William Hildebrand et al.

Patent Trials and Appeals Board

Aug 13, 2021

2021001720 (P.T.A.B. Aug. 13, 2021)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/859,002 08/18/2010 William H. Hildebrand 66802.126 / OAKU.004P13 7062
20995 7590 08/13/2021
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE, CA 92614
EXAMINER
DIBRINO, MARIANNE
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
08/13/2021 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):
efiling@knobbe.com
jayna.cartee@knobbe.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte WILLIAM H. HILDEBRAND and STEVEN CATE
__________

Appeal 2021-001720
Application 12/859,002
Technology Center 1600
__________

Before JEFFREY N. FREDMAN, TAWEN CHANG, and
JOHN E. SCHNEIDER, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to method
of detecting particular anti-HLA class II antibodies. The Examiner rejected
the claims as failing to comply with the written description and enablement
requirements, as obvious, and on the ground of provisional non-statutory
obviousness-type double patenting. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Parties in Interest as the Board
of Regents of the University of Oklahoma and Pure Transplant Solutions,
LLC. (see Appeal Br. 2). We have considered the Specification of Aug. 18,
2010 (“Spec.”); Final Office Action of Jan. 20, 2020 (“Final Act.”); Appeal
Brief of July 21, 2020 (“Appeal Br.”); and Examiner’s Answer of Oct. 30,
2020 (“Ans.”).
Appeal 2021-001720
Application 12/859,002

2
Statement of the Case
Background
“HLA class I and class II molecules are responsible for presenting
peptide antigens to receptors located on the surface of T-lymphocytes,
Natural Killer Cells (NK), and possibly other immune effector and
regulatory cells” (Spec. ¶ 4). “Display of peptide antigens . . . are the basis
for the recognition of ‘self vs. nonself’ and the onset of important immune
responses” (id.). “HLA class I and class II molecules differ from person to
person. . . . For transplant purposes it is important to determine which of the
multiple HLA expressed on a cell are recognized by the antibodies of
another individual. Anti-HLA antibodies can lead to hyperacute organ
rejection” (id. ¶ 5).
The Specification teaches “a method of producing and purifying
individual soluble HLA class II trimolecular complexes, as well as methods
of use of said complexes in methods of antibody detection and epitope
discovery” (Spec. ¶ 12).
The Claims
Claims 42–45, 47, 48, 50, 51, 53, and 64–70 are on appeal.
Independent claims 42 and 48 are representative and read as follows:
42. A method of detecting whether particular anti-HLA class
II antibodies are present in a biological sample, the method
comprising the steps of:
reacting a biological sample with a substrate having a
plurality of different, recombinant, soluble HLA
class II trimolecular complexes covalently bound
thereto, each of the soluble HLA class II
trimolecular complexes comprising a particular
soluble alpha chain allele, a particular soluble beta
chain allele, and a peptide ligand noncovalently
Appeal 2021-001720
Application 12/859,002

3
bound to an antigen binding groove formed from
the soluble alpha and beta chains, and wherein the
soluble, covalently bound HLA class II
trimolecular complexes comprise a glycosylation
pattern and antigenic integrity of a native HLA
class II trimolecular complex;
washing the substrate to remove unbound portions of the
biological sample; and
determining if anti-HLA class II antibodies specific for
the particular HLA class II alpha chain allele or
particular beta chain allele are present in the
biological sample.

48. A method of removing anti-HLA class II antibodies from
a biological sample, the method comprising the steps of:
contacting a biological sample with a column comprising
a solid support and a recombinant soluble HLA
trimolecular complex covalently bound to the solid
support, wherein the recombinant soluble HLA
trimolecular complex comprises a soluble HLA
class II alpha chain allele, a soluble HLA class II
beta chain allele, and a peptide ligand non-
covalently bound in a groove formed from the
soluble alpha and beta chains, wherein the
recombinant soluble HLA class II trimolecular
complex comprises a glycosylation pattern and
antigenic integrity of a native HLA class II
trimolecular complex, and whereby antibodies
present in the biological sample which specifically
bind to the HLA class II trimolecular complex are
removed from the biological sample.

