Daiichi Sankyo Company Limitedv.Alethia Biotherapeutics Inc.

Patent Trial and Appeal Board

Jun 14, 2016

12580943 (P.T.A.B. Jun. 14, 2016)

Trials@uspto.gov Paper 75
Tel: 571-272-7822 Entered: June 14, 2016

UNITED STATES PATENT AND TRADEMARK OFFICE
_______________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
_______________
DAIICHI SANKYO COMPANY, LIMITED,
Petitioner

v.

ALETHIA BIOTHERAPEUTICS, INC.,
Patent Owner
_______________

Case IPR2015-00291
Patent 8,168,181 B2
_______________

Before MICHAEL P. TIERNEY, ERICA A. FRANKLIN, and
SHERIDAN K. SNEDDEN, Administrative Patent Judges.

SNEDDEN, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318 and 37 C.F.R. § 42.73

IPR2015-00291
Patent 8,168,181 B2

2

I. INTRODUCTION
A. Background
Daiichi Sankyo Company, Limited (“Petitioner”) filed a Petition
(Paper 2; “Pet.”) to institute an inter partes review of claims 1−6, 8−11, and
15−23 of US 8,168,181 B2 (Ex. 1001; “the ’181 patent”). Alethia
Biotherapeutics, Inc. (“Patent Owner”) filed a Patent Owner Preliminary
Response. Paper 10 (“Prelim. Resp.”). Based on these submissions, we
instituted trial on the following ground of unpatentability asserted by
Petitioner:
Challenged Claims Basis References
1−6, 8−11, 15−23 § 102(a) Hiruma1
Decision to Institute (Paper 14, “Dec.”).
After institution of trial, the Patent Owner filed a Patent Owner
Response (Paper 43, “PO Resp.”), to which Petitioner filed a Reply (Paper
54, “Pet. Reply”).
Petitioner relies upon the Declarations of Dr. Paul R. Crocker ((Ex.
1003 (“Crocker Declaration”); Ex. 1044 (“Reply Crocker Declaration”)) and
Dr. Michael R. Clark (Ex. 1004) (“Clark Declaration”) in support of its
Petition.
Patent Owner relies upon the Declarations of Dr. Brendan F. Boyce
(Ex. 2074) (“Boyce Declaration”); Dr. Kathryn E. Stein (Ex. 2076) (“Stein
Declaration”); Dr. Mario Filion (Ex. 2100) (“Filion Declaration”); and Dr.

1 Yoshiharu Hiruma et al., WO 2009/048072, published on April 16, 2009.
Ex. 1002. The English translation of Ex. 1002 is provided as Ex. 1023.
IPR2015-00291
Patent 8,168,181 B2

3

Gilles Tremblay (Ex. 2101) (“Tremblay Declaration”) in support of its
Patent Owner Response.
Patent Owner filed a motion to exclude certain of Petitioner’s
evidence. Paper 60. Petitioner filed an opposition (Paper 64), and Patent
Owner filed a reply (Paper 66).
Petitioner filed a motion to exclude certain of Patent Owner’s
evidence. Paper 63. Patent Owner filed an opposition (Paper 65), and
Petitioner filed a reply (Paper 67).
Oral argument was conducted on February 26, 2016. A transcript is
entered as Paper 74 (“Tr.”).
This Final Written Decision is entered pursuant to 35 U.S.C. § 318(a).
We conclude for the reasons that follow that Petitioner has shown by a
preponderance of the evidence that claims 1−6, 8−11, and 15−23 of the ’181
patent are unpatentable.
B. The ’181 Patent (Ex. 1001)
The ’181 patent discloses methods of modulating osteoclast
differentiation, which may be useful in the treatment of bone loss or bone
resorption in patients suffering or susceptible of suffering from certain
conditions such as osteoporosis. Ex. 1001, 7:4–8, 7:41−62.
Independent claims 1 and 15 of the ’181 patent are illustrative
of the challenged claims and provide as follows:
1. A method of impairing osteoclast differentiation in a mammal
in need thereof, the method comprising administering an
antibody or antigen binding fragment which specifically binds to
human Siglec-15 (SEQ ID NO.:2) or murine Siglec-15 (SEQ ID
NO.:108) to said mammal.
IPR2015-00291
Patent 8,168,181 B2

4

15. A method for inhibiting bone resorption comprising
administering to a subject in need thereof, an antibody or antigen
binding fragment which specifically binds to human Siglec-15
(SEQ ID NO.:2) or murine Siglec-15 (SEQ ID NO.:108).
Challenged claims 2−6 and 8−11 depend from claim 1, either directly
or indirectly. Challenged claims 16−23 depend from claim 15, either
directly or indirectly.
II. ANALYSIS
A. Claim Interpretation
The parties agree that a claim construction under either a Phillips
interpretation or broadest reasonable interpretation would not impact the
scope of the claim. Tr. 7, 23; see Phillips v. AWH Corp., 415 F.3d 1303
(Fed. Cir. 2005). Based upon the facts presented, we determine that the
explicit construction of any specific claim term is unnecessary to reach our
decision in this case. See, e.g., Wellman, Inc. v. Eastman Chem. Co., 642
F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim terms need only be construed ‘to
the extent necessary to resolve the controversy.’”) (quoting Vivid Techs.,
Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
B. Asserted Ground of Unpatentability: Anticipation of Claims 1−6, 8−11,
and 15−23 by Hiruma
Petitioner contends that claims 1−6, 8−11, and 15−23 of the ’181
patent are anticipated by Hiruma. Pet. 34−56. Hiruma discloses the amino
acid sequence of human Siglec-15 (SEQ ID NO: 2) and mouse Siglec-15
(SEQ ID NO: 4). Ex. 1023, 20:2–14. Hiruma discloses antibodies that
specifically recognize human or mouse Siglec-15 and inhibit osteoclast
formation and/or osteoclastic bone resorption. Id. at 5:1–20, 56:24–58:4,
IPR2015-00291
Patent 8,168,181 B2

