Further, Rader
similarly discloses an antibody structure with specificity to human RORI
and using such antibody structures to treat blood cancers and other cancers.
FF9-FFI0, FFI2. Moreover, similar to Ast, Rader discloses such an
antibody having specificity to one or more other antigens beyond RORI, i.e.,
a bispecific antibody, for treating blood cancers (B-CLL or MCL), breast
cancer, colon cancer, or lyphatic system cancer. FFI 1; see also FF7 (Ast
teaches treating an overlapping set of cancers).
The Examiner's position is that "substitution of one known element
(the anti-RORI Fab, which targets the tumor antigen RORI found on certain
tumors [ of Rader]) for another ( any of the various anti tumor antigen F abs
used in the construct of Ast)" would have been obvious to the skilled artisan
"so that alternate constructs could be prepared that targeted an alternate
tumor antigen." Answer 14. Furthermore, the Examiner also determined
that "[b ]ecause none of the antibodies of Rader were able to directly kill
CLL cells from patients, the ordinary artisan would have been motivated to
link the anti-RORI antibody to an anti-CD3 antibody [of Ast] to improve its
ability to mediate killing of target tumor cells." Final Action 8. The
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Examiner's position, stated more generally, was that the antibody fragments
taught by Rader and Ast, one for RORI targeting and the other for CD3
targeting, each for treating cancers, including blood cancers, would
complement one another if combined as suggested by each of Rader and Ast.
This determination of obviousness is supported by the evidence of record, as
exemplified by the findings of fact above.
As noted above, we find no error in, and agree with, the Examiner's
determinations on and rationale for the obviousness of the appealed claims.
We address Appellant's arguments below.
Appellant argues the Examiner's rejection does not articulate a
rational reason to combine Rader and Ast. Appeal Br. 5. This argument is
not persuasive.
As noted above, the Examiner articulated the following reasons the
skilled artisan would have combined Rader and Ast: "Because none of the
antibodies of Rader were able to directly kill CLL cells from patients, the
ordinary artisan would have been motivated to link the anti-RORI antibody
to an anti-CD3 antibody to improve its ability to mediate killing of target
tumor cells" and "[t]he rationale to substitute anti-RORI tumor specific Fab
units in a '2+ 1 Crossfab' for any of the tumor specific Fabs taught by Ast
would have been to obtain an alternate construct that could be used in
additional methods of treating cancer that expresses RORI and that could
not have been effectively targeted using the anti-tumor antigen specificities
exemplified by Ast." Final Action 8, 9. We agree with the Examiner that
this is a rational reason to combine the teachings of the two references to
achieve a trivalent, bispecific therapeutic antibody structure as claimed. See,
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e.g., In re Kerkhoven, 626 F.2d at 850 (it is logical and obvious to combine
compositions useful for the same purpose).
Appellant argues the claimed invention was not obvious to try because
the prior art did not provide sufficient guidance to the skilled artisan because
Rader only mentions once (at paragraph 58) that it would be desirable to
engineer an antibody with specificity for RORI and also an antigen that
promotes activation or targeting of cytotoxic effector cells. Appeal Br. 7-8.
Appellant argues that, based on the prior art, there would have been over
seven hundred possible antibody fragment combinations, and Rader does not
provide a single example, so selecting the one that covers the claimed
invention would not have been obvious. See id. at 10-11. This argument is
not persuasive.
The Examiner did not premise the rejection on an obvious-to-try
rationale, but rather on a conventional obviousness rationale based on the
fact that each claim element is taught by the prior art combination, the fact
that the skilled artisan would have been motivated to combine the Rader and
Ast antibody constructs for advantages in cancer treatment, and the fact that
the skilled artisan could have reasonably expected to successfully combine
the references for such a purpose because each reference indicates that its
molecules could be fabricated and provided as therapy by no more than
routine, well-known techniques in the art. See, e.g., Answer 3-9, 12-22; see
also FFI-FFI4. Thus, although the combination of Rader and Ast may well
have been obvious to try based on what we find to be a limited number (13)
of antibody molecules taught by Ast (see Ast, Fig. 1) and the limited number
of effective antibody fragments taught by Rader (see Rader ,r,r 99-132
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(discussing RI2 and other Mab)), the undeniably strong demand for new
cancer treatments, and the presumed functionality of the antibody structures
taught in Radar and Ast (see Amgen, 314 F.3d at 1355), such rationale was
not necessary to the Examiner's position on obviousness and would only
have served to supplement it.