Appeal 2021-001720
Application 12/859,002

4
The Issues
A. The Examiner rejected claims 42–45, 47, 48, 50, 51, 53, and 64–70
under 35 U.S.C. § 112, first paragraph as failing to comply with the written
description requirement (Final Act. 2–4).
B. The Examiner rejected claims 42–45, 47, 48, 50, 51, 53, and 64–70
under 35 U.S.C. § 112, first paragraph as failing to comply with the
enablement requirement (Final Act. 4–6).
C. The Examiner rejected claims 42–45, 47, 48, 50, 51, 53, and 64–70
under 35 U.S.C. § 103(a) as obvious over Buelow,2 Kalandadze,3 Prilliman,4
and Chicz5 (Final Act. 7–13).
D. The Examiner rejected claims 44, 50, and 67 under 35 U.S.C. § 103(a)
as obvious over Buelow, Kalandadze, Prilliman, Chicz, and Harlow6 (Final
Act. 13–14).
E. The Examiner rejected claim 70 under 35 U.S.C. § 103(a) as obvious
over Buelow, Kalandadze, Prilliman, Chicz, Harlow, and Hakim7 (Final Act.
14–15).
F. The Examiner rejected claims 48, 50, 53, and 67–70 on the grounds of

2 Buelow, R., US 5,482,841, issued Jan. 9, 1996.
3 Kalandadze et al., Expression of Recombinant HLA-DR2 Molecules, 271 J.
Biol. Chem. 20156–162 (1996).
4 Prilliman et al., Large scale production of class I bound peptides:
assigning a signature to HLA-B*1501, 45 Immunogenetics 379–85 (1997).
5 Chicz et al., Specificity and Promiscuity among Naturally Processed
Peptides Bound to HLA-DR Alleles, 178 J. Exp. Med. 27–47 (1993).
6 Harlow et al., Antibodies – A Laboratory Manual, pp. 528–530 (Cold
Spring Harbor Labs (1988)).
7 Hakim et al., Extracorporeal Removal of Anti-HLA Antibodies in
Transplant Candidates, 16 Am. J. Kidney Disease 429–31 (1990).
Appeal 2021-001720
Application 12/859,002

5
non-statutory obviousness-type double patenting over claims 1, 5–7, 21, 23–
25, 32–40, and 42 of copending US 13/860,897 (Final Act. 16–17).

A. 35 U.S.C. § 112, first paragraph, written description
The Examiner finds
the soluble HLA class II trimolecular complex used in the
claimed method that comprises a particular soluble alpha chain
allele [product] and a soluble beta chain allele [product] must
be associated with a peptide ligand noncovalently bound to an
antigen binding groove formed from the said soluble alpha and
beta chains and must comprise the antigenic integrity of a
native HLA class II trimolecular complex. As such, the
complex must be associated to provide the functional properties
of forming a peptide binding groove sufficient to bind peptide
and remain bound thereto, and the resulting complex must be
associated sufficiently to possess the functional property of
antigenic integrity of a native HLA class II trimolecular
complex.
(Final Act. 3). The Examiner finds that the Specification and Kalandadze
teach “that adding leucine zipper dimerization motifs helps assembly of the
HLA class II molecules . . . because the alpha and beta chains did not
assemble in mammalian cells when the transmembrane regions were
truncated” (id. at 6). However, the Examiner finds that an “artisan would
reasonably conclude that Applicant was not in possession of the genus of all
such HLA class II trimolecular complexes, and hence not in possession of
the claimed method” (id. at 4).
Appellant contends:
The specification teaches that the leucine zipper is merely one
type of super secondary structural motif that would work in
embodiments of the invention. There is no mention that the
leucine zipper is “critical” or that the alpha and beta chains of
Appeal 2021-001720
Application 12/859,002