5

claim 33; Ex. 1003 ¶ 19. Examples 17, 19–26, and 35 of Hiruma disclose
the results of experiments showing the inhibitory effect of Siglec-15
antibodies on osteoclast differentiation. Ex. 1023, 103:19–105:13, 106:17–
119:4, 138:3–139:15; Ex. 1003 ¶¶ 19–20. Example 37 of Hiruma discloses
the results of an experiment showing the use of a Siglec-15 antibody for
inhibiting bone resorption. Ex.1023, 141:10–144:22. Hiruma further
discloses administering a Siglec-15 antibody for the purposes of inhibiting
or neutralizing the biological activity of Siglec-15 (i.e., the differentiation
and/or maturation of osteoclasts). Id. at 56:24–59:7, 11:3–5, 5:1–7:1, 17:5–
8, Fig. 36, claim 33; Ex. 1003 ¶ 23; Ex. 1004 ¶¶ 31, 33–34.
In support of its assertion that Hiruma teaches each element of claims
1−6, 8−11, and 15−23, Petitioner sets forth the foregoing teachings of
Hiruma and provides a detailed claim chart explaining how each claim
limitation is disclosed. Pet. 36−40.
We credit the testimony of Dr. Crocker and Dr. Clark that Hiruma
describes an antibody or a functional fragment thereof that specifically
recognizes Siglec-15 and inhibits osteoclast formation and/or osteoclast
bone resorption Ex. 1003 ¶¶ 19–25; Ex. 1004 ¶¶ 31–34
Patent Owner does not dispute that Hiruma discloses the limitations
recited in the challenged claims. Rather, a first dispute between the parties
is whether the challenged claims of the ’181 patent, filed on October 16,
2009, are entitled to its priority claim as a continuation-in-part to WO
2007/093042 (Ex. 1010) (“Parent Application”), filed on February 13, 2007.
PO Resp. 17–60. Without the benefit of priority, Hiruma, a PCT Publication
published in Japanese on April 16, 2009, becomes available as prior art to
the ’181 patent under 35 U.S.C. § 102(a).
IPR2015-00291
Patent 8,168,181 B2

6

The second dispute between the parties is whether Patent Owner can
successfully antedate Hiruma, thus removing the reference as prior art under
35 U.S.C. § 102(a). See 35 U.S.C. § 102(g) (2011); Mahurkar v. C.R. Bard,
Inc., 79 F.3d 1572, 1576 (Fed. Cir. 1996) (“Thus, under section 102(a), a
document is prior art only when published before the invention date.”).
Accordingly, the question of whether Hiruma anticipates the
challenged claims rests on our determination of 1) whether the challenged
claims are entitled to the benefit of priority to the Parent Application, and/or
2) whether Hiruma is prior art under 35 U.S.C. § 102(a).
C. The ’181 Patent Priority Claim
To be entitled to the benefit of a parent application, one requirement is
that the invention claimed must have been disclosed in the parent application
in the manner provided by 35 U.S.C. § 112, ¶ 1. See 35 U.S.C. § 120; In re
Lukach, 442 F.2d 967, 968−69 (CCPA 1971). Section 112, ¶ 1, contains
both a written description requirement and an enablement requirement.
Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1344–55
(Fed. Cir. 2010) (en banc). That is, a patent specification must describe the
invention sufficiently so that one of ordinary skill in the art would
understand that the inventor was in possession of the claimed subject matter
and, separately, must teach one of ordinary skill in the art how to make and
use the invention. Id.
Petitioner contends that the challenged claims are neither adequately
described nor enabled and thus not entitled to an earlier priority claim. Pet.
9–34; Pet. Reply 2–18. Patent Owner disagrees. PO Resp. 17–60.
IPR2015-00291
Patent 8,168,181 B2

7

After considering the parties’ arguments and evidence of record, we
conclude that the Parent Application fails to enable a person of ordinary skill
in the art to make and use the invention and further fails to adequately
describe the subject matter of the challenged claims. Accordingly, the
challenged claims are not entitled to the benefit of priority to the Parent
Application. Our reasoning follows.
1. Whether the Parent Application Enables the Challenged Claims
Whether a claim is invalid for lack of enablement is a question of law.
Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1336 (Fed. Cir.
2013). The enablement requirement is set forth in 35 U.S.C. § 112, ¶ 1, and
provides, in pertinent part, that the specification shall describe “the manner
and process of making and using [the invention], in such full, clear, concise,
and exact terms as to enable any person skilled in the art to which it pertains,
or with which it is most nearly connected, to make and use the [invention].”
The enablement requirement is met when one skilled in the art, having
read the specification, could practice the invention without “undue
experimentation.” Cephalon, 707 F.3d at 1336. When determining whether
undue experimentation would be required, courts may consider: “(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.” In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
These factors “are illustrative, not mandatory.” Amgen, Inc. v. Chugai
Pharm. Co., Ltd., 927 F.2d 1200, 1213 (Fed. Cir. 1991).
IPR2015-00291
Patent 8,168,181 B2