Appellant argues there would not have been a reasonable expectation
of success in combining the antibody fragments of Rader and Ast to treat the
claimed cancers because the art includes many possible combinations, the art
is complex, and the art is unpredictable. Appeal Br. 12-14. This argument
is not persuasive.
Treating cancer is unpredictable, according to the Federal Circuit.
See, e.g., OSI Pharmaceuticals, LLC v. Apotex Inc., 939 F.3d 1375, 1376
(Fed. Cir. 2019). However, each of Rader and Ast discloses that its antibody
fragments (RORI-targeting for Rader and CD3-targeting for Ast) effectively
target blood cancer cells for therapeutic treatment and we presume that these
references' disclosures are enabling. Amgen, 314 F.3d at 1355; see also
FF1-FFI2. Moreover, each prior art reference discloses that, although its
specific antibody therapy is inventive, the technology to prepare the
antibody construct and practice such therapy was well-known to the skilled
artisan. FFI3, FFI4. As noted above, "[t]he combination of familiar
elements [ or steps] according to known methods is likely to be obvious
when it does no more than yield predictable results." KSR, 550 U.S. at 416.
Although cancer treatment is generally unpredictable, the prior art references
explain their cancer treatments, indicate that they worked, and suggest their
combination to enhance cancer treatment using known methods.
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Appellant argues the Examiner failed to establish that Ast's antibody
structure shown at the reference's Figure 1 G would be a lead compound and,
so, selected by the skilled artisan for modification. Appeal. Br. 15-17. This
argument is not persuasive.
A "lead compound" obviousness analysis is not warranted in this case.
As explained in Eisai Co. Ltd. v. Dr. Reddy 's Labs, Ltd., a lead compound
analysis is warranted when obviousness is based on structural similarity of
two compounds and obviousness is supported when there would be some
motivation to lead a skilled artisan to select and modify the prior art
compound to achieve the claimed compound. 533 F.3d 1353, 1357 (Fed.
Cir. 2008); see also Bristol-Myers Squibb Co. v. Teva Pharma.s USA, Inc.,
752 F.3d 967 (Fed. Cir. 2014) (patent cases involving new chemical
compounds warrant a lead compound analysis). Here, the Examiner did not
propose such a scenario, nor need she have. See Answer 19-20.
Obviousness here is predicated on combining the teachings of two prior art
references in ways taught or suggested to be advantageous by those
references. The Examiner does not rely on modification of a proposed lead
compound to create a new and closely related claimed chemical compound.
Appellant argues that the existence of prior art success in Tandem
scFv and DART antibody treatment formats in a clinical setting teaches
away from the claimed invention. Appeal Br. 17. Appellant's point is that,
if prior art techniques were successful to some degree, the skilled artisan
would use those and not try other, similar paths for cancer treatment. This
argument is not persuasive.
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As an initial matter, "[t]he prior art's mere disclosure of more than
one alternative does not constitute a teaching away from ... alternatives
because such disclosure does not criticize, discredit, or otherwise discourage
the solution claimed." In re Fulton, 391 F.3d at 1201. BiTE and DART are
merely alternatives to the claimed inventions, they do not criticize, discredit,
or discourage the claimed invention. Thus, the existence of these
alternatives does not teach away from the invention.
Furthermore, Appellant's argument does not follow logically.
Appellant points out that the drug Blinatumomab (CD19 x CD3 bispecific
BiTE® technology) was the first bispecific antibody with FDA approval for
treating B-cell lymphoblastic leukemia (it underwent the clinical testing
necessary therefore). Appeal Br. 17. Appellant next points out that a CD 19
x CD3 bispecific antibody with a dual-affinity retargeting molecule
(DART® technology) was then shown to be even more potent than the
BiTE® molecule for the same treatment. Id. at 18. Under Appellant's
reasoning, once BiTE was discovered and, in particular, FDA-approved,
there would be no motivation to develop DART® absent some clinical
testing to show it worked. Under such reasoning, however, how would one
in the field get so far as to clinically test such a follow-on antibody treatment
without first developing it to be tested? Under such reasoning, however,
why would one develop such a new antibody treatment with no motivation
to do so, as argued by Appellant? Thus, Appellant's own argument works to
its unraveling.