6
the HLA class II molecules must “necessarily comprise” this
one specific type of super secondary structure.
(Appeal Br. 4). Appellant contends “one of ordinary skill in the art would
appreciate that other similar super secondary structural motifs would work
similarly as the leucine zipper motif embodiment chosen” (id.). Appellant
contends the Examiner “failed to analyze the full teaching of Kalandadze.
Kalandadze mentions a variety of techniques that can associate soluble HLA
alpha and beta chains” (id.). Appellant also contends
Kalandadze discussed that Wettstein was able to
successfully express truncated soluble HLA class II
trimolecular complexes using CHO cells, where a leucine
zipper was not used to hold the alpha and beta chains of the
HLA class II molecule together. Kalandadze at p. 20158.
Instead, Wettstein expressed soluble HLA class II chains by
removing the transmembrane domain and using a glycan-
phosphatidyl inositol anchor to obtain functioning trimolecular
complexes. Id. One of ordinary skill in the art reading
Appellant’s specification would have been aware of at least this
alternative method of linking class II chains together to form an
active trimolecular complex that does not require a leucine
zipper domain.
(id. at 5). Appellant contends “there are many ways to associate proteins
chains together. Examples may include disulfide bonds, streptavidin/biotin,
along with many other techniques that would have been known to one of
ordinary skill reviewing the specification” (id.).
Our analysis starts with the written description requirement itself.
At one end of the written description landscape, the structure of features is
fully described in the Specification itself; as less structure is provided,
the determination of what is needed to support generic claims to
biological subject matter depends on a variety of factors, such
as the existing knowledge in the particular field, the extent and
Appeal 2021-001720
Application 12/859,002

7
content of the prior art, the maturity of the science or
technology, the predictability of the aspect at issue, and other
considerations appropriate to the subject matter.
Capon v. Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005). Thus, when the
prior art demonstrates a mature field and predictable technology as
demonstrated by evidence such as Declarations or detailed prior art
disclosures, the Specification “need not teach, and preferably omits, what is
well known in the art.” Spectra–Physics, Inc. v. Coherent, Inc., 827 F.2d
1524, 1534 (Fed. Cir. 1987).
At the other end of this landscape, a Specification fails to comply with
the written description requirement when providing “only a research plan,
leaving it to others to explore the unknown contours of the claimed genus.”
AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d
1285, 1300 (Fed. Cir. 2014). In order to comply:
An adequate written description must contain enough
information about the actual makeup of the claimed products —
“a precise definition, such as by structure, formula, chemical
name, physical properties, or other properties, of species falling
within the genus sufficient to distinguish the genus from other
materials,” which may be present in “functional” terminology
“when the art has established a correlation between structure
and function.”
Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378 (Fed. Cir. 2017) (citing Ariad
Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010)).
We apply these principles to the broadly claimed non-covalent HLA
class II trimolecular complex formed from soluble alpha chains, soluble beta
chains, and peptide ligand, where the trimolecular complex includes these
three components in a form that functionally retains antigenic integrity of the
native trimolecular complex (see claim 42).
Appeal 2021-001720
Application 12/859,002

8
The Specification explains that in “native form, the alpha and beta
chains of the HLA class II trimolecular complexes rely on the
transmembrane domain to maintain a native conformation. While removal
of this transmembrane domain facilitates secretion, this removal prevents
formation of a trimolecular complex” (Spec. ¶ 72). This understanding that
soluble alpha and beta chains prevent trimolecular complex formation is
echoed by Kalandadze, who teaches alpha and beta chain “transmembrane
regions were important for the assembly of DR2 molecules since the α and β
chains did not assemble in mammalian or insect cells when the
transmembrane regions were truncated” (Kalandadze 20156, col. 2).
Therefore, in order to achieve the functional requirement of claim 42
that the trimolecular complex form and retain antigenic integrity, linkers
must connect the DR2 alpha and beta chains in a way that maintains the very
precise relative positioning of these chains necessary to bind peptide ligand.
However, claim 42 also requires this peptide ligand linkage to the alpha and
beta chains to be non-covalent, and therefore excludes the use of covalent
linkers.
As to the non-covalent linkers at issue here, the Specification teaches
the “presently disclosed and claimed inventive concept(s) removes the
transmembrane domain and replaces it with a super secondary structural
motif, such as but not limited to, a leucine zipper protein sequence” (Spec.
¶ 72). Kalandadze teaches a working example with a particular leucine
zipper, teaching the “leucine zipper dimerization motifs from the
transcription factors Fos and Jun were therefore used to replace the
hydrophobic transmembrane regions. Synthetic peptides of the Fos and Jun
leucine zipper dimerization motif are known to assemble as stable, soluble
Appeal 2021-001720
Application 12/859,002