8

We consider each of the Wands factors in view of the argument and
evidence of record.
a. The nature of the invention and breadth of the claims
The claims recite methods for impairing osteoclast differentiation
(claims 1–6, 8–11) or inhibiting bone resorption in subjects in need of such
treatment (claims 15–23). The methods are carried out by the administration
of any antibody or antigen binding fragment that specifically binds to human
Siglec-15 to produce the desired therapeutic effect. Thus, the claims require
the recited antibody to have a desired therapeutic effect when administered
to subjects for the purposes of medical treatment. PO Resp. 51 (“These
claims cover anti-Siglec-15 antibodies generated for therapeutic purposes,
including those that have or are reasonably likely to have a measurable
effect on osteoclast differentiation in vivo as measured in a correlative in
vitro bioassay.”); Ex. 1003 ¶ 9; Ex. 1004 ¶ 23.
b. Relative skill of those in the art
The parties generally agree that there was a high level of knowledge
and skill in the field of antibodies. Specifically, a person of ordinary skill in
the relevant art would have at least a Ph.D. in the field of bone biology,
immunology, molecular biology, or related field and have at least 1–2 years
of experience in antibody development. PO Resp. 48, Ex. 2074 ¶ 7; Ex.
2076 ¶ 6; Ex. 1003 ¶ 7; Ex. 1004 ¶ 13.
c. The state of the prior art
It was known that the biological process of bone remodeling is
regulated by the activities of two principal cell types: osteoblasts and
IPR2015-00291
Patent 8,168,181 B2

9

osteoclasts. Ex. 1010, 1–2. Osteoblasts are responsible for bone formation
and osteoclasts are responsible for bone resorption or degradation. Id. In
the biological process of bone remodeling, osteoclasts remove damaged
bone and osteoblasts restore bone. Ex. 2074 ¶ 8; Ex. 1010, 1–5. Disruption
of the bone remodeling process occurs during aging and from various bone
diseases. Ex. 2074 ¶ 8–9. It was known that impairing osteoclast
differentiation or inhibiting bone resorption could prevent bone destruction
and provide therapeutic benefit in certain bone diseases. Ex. 2074 ¶¶ 8–9;
Ex. 1010, 1–5. For example, at the time of the filing of the Parent
Application, the monoclonal antibody denosumab, which binds to Receptor
Activator of Nuclear Factor Kappa-B Ligand (“RANKL”) to inhibit
osteoclast formation, was in phase III clinical trials for treating bone disease.
Ex. 2074 ¶¶ 9–11, 16–17, 28.
It was known that Siglec-15 was likely a cell surface protein. PO
Resp. 11 (citing Nakamura2; Ex. 2074 ¶¶ 17–21 (“[O]ne of ordinary skill in
the art would have recognized that AB0326 was likely a cell surface
protein.”); Ex. 2076 ¶¶ 29, 34–42); Pet. Reply 15. However, prior to the
filing of the Parent Application, it was not known that Siglec-15 was a
protein specifically upregulated in osteoclasts and thus a potential key
regulator of osteoclast differentiation. PO Resp. 11–12; Ex. 1010, 1–5; Ex.
2074 ¶¶ 12–21.
It was known that “‘one could obtain an antibody to specifically bind
to any particular target antigen through routine use of those well-developed

2 Yusuke Nakamura et al., US 2004/0076992, published April 22, 2004. Ex.
2065.
IPR2015-00291
Patent 8,168,181 B2

10

methods long before 2007.’” PO Resp. 21 (quoting Ex. 2076 ¶ 16); Ex.
2076 ¶ 48; Ex. 2076 ¶ 20; Ex. 2074 ¶¶ 27–29. We note, however, that
producing an antibody to an antigen is distinct from producing an antibody
to that same antigen having a desirable therapeutic effect. Ex. 2075,
273:15–274:24.
d. The amount of direction or guidance presented
The amount of guidance or direction needed to enable the invention is
inversely related to the amount of knowledge in the state of the art as well as
the predictability in the art. In re Fisher, 427 F.2d 833, 839 (CCPA 1970).
The Parent Application disclosed Siglec-15 (referred to as
“AB0326”), including both the gene and protein sequences of Siglec-15.
Ex. 1010, 89 (SEQ ID NOS.: 1 and 48, respectively). The Parent
Application discloses Siglec-15 as a protein that is specifically upregulated
in osteoclasts. Ex. 1010, 70:26–29 (The Siglec-15 gene “is markedly
upregulated in intermediate and mature osteoclast compared to precursor
cells,” and thus “this gene may be required for osteoclastogenesis and/or
bone remodeling.”); Ex. 2074 ¶¶ 12–15.
The Parent Application disclosed that inhibiting expression of Siglec-
15 using a short hairpin RNA (shRNA) knockdown assay impaired
formation of osteoclasts from precursor cells. Ex. 1010, 84–85, Fig. 35.
The Parent Application further disclosed that Siglec-15 is capable of
restoring the osteoclastogenesis capabilities of the model cell line. Ex. 1010,
87:9–31. We are persuaded that both studies would have indicated to a
person of ordinary skill in the art that inhibiting Siglec-15 can potentially
impair formation of osteoclasts from precursor cells. Ex. 2074 ¶¶ 9–15, 26,
IPR2015-00291
Patent 8,168,181 B2