There is a universal, strong motivation in the therapeutic arts to
develop cancer treatments and there would be logical motivation to combine
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cancer therapies in routine ways that have been identified as useful for a
common purpose. In re Kerkhoven, 626 F.2d at 850; see also Dystar
Textilfarben Gmbh & Co. Deutsch/and KG v. CH Patrick Co., 464 F.3d
1356, 1368 (Fed. Cir. 2006) (universal, implicit motivating factors can
contribute to obviousness, particularly where the skilled artisan is capable of
combining the prior art references). Here, Rader teaches B-cell tumor
(blood cancer) and other cancer treatment with anti-RORI antibodies and
specifically states that such antibodies can also have specificity for antigens
in addition to RORI, e.g., specificity to promote activation or targeting of
cytotoxic effector cells. See FF9--FFI2. Ast similarly teaches bispecific
antigen biding molecules (e.g., antibodies) for T cell activation and re-
direction to specific target cells to treat cancer (including blood cancer). See
FF1-FF8. The references suggest their combination.
Further to the discussion above, Ast discussed the shortcomings of
BiTE® and DART® technologies, which it indicated motivated its disclosed
invention. Ast ,r,r 7-10 (short half-life, potential toxicity, and undesirable
non-functional side products were problems to be overcome). Ast stated that
the difficulties and disadvantages associated with currently
available bispecific antibodies for T cell mediated
immunotherapy, there remains a need for novel, improved
formats of such molecules. The present invention provides
bispecific antigen binding molecules designed for T cell
activation and re-direction that combine good efficacy and
produceability with low toxicity and favorable pharmacokinetic
properties.
Id. ,r 10. Thus, contrary to Appellant's arguments, Ast suggests that there is
motivation to explore beyond the known technologies in cancer therapy, in
spite of and based on the knowledge of those existing technologies.
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At oral argument, Appellant focused its arguments on the absence of
clinical trials relating to the subject matter of Rader and Ast as evidence that
there would not have been motivation to combine Rader and Ast to
formulate a cancer treatment, specifically, a hematological cancer treatment,
or a reasonable expectation of success in doing so. See, e.g., Hr'g Tr. 4:23-
5: 10, 5:18-25, 7:15-18, 11:5-18, 13:8-14:2, 16:11-17 (citing OSI Pharm.,
939 F.3d 1375 (Fed. Cir. 2019); In re Copaxone Consol. Cases, 906 F.3d
1013 (Fed. Cir. 2018); Yeda Res. v. Mylan Pharm. Inc., 906 F.3d 1031 (Fed.
Cir. 2018); and Grunenthal GMBHv. AlkemLabs. Ltd., 919 F.3d 1333 (Fed.
Cir. 2019)). Although this take on clinical trials evidence was not expressly
presented in Appellant's briefing and, thus, could be considered waived,
Appellant appears to assert that, as a matter of law, the lack of clinical trials
for hematological cancer treatment with the Rader and Ast antibodies ( or
fragments) forecloses obviousness here. See Borden, 93 USPQ2d at 1474.
Appellant's point appears to be that, under the law of our reviewing court,
absent a clinical trial to support that the Rader and Ast technologies have
some merit in cancer treatment, there would have been no reason to combine
the references or expect to successfully do so. Appellant's argument is not
persuasive.
OSI Pharmaceuticals begins with a statement that non-small lung
cancer was the leading cause of cancer deaths in 2000, causing over
1 million deaths, followed by a statement that cancer treatment, in general, is
of an unpredictable nature. OSI Pharma., 939 F.3d at 1377-78. We noted
this above as supporting strong motivation to develop new cancer
treatments. While the Federal Circuit's identification that cancer research is
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unpredictable is not a statement of law universally applicable to
patentability, it underscores a well-known fact, viz., that there is no cure for
cancer and, therefore, drug development innovation is a continuing and quite
necessary journey. The Federal Circuit held that the Board's conclusion of
obviousness in an inter partes review (IPR), in particular, the Board's
finding of a reasonable expectation of success, was not supported by
substantial evidence. Id. at 1377. However, the holding in OSI
Pharmaceuticals is specific to the facts of that case, which are different and
distinguishable from the facts here.