9
heterodimers” (Kalandadze 20156, col. 2).
However, the Specification does not provide descriptive support for
any other super secondary structural motif that would function to form a
trimolecular complex of alpha and beta chains capable of binding ligand in a
form that functionally retains antigenic integrity of the native trimolecular
complex as required by claim 42.8 And while Kalandadze states the “DRα
and DRβ transmembrane regions could be replaced with a glycan-
phosphatidyl inositol anchor from human placental alkaline phosphatase
(Wettstein et al., 1991),” Kalandadze does not explain what composes a
“glycan-phosphatidyl inositol anchor”9 nor does Kalandadze state that
complexes with the inositol anchor yield trimolecular complexes with the
“antigenic integrity of a native HLA class II trimolecular complex” as
required by claim 42.
In addition, Kalandadze’s next statement is that “DR2 molecules were
not assembled when the transmembrane region of one chain was truncated”
(Kalandadze 20158, col. 1). Thus, even to the extent that Kalandadze
reports a teaching by Wettstein replacing transmembrane regions with an
“anchor”, Kalandadze then teaches that DR2 molecules were not assembled,
reasonably suggesting that more details or teachings are necessary to ensure

8 We recognize Appellant pointed to a citation in Kalandadze regarding a
Wettstein reference (see Appeal Br. 5) but Appellant did not submit a copy
of Wettstein into the record, nor did Appellant provide a Declaration or other
evidence explaining how the teachings of Wettstein apply to the instant
claims.
9 We do recognize that glycan is a polysaccharide and phosphatidylinositol
is an amphiphilic lipid but the word “anchor” lacks a definitive meaning in
this context.
Appeal 2021-001720
Application 12/859,002

10
formation of trimolecular complexes with “antigenic integrity of a native
HLA class II trimolecular complex.”
Thus, a review of the evidence shows that only a single species of
leucine zipper, the Fos-Jun zipper, representing a single subspecies of the
large genus of super secondary structural motifs discussed in the
Specification (Spec. ¶ 72), demonstrates efficacy in forming a trimolecular
complex with “antigenic integrity of a native HLA class II trimolecular
complex” as required by claim 42. Consequently, the instant situation is one
where the “claims merely recite a description of the problem to be solved
while claiming all solutions to it and . . . cover any compound later actually
invented and determined to fall within the claim’s functional boundaries—
leaving it to . . . industry to complete an unfinished invention.” Ariad, 598
F.3d at 1350.
Based on the single described embodiment, we find the claims are
drawn to undescribed features in the landscape, that were not disclosed or
described by the prior art. The single Fos-Jun leucine zipper is fewer than
the number of species described in Amgen, where the claim at issue recited
an antibody that bound to a region containing one of 15 particular amino
acids within a particular antigen, PCSK9, and blocked binding to the LDL
receptor. Amgen, 872 F.3d at 1372. The Amgen patentee disclosed eighty-
five antibodies to PCSK9 that blocked binding to the LDL receptor of which
twenty-four satisfied the claim limitations. Id. However, the Court found
these twenty-four species insufficient to satisfy the written description
requirement.
Similarly, Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d
1341–1353 (Fed. Cir. 2011) addressed a claim drawn to an anti-TNF
Appeal 2021-001720
Application 12/859,002

11
antibody which comprised a human constant region, inhibited binding to
TNF, and bound to TNF with a particular affinity. Centocor, 636 F.3d at
1346. Centocor found the applicant did “not disclose any relevant
identifying characteristics for such fully-human antibodies or even a single
human variable region.” Id. at 1351. Centocor concluded that the
“specification at best describes a plan for making fully-human antibodies
and then identifying those that satisfy the claim limitations. But a ‘mere
wish or plan’ for obtaining the claimed invention is not sufficient.” Id. In
the instant facts, Appellant has not provided any relevant identifying
characteristics for super secondary structural motifs or other components
that will allow formation of soluble HLA class II trimolecular complexes
with “antigenic integrity of a native HLA class II trimolecular complex” as
required by claim 42.
Therefore, while we agree with Appellant that the burden of
demonstrating a failure to comply with the written description requirement is
placed on the Examiner, we find the Examiner has satisfied this burden. The
Examiner determined that the Specification and prior art did not sufficiently
describe the claimed soluble HLA class II trimolecular complexes composed
of soluble alpha and beta chain alleles and bound peptide ligand that retained
antigenic integrity of the native HLA class II trimolecular complex as
required by claim 42 (see Final Act. 3–4).