11

41; Ex. 2058, 86:2–17; 87:16–88:10; Ex. 1003 ¶ 17.
The Parent Application provides a general disclosure regarding
inhibitory compounds to osteoclast differentiation, but does not expressly
disclose anti-Siglec-15 antibodies that can inhibit bone resorption or impair
osteoclast differentiation. Ex. 1010, 30:30–33; Pet. 19−21 (citing Ex. 1003
¶¶ 7, 17, 18; Ex. 1004 ¶¶ 7, 8, 12, 13, 16, 21, 23); Pet. Reply 2–3 (citing Ex.
1045 at 90:25–91:6, 96:19–97:9); PO Resp. 12–13. The Parent Application,
however, provides a general disclosure of known methods for making
antibodies against a target protein. Ex. 1010, 35–44; Ex. 2058, 95:18–22;
Ex. 2075, 25:2–10, 28:22–29:4; Ex. 2076 ¶ 31; Ex. 2074 ¶ 27; Ex. 2076 ¶
31.
The Parent Application does not disclose any structural information
regarding an antibody that binds Siglec-15 or any epitopes or unique
antigenic regions useful for generating antibodies having the desired
functional properties. Ex. 1004 ¶¶ 16, 17, 23, 25; cf. Ex. 2076 ¶ 19 (“To
perform these conventional methods to develop an antibody with desired
activity by 2007, one would not need to determine the precise mechanism of
action (of the protein or antibody), the specific epitope target on the protein,
or the amino acid sequence of the antibody.”).
The Parent Application discloses functional assays, including an
osteoclastogenesis assay, that may be used to screen for and identify agents,
including antibodies, that inhibit the differentiation of osteoclast precursor
cells via their association with Siglec-15. Ex. 1010, 61:28–62:23, 86:1–3;
Ex. 2074 ¶¶ 10–11, 27–29. The disclosed osteoclastogenesis assay,
however, is an in vitro assay, which may not reflect how an antibody would
behave in vivo. Ex. 1004 ¶ 27. For example, an epitope to which an
IPR2015-00291
Patent 8,168,181 B2

12

antibody binds in vitro may not be available when the protein is folded into
its in vivo conformation. Ex. 1004 ¶¶ 20, 27; Ex. 1044 ¶ 10.
e. The presence or absence of working examples
The Parent Application contained no working example of a Siglec-15
antibody having the desired biological properties.
f. The predictability or unpredictability of the art
In cases involving unpredictable factors, the scope of enablement
varies inversely with the degree of unpredictability of the factors involved.
In re Fisher, 427 F.2d 833, 839 (CCPA 1970). Here, the art involves
therapeutically regulating the biological process of bone remodeling, the
successful completion of which necessitates laboratory research, clinical
studies, and other trial-and-error experimentation. The evidence of record
supports a finding that the prior art was at least somewhat unpredictable.
Ex. 2075, 82–106.
g. The quantity of experimentation necessary
The fact that some experimentation is necessary does not preclude
enablement; what is required is that the amount of experimentation must not
be unduly extensive. Atlas Powder Co., v. E.I. DuPont de Nemours & Co.,
750 F.2d 1569, 1576 (Fed. Cir. 1984).
Patent Owner argues that any experimentation needed to make and
use the claimed antibodies would have been routine. PO Resp. 46–59, citing
In re Wands, 858 F.2d 731, 736 (Fed. Cir. 1988) (“Enablement is not
precluded by the necessity for some experimentation such as routine
screening.”). In particular, Patent Owner contends that anti-Siglec-15
IPR2015-00291
Patent 8,168,181 B2

13

antibodies could have been made without undue experimentation using
conventional techniques known in the art. PO Resp. 47. Petitioner does not
appear to dispute this point. Pet. Reply 12–14.
What is disputed is whether the functional assays disclosed in the
Parent Application to identify antibodies with a particular function would
have been considered routine screening or “undue” experimentation. In this
regard, Patent Owner argues that the osteoclastogenesis assay disclosed in
the Parent Application “was a well-known and robust assay in 2007 to
demonstrate osteoclast differentiation function, to identify regulators (e.g.,
inhibitors) of osteoclast differentiation and bone resorption, and to correlate
and reliably predict in vivo osteoclast and bone resorptive activity.” PO
Resp. 47–48 (citing Ex. 2074 ¶¶ 10–11, 28–29; Ex. 2058, 93:20–95:3,
181:4–9; Ex. 2075, 100:10–18, 101:17–102:1).
Petitioner contends that the Parent Application is a research plan or an
invitation for further experimentation. Pet. 26 (citing Ex. 1004 ¶ 26).
Specifically, Petitioner contends that the osteoclastogenesis assay disclosed
in the Parent Application “is, at best, a screening tool for any number of
inhibitors, not necessarily antibodies, of osteoclast differentiation,” and “by
no means is this assay an indication that a therapeutic Siglec-15 antibody
even could be made, much less a recipe for actually making such a
therapeutic antibody.” Id. at 29 (citing Ex. 1004 ¶ 27). Petitioner further
contends that “the amount of experimentation required to identify such an
antibody would be excessive, at least because it is uncertain whether such an
antibody could even be made.” Id. at 27 (citing Ex. 1004 ¶¶ 7, 11, 13, 17,
28).
IPR2015-00291
Patent 8,168,181 B2