In OSI Pharmaceuticals, the claims at issue were directed to the use
of the drug compound erlotinib in the treatment of non-small cell lung
cancer (NSCLC) and other cancers related to human papilloma virus,
Barrett's esophagus, or neoplastic cutaneous diseases. Id. at 1378-79. In
the IPR, the claims were found to be obvious over the combination of the
"Schnur" and "Gibbs" references. Id. at 1379. As of the time of filing those
claims, there had been over 1,600 new drugs tested in clinical trials directed
to NSCLC therapies and all but 7 failed to show efficacy (in Phase II trials).
Id. at 1378. The Schnur reference disclosed over 100 compounds, including
erlotinib, useful in treating hyperproliferative diseases, such as cancer,
including lung cancer ( and head and neck tumors), but did not discuss
treating NSCLC, specifically. Id. at 1329. The Gibbs reference disclosed
erlotinib had good anti-cancer activity in preclinical models, particularly in
patients with NSCLC, but provided no data on such treatment. Id. at 1379-
80; see also id. at 1380 (an OSI 10-K statement had a similarly conclusory,
but data-free disclosure). The Board found that the claims directed to
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NSCLC treatment with erlotinib would have been obvious over Schnur and
Gibbs ( or the OSI 10-K), because Schnur taught all but the specific
treatment ofNSCLC and Gibbs taught (clearly inferred) that missing
element because Gibbs's statement regarding preclinical anti-cancer activity
could be relied upon as accurate ( even in the face of a declaration statement
by the author that the statement was not based on data). Id. at 13 81.
The Federal Circuit found that the Board's reliance on Gibbs was
error because Gibbs's statement regarding effectively treating NSCLC with
erlotinib was based only on Gibbs' s cited references Woodburn, which
related to a different compound (not erlotinib ), and Moyer, which disclosed
treatment of cancers other than NSCLC with erlotinib. Id. at 1383. Thus,
there was no real evidence that erlotinib could be used to treat NSCLC and
the Board's finding that there was a clear inference in Gibbs to that end was
not supported by substantial evidence. Id. at 1384.
Similarly, the court found that the Board's finding of reasonable
expectation of success in the asserted combination of Schnur and Gibbs ( or
the OSI 10-K) was not supported by substantial evidence because Schnur did
not disclose or provide data on treating NSCLC with erlotinib and Gibbs
could not cure this deficiency. Id. The court held that this lack of disclosure
and data was significant in view of the evidence of a 99.5% failure rate in
1,630 NSCLC-treatment Phase II clinical trials. There was a complete
absence of data on NSCLC treatment with erlotinib and a complete absence
of teaching of the indicator or mechanism on which a skilled artisan could
rely to reasonably expect success. Id. at 1384--85. The Federal Circuit
concluded its analysis as follows:
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To be clear, we do not hold today that efficacy data is always
required for a reasonable expectation of success. Nor are we
requiring "absolute predictability of success." See Appellee's
Br. 39. We conclude only that, on these particular facts, a
reasonable fact finder could not find a reasonable expectation of
success. The Board's finding is thus not supported by substantial
evidence, and accordingly we reverse its obviousness
determination.
Id. at 1385.
The facts before this Panel are different from those that were
determinative in OSI Pharmaceuticals and compel a different result. Here,
there is no evidence of over a thousand, or even a few, clinical trials relating
to antibody therapies for blood cancers, much less evidence of a 99 .5%
failure rate in such an impressive number of clinical trials as in OSI
Pharmaceuticals. And, while cancer treatment is an unpredictable field,
each of Rader and Ast discloses an antibody therapy useful to treat blood
cancer (as well as breast cancer, colorectal/colon cancer, lymphatic cancers,
and other cancers). See FF2, FF7, FF9, FFl 1. Furthermore, each of Rader
and Ast teaches that no more than well-known techniques would be required
to produce and therapeutically use their disclosed antibody structures. FF13,
FF14. Finally, each of Rader and Ast suggests its own antibody structure's
combination with other antibody structures, like the antibody constructs
taught by the other reference. FF4, FF7, FFl 1. Therefore, OSI
Pharmaceuticals is not determinative on the evidence before this panel.
In In re Copaxone, the Federal Circuit affirmed a district court's
ruling that claims to a multiple sclerosis (MS) drug, glatiramer acetate (GA),
dosed at 40mg 3x/week, were obvious. See 906 F.3d at 1016-17, 1024.