B. 35 U.S.C. § 112, first paragraph, enablement
The Examiner finds
specification has not enabled the breadth of the claimed
invention because the claims encompass a method that utilizes
Appeal 2021-001720
Application 12/859,002

12
an HLA class II complex bound to a solid support, wherein the
said HLA class II complex does not necessarily comprise an
endogenous peptide in the antigen binding groove and wherein
the said HLA class II complex does not comprise the antigenic
integrity of a native HLA class II trimolecular complex.
(Final Act. 4).
Appellant contends the “instant application has disclosed at least one
method for making and using the claimed invention” (Appeal Br. 6).
Appellant further contends
While it may require some experimentation to determine other
ways of linking HLA class II chains together, in addition to the
leucine zipper approach described in the specification, such
experimentation would be routine and not undue. The Examiner
has not provided any evidence to support the contention that
determining additional binding mechanisms would require
undue experimentation when multiple ways of linking proteins
together are well-known and routine in the art.
(id. at 7).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that the
Specification does not enable the full scope of the claimed invention?
Findings of Fact
Breadth of Claims
1. Claim 42 broadly encompasses a method that requires a
trimolecular complex composed of soluble alpha chain, soluble beta chain
and peptide ligand that maintains the “antigenic integrity of a native HLA
class II trimolecular complex.”
Appeal 2021-001720
Application 12/859,002

13
Amount of Direction or Guidance Presented
2. The Specification teaches that in the invention, “each of the α
and β chains of the HLA class II complex is truncated such that the domain
normally anchoring the complex to the cell surface is removed” and notes
that “[w]hile removal of this transmembrane domain facilitates secretion,
this removal prevents formation of a trimolecular complex” (Spec. ¶ 72).
3. The Specification teaches the transmembrane domain is
replaced “with a super secondary structural motif, such as but not limited to,
a leucine zipper protein sequence, which serves as a tethering moiety for the
class II alpha and beta chains. The super secondary structural motif . . .
thereby creates adhesion or fusion forces between proteins” (Spec. ¶ 72).
4. The Specification teaches
regions encoding the transmembrane domains of the alpha and
beta chains have been removed and replaced with a super
secondary structural motif that enables the alpha and beta
chains (which previously interacted through their
transmembrane domains) to interact. In one embodiment, the
super secondary structural motif is a leucine zipper protein
sequence that acts as a tethering moiety for the alpha and beta
chains.
(Spec. ¶ 86).
5. The Specification teaches the “functionally active, soluble
individual HLA class II trimolecular complex maintains the physical,
functional and antigenic integrity of a native HLA trimolecular complex”
(Spec. ¶ 91).
Presence of Working Examples
6. The Specification teaches, in Example 1, that “cells transfected
with a soluble HLA-DRB*0103/DRA*0101 construct (DRB1 *0101 soluble
Appeal 2021-001720
Application 12/859,002

14
alpha chain with leucine zipper and DRB1 *0103 soluble beta chain with
leucine zipper) were grown in a roller bottle format” resulting in “milligram
quantities of a soluble form of a single class II HLA heterodimer” (Spec.
¶¶ 139–140).
Relative skill in the art
9. Neither the Examiner nor Appellant identified the level of skill
in the art but prior art such as Kalandadze demonstrates a high level of skill
involving research scientists (see Kalandadze 20156, author affiliations).
State of the Prior Art and Unpredictability of the Art
10. Kalandadze teaches the “transmembrane regions were
important for the assembly of DR2 molecules since the α and β chains did
not assemble in mammalian or insect cells when the transmembrane regions
were truncated” (Kalandadze 20156, col. 2).
11. Kalandadze teaches “DR2 molecules were not assembled when
the transmembrane region of one chain was truncated” (Kalandadze 20158,
col. 1).
12. Kalandadze teaches, with regard to expression of the alpha and
beta chains, that “[m]olecules expressed as fusions with the α-mating factor
secretion signal were efficiently secreted, while usage of the PHO1 secretion
signal (vector pHIL-S1, Invitrogen) resulted in little or no secretion”
(Kalandadze 20158, col. 2).
Appeal 2021-001720
Application 12/859,002