14

h. Discussion
The central enablement issue in this case is whether the development
of antibodies having the desired function would have required undue
experimentation. In view of the forgoing, we find that practicing the
methods of the challenged claims at the time of the filing of the Parent
Application would have required excessive experimentation, even if routine.
ALZA Corp. v. Andrx Pharm., LLC, 603 F.3d 935, 941 (Fed. Cir. 2010).
In this case, the Parent Application discloses a potential target for
drug development (i.e., Siglec-15), an assay by which to screen potential
inhibitory compounds to osteoclast differentiation, and a general description
pertaining to conventional methods of producing antibodies. Thus, to arrive
at the invention of the challenged claims, a person of ordinary skill in the art
would have had to choose to pursue anti-Siglec-15 antibodies as a potential
inhibitor to test in the disclosed osteoclastogenesis assay, generate anti-
Siglec-15 antibodies, and then screen those antibodies until an antibody
having the desired biological properties was identified. Ex. 1045, 48:18–
50:6; Ex. 2075, 82–106. We note the considerable amount of time, skill and
labor necessary to practice the invention and the uncertainty as to whether
antibodies having the desired therapeutic properties could be achieved. Ex.
1004 ¶¶ 7, 11, 13, 17, 20, 27–28; Ex. 1044 ¶ 10; Ex. 2075, 82–106.
The Parent Application discloses Siglec-15 can potentially impair
formation of osteoclasts from precursor cells. Ex. 2074 ¶¶ 9–15, 26, 41; Ex.
2058, 86:2–17; 87:16–88:10; Ex. 1003 ¶ 17. However, the Parent
Application fails to provide sufficient detailed guidance to a person of
ordinary skill in the art suggesting more than a mere starting point or
direction for further research. For example, the Parent Application discloses
IPR2015-00291
Patent 8,168,181 B2

15

the protein sequence of Siglec-15, but offers no credible guidance as to
unique antigenic regions or epitopes in Siglec-15 that would have been
useful for generating antibodies having the required functional properties.
While epitope mapping may not be required to screen antibodies (Ex. 2076
¶ 19), the lack of such specific guidance would have required a person of
ordinary skill in the art to engage in a complicated and lengthy screening
process to practice the invention. Ex. 1004 ¶¶ 7, 11, 13, 17, 20, 27–28; Ex.
1044 ¶ 10; Ex. 2075, 82–106. That is, one of ordinary skill “would have
been required to engage in an iterative, trial-and-error process to practice the
claimed invention even with the help of the . . . specification.” ALZA Corp.,
603 F.3d at 943.
Accordingly, undue experimentation was required to practice the
methods claimed in the ’181 patent based on the specification of the Parent
Application. “The amount of required experimentation [to satisfy the
enablement requirement] . . . must be reasonable.” White Consol. Indus.,
Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 (Fed. Cir. 1983).
2. Whether the Parent Application Provides Adequate Written
Description for the Challenged Claims
Adequacy of the written description is a question of fact. Ariad
Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en
banc). “The purpose of the written description requirement is to prevent an
applicant from later asserting that he invented that which he did not; the
applicant for a patent is therefore required to ‘recount his invention in such
detail that his future claims can be determined to be encompassed within his
original creation.’” Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d
1313, 1330 (Fed. Cir. 2003), quoting Vas–Cath Inc. v. Mahurkar, 935 F.2d
IPR2015-00291
Patent 8,168,181 B2

16

1555, 1561.
The question before us is whether the Parent Application provides
adequate written description support for a genus of antibodies having the
desired functional properties required to practice the claimed method—the
ability to inhibit osteoclast differentiation (claims 1–6, 8–11) or the ability to
inhibit bone resorption (claims 15–23). Pet. 11−24. We conclude that the
Parent Application fails to provide adequate written description support for
the challenged claims. Our reasoning follows.
Patent Owner contends that the Parent Application fully characterizes
Siglec-15 as an antigen, which is sufficient to provide adequate written
description support to an antibody that binds the antigen. PO Resp. 19–21
(quoting Noelle v. Lederman, 355 F.3d 1343, 1348 (Fed. Cir. 2004) (“As
long as an applicant has disclosed a ‘fully characterized antigen,’ either by
its structure, formula, chemical name, or physical properties . . . , the
applicant can then claim an antibody by its binding affinity to that described
antigen.”)). Patent Owner refers to this legal principle as “the antibody rule”
and further notes that “[t]his antibody rule has been incorporated into the
USPTO’s examiner training materials on written description since at least
2001.” Id. at 19 (siting Ex. 20773 (Example 13); Ex. 20784 (Example 16)).
We are not persuaded by this reasoning. The challenged claims
contain functional claim language concerning the biological properties of the
recited antibody. The Federal Circuit, however, has on several occasions
distinguished between claims not involving functional claim language and

3 USPTO Written Description Training Materials (2008).
4 Revised Interim Written Description Guidelines Training Materials (2001).
IPR2015-00291
Patent 8,168,181 B2