Some of the prior art cited in that case consisted of clinical trials for GA for
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MS treatment. The Federal Circuit stated,"[ w ]e recognize that the prior art
did not conclusively teach that a regimen of 40mg GA 3x/week would be
effective. However, ' [ c ]onclusive proof of efficacy is not necessary to show
obviousness. All that is required is a reasonable expectation of success." Id
at 1026 (quoting Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326,
1331 (Fed. Cir. 2014)). Other than "obviousness [being] proven through
human clinical studies establishing the safety, efficacy, and tolerability of
GA at dose and dose frequencies similar to the claimed regimen," the
Federal Circuit did not discuss the significance of clinical trials, per se. See
id. at 1028. While the court in In re Copoxone held that clinical testing data
can be evidence supporting a reasonable expectation of success, it did not
hold that the converse is also true, i.e., that a lack of clinical trial data
supports a finding of no reasonable expectation of success. Id. at 1031.
Therefore, In re Copoxone is not on point here and is not supportive of
Appellant's arguments on appeal.
Yeda relates to substantially the same patented subject matter as In re
Copoxone and the Federal Circuit affirmed the Board's conclusion that the
claims would have been obvious over the same, or at least substantially
similar, prior art as at issue in In re Copoxone. 906 F.3d at 1035-37. The
Federal Circuit's conclusions and ultimate holding on the Board's
obviousness determination are also substantially the same as presented in In
re Copoxone, therefore, we find Yeda not to be determinative here for the
same reasons. See id. at 1042--48. Furthermore, we note that in Yeda the
Federal Circuit stated:
The Board's finding that the uncertainty around GA's
mechanism of action would motivate a POSIT A to stick to
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dosing regimens with existing clinical support, such as 20mg and
40mg, is supported by substantial evidence from Dr. Green. Id.
at 18. Because "the expectation of success need only be
reasonable, not absolute," we find no error in these findings.
Id. at 1044. Here, although cancer treatment is somewhat unpredictable in
general, we do not have similar evidence that the mechanism of action for
Rader's RORI antibody fragments or Ast's CD3 antibody fragments have an
uncertain mechanism of action; quite the contrary, the references explain
such action. See e.g., FF8, FFI2 (and related portions of the references).
Thus, as in In re Copoxone, Yeda supports that clinical trial evidence can
support the existence of a reasonable expectation of success in the face of
uncertainly or unpredictability, but does not support that the lack of such
trials is proof of an absence of such an expectation. Appellant's arguments
are not supported by Yeda.
In Grunenthal, the Federal Circuit affirmed a district court's ruling of
infringement and also non-infringement, and of no invalidity of claims
directed to a drug, a polymorph of tapentadol hydrochloride, for treating
polyneuopathic pain. See 919 F.3d at 1336. In affirming the district court's
ruling that the claims were not obvious, the Federal Circuit noted that the
claimed technology, i.e., polymorphism of tapentadol hydrochloride, was
unknown at the time of the filing of the patent. Id. at 1341. Further, the
Federal Circuit observed that these characteristics of compounds in the
relevant field could not be extrapolated from other compounds and the
reference cited for teaching polymorphism discussed a "huge variety" of
variables without specifying or providing guidelines therefor. Id. at 1341-
42. The Federal Circuit found that this evidence, in view of the expert
testimony thereon, supported the district court's ruling that the claims were
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not proved to be obvious; there was no reasonable expectation of success.
Id. at 1342--43. After discussing several precedential cases regarding the
need for support for a reasonable expectation of success, rather than proof of
absolute certainty in an obviousness analysis, the Federal Circuit went on to
conclude that the skilled artisan's total lack of understanding as to the
claimed polymorphic nature of tapentadol hydrochloride supported that there
was no reasonable expectation of success in the case. Id. at 1344 (discussing
Pfizer, 480 F.3d 1348 (reasonable to combine narrowed list of compounds of
prior art based on known characteristics); AstraZeneca LP v. Breath Ltd.,
603 F. App'x 999 (Fed. Cir. 2015) (actual success not required; use of
known techniques would be reasonably expected to be successful); and
Cubist Pharm., Inc. v. Hospira, Inc., 805 F.3d 1112, (Fed. Cir. 2015)
( obvious to use known techniques to achieve claimed purity levels with
reasonable expectation of success)). Gruenthal does not address evidence of
clinical trials as supporting or refuting a reasonable expectation of success.