15
13. Wilson10 teaches “the addition of the carbohydrate side chain to
the HLA-A,B,C heavy chain affects the protein antigenic conformation of
this molecule. To our knowledge, this is the first demonstration that
glycosylation may affect the conformation of HLA antigens” (Wilson 203,
col. 2).
Quantity of Experimentation
14. Appellant asserts: “While it may require some experimentation
to determine other ways of linking HLA class II chains together, in addition
to the leucine zipper approach described in the specification, such
experimentation would be routine and not undue” (Appeal Br. 7).
15. The Examiner finds: “Undue experimentation would be
required of one skilled in the art to practice the instant invention” (Final Act.
6).
Principles of Law
When rejecting a claim under the enablement requirement of
section 112, the PTO bears an initial burden of setting forth a
reasonable explanation as to why it believes that the scope of
protection provided by that claim is not adequately enabled by
the description of the invention provided in the specification of
the application.
In re Wright, 999 F.2d 1557, 1561–62 (Fed. Cir. 1993).

Factors to be considered in determining whether a disclosure
would require undue experimentation … include (1) the
quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of

10 Wilson et al., Effect of Tunicamycin on the Assembly and Antigenicity of
HLA Antigens: Analysis with Monoclonal Antibodies, 14 Scandinavian J.
Immunology 201–5 (1981).
Appeal 2021-001720
Application 12/859,002

16
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).
Analysis
In addressing the Wands factors, the Examiner has provided
substantial evidence of unpredictability that relates to two different
dimensions of claim scope. The scope of independent claim 42 requires
formation of a trimolecular complex composed of soluble alpha chain,
soluble beta chain, and peptide ligand and that trimolecular complex must
retain antigenic integrity of the native form.
The Specification itself recognizes that to make the alpha and beta
chains soluble, the transmembrane domain must be removed and “removal
of this transmembrane domain facilitates secretion, this removal prevents
formation of a trimolecular complex” (FF 2). To overcome this problem, the
Specification teaches that addition of a “super secondary structural motif . . .
thereby creat[ing] adhesion or fusion forces between proteins” (FF 3). The
Specification has a single example using a leucine zipper (FF 6).
However, other than the leucine zipper, the Specification provides no
further guidance or disclosure regarding which other secondary structural
motifs, if any, will result in soluble alpha and beta chains capable of forming
the trimolecular complex while also retaining antigenic integrity of the
native form.
Kalandadze reinforces that soluble alpha and beta chains alone will
not form a complex (FF 10–11) and further teaches that simply appending
Appeal 2021-001720
Application 12/859,002

17
known motifs, such as secretion signal sequences, may not obtain the desired
function (FF 12), establishing that modifying proteins to obtain particular
functions remains unpredictable. Wilson similarly shows that modification
of protein sequences may impact structure including the antigenic
conformation (FF 13), impacting the antigenic integrity of the molecule.
We agree with the Examiner that to establish that other super
structural motifs, or other modes of joining the soluble alpha and beta
chains, would function, would require significant research programs to
demonstrate that a reasonable number of species in the genus of all
interacting and binding protein motifs would result in a soluble HLA class II
trimolecular complex capable of binding peptide ligand while retaining the
antigenic integrity of the native complex as required by claim 42 (see Ans.
10, “One of skill in the art did not know which members (of a functionally
described element that is not presently recited in the claims and not defined
in the specification) in the genus of ‘super secondary structural motifs’
would predictably allow for association of the alpha and beta chains of HLA
as a heterodimer.”)
Therefore, in light of the single working example, the very limited
disclosure in the Specification, the large and unpredictable amount of
experimentation necessary, and the large breadth of claim 42, we agree with
the Examiner that the evidence supports the Examiner’s finding that the
Specification does not enable the broad scope of claim 42. See In re Fisher,
427 F.2d 833, 839 (CCPA 1970) (“[T]he scope of the claims must bear a
reasonable correlation to the scope of enablement provided by the
specification to persons of ordinary skill in the art.”).
Appeal 2021-001720
Application 12/859,002