17

claims that contain functional claim language, such as the claims at issue in
the present case. See e.g., Centocor Ortho Biotech, Inc. v. Abbott Labs., 636
F.3d 1341, 1352 (Fed. Cir. 2011); GlaxoSmithKline LLC v. Banner
Pharmacaps, Inc., 744 F.3d 725, 731 (Fed. Cir. 2014). In Centocor, for
example, at issue were claims to TNF-α antibodies having particularly
desirable therapeutic properties. The court distinguished Noelle as follows:
While [Noelle] suggests that written description for certain
antibody claims can be satisfied by disclosing a well-
characterized antigen, that reasoning applies to disclosure of
newly characterized antigens where creation of the claimed
antibodies is routine. Here, both the human TNF-α protein and
antibodies to that protein were known in the literature. The
claimed “invention” is a class of antibodies containing a human
variable region that have particularly desirable therapeutic
properties: high affinity, neutralizing activity, and A2 specificity.
Claiming antibodies with specific properties, e.g., an antibody
that binds to human TNF-α with A2 specificity, can result in a
claim that does not meet written description even if the human
TNF-α protein is disclosed because antibodies with those
properties have not been adequately described.
Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed.
Cir. 2011) (emphasis added).
In view of the court’s logic set out in Centocor, we are not persuaded
by Patent Owner’s arguments that disclosure of Siglec-15 as a fully
characterized antigen in the Parent Application, without more, is sufficient
to provide adequate written description support for a Siglec-15 antibody that
produces a desirable biological activity or therapeutic result.
Patent Owner argues, however, that the Parent Application does
provide more. PO Resp. 21–24. Specifically, Patent Owner contends that
the Parent Application, in addition to disclosing “extensive characterization
IPR2015-00291
Patent 8,168,181 B2

18

of Siglec-15” in terms of both structure and function, further describes, “in
great detail[,] procedures for generating antibodies, such as hybridoma
technology, phage display technology and mammal immunization
techniques, all of which were well-known.” Id. at 24 (citing Ex. 2058,
95:18–22; Ex. 2075, 25:2–10, 28:22–29:4; Ex. 2076 ¶ 31; Ex. 2074 ¶ 27);
see also, Id. at 36 (“The [Parent Application] devoted at least seven (7)
entire pages to describing techniques for generating antibodies.”) (citing Ex.
2076 ¶¶ 30–31; Ex. 1010, 33–40). Patent Owner further notes that the
Parent Application “clearly describes using such techniques with well-
known osteoclastogenesis assays to generate and identify antibodies that
specifically inhibit Siglec-15.” Id. (citing Ex. 1010, 86:1–3 (disclosing a
process “to identify molecules (small molecule drugs, peptides, or
antibodies) capable of inhibiting AB0326.”); see also, Id. at 36 (citing Ex.
1010, 61:28–62:23, Example L). Patent Owner further argues that the
Parent Application discloses well-accepted osteoclastogenesis assays that are
predictive of inhibitory activity in vivo. PO Resp. 30–31 (citing Ex. 2074 ¶¶
10–11, 28–29, 33).
We are not persuaded by the argument and evidence presented by
Patent Owner. The Parent Application fails to disclose any species of
antibody that impairs osteoclast differentiation or inhibits bone resorption.
The Parent Application also fails to provide any specific structural or
physical information so as to define a genus of antibodies having the desired
therapeutic properties. Patent Owner’s arguments merely rely on the
identification of Siglec-15 as the antigen and the well-known structure of
antibodies in general. As noted by Petitioner, however, the claims do not
recite a general antibody, but an antibody having a specific desired activity.
IPR2015-00291
Patent 8,168,181 B2

19

Pet. Reply 7. In this regard, the evidence of record suggests that
identification of Siglec-15 itself is insufficient to describe a genus of
antibodies that bind to Siglec-15 and produce a desired therapeutic effects.
Ex. 1046, 39:5–9 (“In my understanding when antibodies are being
generated, some will be inhibitory because they bind specifically to critical
parts of the polypeptide and others may not and will not be inhibitory.”); Ex.
2075, 117:8–19.
Here, as in Alonso, “[t]he specification teaches nothing about the
structure, epitope characterization, binding affinity, specificity, or
pharmacological properties common to the large family of antibodies
implicated by the method.” In re Alonso, 545 F.3d 1015, 1022 (Fed. Cir.
2008). Accordingly, we determine that the Parent Application fails to
sufficiently describe common structural information to show possession to
the genus of antibodies recited in the challenged claims. See Boston
Scientific Corp. v. Johnson & Johnson, 647 F.3d 1353, 1366–67 (Fed. Cir.
2011) (holding written description inadequate “[g]iven the absence of
information regarding structural characteristics of” the claimed genus);
Regents of the Univ. of California v. Eli Lilly & Co., 119 F.3d 1559, 1568
(Fed. Cir. 1997) (holding that adequate written description requires
identification of “structural features commonly possessed by members of the
genus that distinguish them from others,” allowing one of skill in the art to
“visualize or recognize the identity of the members of the genus”).
3. Conclusion
In view of the forgoing, we conclude that the claims of the ’181 patent
are not entitled to the priority date of February 13, 2007. Hiruma is thus
IPR2015-00291
Patent 8,168,181 B2