As discussed above, the case law cited by Appellant does not support
Appellant's position that the existence or absence of clinical trials would
have either led the skilled artisan toward therapies other than the claimed
antibody or would have established that the skilled artisan would not have
had a reasonable expectation of successfully combining the antibody
components taught by Ast and Rader to achieve the claimed trivalent,
bispecific antibody therapeutic.
Finally, Appellant argues that evidence of unexpected results refutes
the Examiner's position on obviousness. Appeal. Br. 18. Appellant points
to the disclosure at page 63 and Figure 1 OB of its Specification as evidence
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of unexpected results relating to "the EC50 value of a bispecific anti-CD3E
anti-RORI antibody having the claimed format for killing the multiple
myeloma cell line RPMI8226 is approximately 5-fold lower than for a
bispecific anti-CD3E anti-RORI antibody having an alternative format
'RORI TCB 1 + 1 Fe'." Id. at 19--20.
We reproduced Appellant's Figure IOB below:
antibody concentration (pM)
..... Rt)R·1 TCB ·1+·1 Fe
-11- RoR·1 TCB 2+·1 Fe
-o- non binder TCB 1+ 1
-II· non ti1nder TCB 2+ ·1
Figure 1 OB is a graph comparing percentage of tumor lysis ( at 24 hours)
along the Y axis to antibody concentration along the X axis, showing data
points for the following four samples: RORI TCB 1 + 1 Fe; RORI TCB 2+ 1
Fe; non-binder TCB 1 + 1; and non-binder TCB 2+ 1. The graph shows the
data points for each of these samples at concentrations of0.01, 0.1, 1, 10,
and 100 pM. Although the graph purports to depict differences in the rate of
tumor lysis among these samples between the 10 and 100 pM
concentrations, it is unclear why because there are no intermediary data
points shown to support the differing slopes of the lines drawn. The portion
of the Specification cited by Appellant as directed to this figure states:
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Experiment 2 (20h time point): The study was repeated in RORI-
positive RPMI8226 and measurement of LOH release was
assessed after 20h incubation. 30-40% target cell lysis was
observed with anti-ROR1/anti-C03 TCBl+l and TCB2+ 1
antibodies at a concentration of 100 pM while non-binder TCB
controls at 100 pM did not induce any tumor lysis. The results
corroborate with an increase in T cell activation as 25 measured
by upregulation of C025 marker on the C08 T cells (Figure 9B).
Spec. 63:20-25. The EC50 value of a bispecific anti-CD3E anti-RORI
antibody is not expressly discussed, other than a preceding statement that
"EC5 0 could not be calculated." See id. at 63: 13.
Appellant's evidence of unexpected results is not sufficient to
overcome the Examiner's prima facie case for obviousness. Although
Appellant has presented some evidence of improvements with an
embodiment appearing to fall within the scope of the invention over
comparative examples, the evidence does not clearly compare the results
achieved in the invention with the closest prior art and does not clearly show
an improvement in kind versus a mere improvement by degree so as to be
particularly persuasive. See Bristol-Myers Squibb, 752 F.3d at 977; and In
re Soni, 54 F.3d at 751. Furthermore, there is no evidence that the results
shown in Figure 1 OB were unexpected. "Attorneys' argument [ which is all
we have here,] is no substitute for evidence." Johnston v. IVAC Corp., 885
F.2d 1574, 1581 (Fed. Cir. 1989).
We discern no error in the Examiner's determinations, which we
conclude presented a prima facie case for the claims' obviousness over the
cited prior art combination. We have considered Appellant's arguments
over the rejections in their entirety, but find them unpersuasive on the record
on appeal.
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CONCLUSION
In summary, the obviousness rejection of claims 18-21 is affirmed.
The obviousness-type double patenting rejection of claims 18-21 over
U.S. Patent Application No. 13/590,886 and Rader is affirmed.
The obviousness-type double patenting rejection of claims 18-21 over
U.S. Patent Application No. 15/517, 296 is affirmed.
18-21 § 103 over Rader and Ast
18-21
18-21
Overall
Outcome
obviousness-type double
patenting over 13/590,886 and
Rader
obviousness-type double
patentin over 15/517 ,296
18-21
18-21
18-21
18-21
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l ). See 37 C.F.R.
§ 1.136(a)(l )(iv).
AFFIRMED
29