20

prior art to the ’181 patent and anticipates the challenged claims under 35
U.S.C. § 102(a).
D. Antedating Hiruma
1. Background
Patent Owner attempts to antedate Hiruma. PO Resp. 60–84. An
inventor may antedate a prior art reference under 35 U.S.C. § 102(a) if the
inventor was the first to conceive of a patentable invention, and then
connects the conception of the invention with its constructive reduction to
practice by reasonable diligence on the inventor’s part, such that conception
and diligence are substantially one continuous act. Mahurkar v. C.R. Bard,
Inc., 79 F.3d 1572, 1577 (Fed. Cir. 1996).
Hiruma is dated April 16, 2009. Patent Owner contends that the
claimed invention of the ’181 patent was conceived prior to April 16, 2009,
and constructively reduced to practice on October 16, 2009, the filing date of
the ʼ181 patent. PO Resp. 61, 71. Patent Owner further contends that the
inventors were reasonably diligent from April 9, 2009, to the date of the
constructive reduction to practice. Id. Patent Owner contends that, as a
consequence, Hiruma does not qualify as prior art. Id.
For support, Patent Owner relies on the Parent Application to
demonstrate conception. Id. at 63–68. Patent Owner further relies on the
declaration testimony of Dr. Mario Filion, who is named as a co-inventor on
the ʼ181 patent. PO Resp. 68–69; Ex. 2100. Dr. Filion testifies that the
subject matter claimed in the ʼ181 patent was conceived prior to February
13, 2007, the filing date of the Parent Application, or alternatively, prior to
June 19, 2007, the date in which Dr. Filion presented Patent Owner’s clinical
IPR2015-00291
Patent 8,168,181 B2

21

programs to Petitioner. Ex. 2080 ¶¶ 1–2. Patent Owner additionally
provides a copy of the slide deck that accompanied Mr. Filion’s presentation
to Petitioner. Ex. 2080 (“Patent Owner Presentation”).
To show diligence, Patent relies on the declaration testimony of Dr.
Dr. Gillis Tremblay (Ex. 2101), who is named as a co-inventor on the ʼ181
patent, and the accompanying Diligence Chart (Ex. 2015), which provides
time logs prepared by Dr. Tremblay relating to activities he and his research
team performed during the relevant timeframe between April 9, 2009 and
October 16, 2009. PO Resp. 71–77; Ex. 2101 ¶ 8.
Petitioner responds, first, by challenging Patent Owner’s conception
proofs. Pet. Reply 20–25. According to Petitioner, the Parent Application
and Patent Owner Presentation amount to a plan to target Siglec-15 for
development, which is insufficient to establish conception. Id. Second,
Petitioner challenges Patent Owner’s proofs to show reasonable diligence.
2. Discussion
“Conception requires both the idea of the invention’s structure and
possession of an operative method of making it.” Amgen, Inc. v. Chugai
Pharm. Co., 927 F.2d 1200, 1206 (Fed. Cir. 1991), citing Oka v. Youssefyeh,
849 F.2d 581, 583 (Fed.Cir.1988). In Amgen, the court said:
Conception does not occur unless one has a mental picture of the
structure of the chemical, or is able to define it by its method of
preparation, its physical or chemical properties, or whatever
characteristics sufficiently distinguish it. It is not sufficient to
define it solely by its principal biological property . . . because
an alleged conception having no more specificity than that is
simply a wish to know the identity of any material with that
biological property.
927 F.2d at 1206.
IPR2015-00291
Patent 8,168,181 B2

22

The evidence of record does not support Patent Owner’s contention
that the invention of the challenged claims was conceived prior to the critical
date, April 16, 2009, the publication date of Hiruma. As discussed above,
the Parent Application does not adequately describe an antibody capable of
performing the functions recited in the challenged claims. Such a disclosure
is also absent in Patent Owner Presentation, which instead discloses possible
directions for development. See Ex. 2080, 37 (disclosing “[a] plethora of
high-potential targets to self-sustain clinical pipeline.”). Thus, neither the
Parent Application nor Patent Owner Presentation is sufficient to establish
that antibodies that could function in the claimed methods had been defined
prior to the critical date. Amgen, 927 F.2d at 1206 (“it is well established in
our law that conception of a chemical compound requires that the inventor
be able to define it so as to distinguish it from other materials, and to
describe how to obtain it”); Pet. Reply 19–25.
Furthermore, as noted by Petitioner, “the claimed subject matter is
recognized as unpredictable and therefore could not have been conceived
until it was determined that the antibodies recited in the claims actually
worked for their intended purpose as claimed in the methods.” Pet. Reply 20
(citing Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed.
Cir. 2001)). In this regard, the weight of the evidence of record suggests that
Patent Owner was still conducting trial and error experimentation of the type
that the Alpert court characterized as evidencing a lack of conception.
Alpert v. Slatin, 305 F.2d 891, 894 (CCPA 1962). For example, as of April
9, 2009, Patent Owner was in possession of DNA encoding 46 candidate
fragment antigen-binding (Fab) sequences identified as binding a Siglec-15
fusion protein. Ex. 2105, 1. To identify antibodies with a therapeutic
IPR2015-00291
Patent 8,168,181 B2

23

function, however, additional characterization and experimentation was
necessary. For example, the candidate antibodies were tested in vitro to
determine their effect on isolated osteoclasts, which did not occur until at
least May 15, 2009. PO Resp. 74; Ex. 2105, 7. Subsequent to that
experimentation, Patent Owner used epitope mapping, functional
characterization of lead sequences, and bioinformatics analysis in its efforts
to identify the desired antibodies. PO Resp. 73–76; Ex. 2105, 3, 21–23, 28–
29. The information development during this period, after the critical date,
was essential to define a class of antibodies by its physical or chemical
properties and not solely by its desired biological property. See Alpert, 305
F.2d at 894 (“[W]here results at each step [of experimentation] do not follow
as anticipated, but are achieved empirically by what amounts to trial and
error[,]” “the inventor’s mind cannot formulate a completed invention until
he finally performs a successful experiment.”).
Because Patent Owner’s records indicate that critical research activity
was still necessary before identifying a Siglec-15 antibody capable of
performing the functions recited in the challenged claims, the mental
embodiment of such antibodies as of the critical date “was a mere hope or
expectation, a statement of a problem, but not an inventive conception.” Id.
There is insufficient conception of an antibody based solely on its proposed
or expected biological activity. See Amgen, 927 F.2d at 1206 (finding no
conception of a nucleic acid based solely on its proposed biological activity).
Accordingly, we determine that Patent Owner has failed to establish
conception prior to the critical date.
In view of our determination that Patent Owner has not proved
conception, we do not need to determine whether Patent Owner adequately
IPR2015-00291
Patent 8,168,181 B2

24

demonstrated diligence, and therefore do not need to reach the issues raised
by Patent Owner and opposed by Petitioner.
We conclude, therefore, that Patent Owner has not antedated Hiruma,
which is thus prior art under 35 U.S.C. § 102(a).
E. Patent Owner’s Motion to Exclude Evidence
Patent Owner’s motion filed on January 5, 2016, seeks to exclude
portions of Petitioner’s expert testimony. Paper 60. Specifically, Patent
Owner seeks to exclude 1) paragraphs 14–18 and 20–25 of the Crocker
Declaration (id. at 1–9); 2) paragraphs 16, 21, 22, 28, and 30–33 of the Clark
Declaration (id.); and 3) paragraphs 4–9 of the Reply Crocker Declaration
(id. at 10–15).
We have reviewed the cited portions of the testimony provided by
Drs. Crocker and Clark and see no credible basis that would warrant their
exclusion. Patent Owner’s objections go to the weight and sufficiency of the
testimony, rather than its admissibility. We are capable of discerning from
the testimony, and the evidence presented, whether the witness’ testimony
should be entitled to any weight, either as a whole or with regard to specific
issues. We weigh such testimony on an issue-by-issue basis, as appropriate.
Furthermore, Patent Owner had the opportunity to address any alleged
deficiencies in the testimony of Drs. Crocker and Clark in its Patent Owner’s
Response, and we are capable of weighing that testimony accordingly.
Thus, we deny Patent Owner’s motion seeking to exclude the
testimony of Drs. Crocker and Clark in this proceeding.
IPR2015-00291
Patent 8,168,181 B2

25

F. Petitioner’s Motion to Exclude Evidence
Petitioner seeks to exclude the following: (1) the entirety of the Boyce
Declaration; (2) paragraphs 6, 14, 28, and 36 of the Stein Declaration; and
(3) Ex. 2152 (Alethia Laboratory Notebook 110). Paper 63.
With regard to the issues raised by Petitioner challenging Patent
Owner’s submission of the testimony provided by Drs. Boyce and Stein, we
have reviewed the cited portions of that testimony and we see no basis for
excluding it. Petitioner’s objections go to the weight and sufficiency of the
testimony, rather than its admissibility. Thus, for the same reasons indicated
above, we deny Petitioner’s motion seeking to exclude the testimony of Drs.
Boyce and Stein in this proceeding.
We find it unnecessary to consider the objections to the admissibility
of Exhibit 2152. Paper 63, 10–14. We have not relied upon the details of
Exhibit 2152 in reaching our decision. In other words, even without relying
on Exhibit 2152, we have determined that Petitioner has demonstrated, by a
preponderance of the evidence, that the challenged claims of the ’181 patent
are unpatentable. Accordingly, the issues raised by Petitioner regarding Ex.
2152 are moot.
III. CONCLUSION
For the foregoing reasons, we determine that the information
presented in the Petition demonstrates, by a preponderance of the evidence,
that claims 1−6, 8−11, and 15−23 are unpatentable under 35 U.S.C. § 102(a)
over Hiruma. This is a final written decision of the Board under 35 U.S.C.
§ 318(a). Parties to the proceeding seeking judicial review of the decision
must comply with the notice and service requirements of 37 C.F.R. § 90.2.
IPR2015-00291
Patent 8,168,181 B2

26

IV. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that claims 1–6, 8–11, and 15–23 of the ’181 patent are
unpatentable;
FURTHER ORDERED that Patent Owner’s Motion to Exclude is
denied;
FURTHER ORDERED that Petitioner’s Motion to Exclude is denied-
in-part and dismissed-in-part.

PETITIONER:
Stephen B. Maebius
Kristel Schorr
Jeffrey N. Costakos
FOLEY & LARDNER LLP
smaebius@foley.com
kschorr-IPR@foley.com
jcostakos@foley.com

PATENT OWNER:
Fangli Chen
Eric J. Marandett
CHOATE HALL & STEWART LLP
PTABMattersBoston@proskauer.com
emarandett@choate.com

Janique Forget
ALETHIA BIOTHERAPEUTICS INC.
janique.forget@alethiabio.com