18
Appellant contends: “As long as the specification discloses at least
one method for making and using the claimed invention that bears a
reasonable correlation to the entire scope of the claim, then the enablement
requirement of 35 U.S.C. 112 is satisfied” (Appeal Br. 6).
We are not persuaded. In Alza, a specific compound used for treating
ADHD was known and the “enablement issue reduce[d] to factual
considerations with regard to whether undue experimentation is required to
make oral dosage forms other than osmotic dosage forms that meet the
limitations of the claims.” Alza Corp. v. Andrx Pharm., LLC., 603 F.3d 935,
938 (Fed. Cir. 2010). In that simpler situation, where a single compound
was known to be effective and alternative dosage forms were known to exist,
Alza found that the “Wands factors weigh in favor of finding that the
experimentation required to practice part of the claimed invention was not
routine.” Id. at 943–944. Thus, a single example may not necessarily satisfy
the scope of enablement requirement. Moreover, Appellant’s have not
provided any persuasive evidence that the example of leucine zipper bears a
reasonable correlation to all super secondary structural motifs as recited in
the Specification that may be encompassed by the limitation, in claim 42, of
“HLA class II trimolecular complex.”
Appellant also contends that: “While it may require some
experimentation to determine other ways of linking HLA class II chains
together, in addition to the leucine zipper approach described in the
specification, such experimentation would be routine and not undue”
(Appeal Br. 7).
Appeal 2021-001720
Application 12/859,002

19
We find this argument unpersuasive because
Enablement serves the dual function in the patent system of ensuring
adequate disclosure of the claimed invention and of preventing claims
broader than the disclosed invention. . . . This important doctrine
prevents both inadequate disclosure of an invention and overbroad
claiming that might otherwise attempt to cover more than was actually
invented. Thus, a patentee chooses broad claim language at the peril
of losing any claim that cannot be enabled across its full scope of
coverage.
MagSil Corp. v. Hitachi Global Storage Technologies, Inc., 687 F.3d 1377,
1380–81 (Fed. Cir. 2012). Thus, it is precisely the point of the Examiner’s
scope of enablement rejection here that the claimed method will not
predictably function using any other super secondary structural motif.
Therefore, these overbroad claims are not enabled for their full scope of
coverage due to inadequate disclosure of a method that will function across
the full scope being claimed.
A preponderance of the evidence of record support the Examiner’s
conclusion that the Specification does not enable the full scope of the
claimed invention.

C. 35 U.S.C. § 103(a) over Buelow, Kalandadze, Prilliman, and Chicz
The Examiner finds it obvious to
have used, in the assay disclosed by the primary art reference
(Patent 5,482,841), soluble HLA class II complexes that match
the donor HLA class II allele type and constructed so as to
delete the TM and cytoplasmic regions and to add leucine
zipper proteins to each chain as per the teaching of Kalandadze
et al, but produced in the 721.221 human antigen-presenting
cell line taught by Chicz et al and by Prilliman et al or
Appeal 2021-001720
Application 12/859,002

20
produced in any of the other human antigen-presenting cell
lines taught by Chicz et al.
(Final Act. 10). The Examiner further finds it obvious “to have performed a
screening test to identify the HLA class II molecules of the donor to use on
the solid support to detect anti-donor HLA antibodies” “in order to more
easily test and interpret the test results of alloantibodies to a panel of HLA
class II molecules” (id.).
Appellant contends the
Buelow claim is looking for cross-matching between a specific
donor and a specific recipient. It would frustrate the purpose of
the method outlined in claim 11 of Buelow if recombinant HLA
class II molecules were bound to the substrate instead of an
individual donor since the purpose of Buelow’s claim 11 is to
match a donor with a recipient.
(Appeal Br. 9). Appellant further contends: “Replacing the donor molecules
with recombinantly produced HLA is inconsistent with the entire goal of the
assay, which was to see whether the donor’s HLA molecules are likely to be
rejected by the patient” (id. at 10).
We agree with Appellant that the rejection lacks “a reason that would
have prompted a person of ordinary skill in the relevant field to combine the
elements in the way the claimed new invention does.” KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 418 (2007). In particular, we agree that the
Examiner does not provide a persuasive reason to modify the ELISA assay
of Buelow, in which anti-alloantigen antibody capture agents are used to
bind HLA epitopes in order to determine graft rejection, to replace the
antibody with a trimolecular HLA complex including peptide.
To perform the Examiner’s substitution would require recombinantly
producing the HLA alpha and beta chains of an organ donor prior to
Appeal 2021-001720
Application 12/859,002

21
transplant, a complicated process rendered more difficult in cases where
donor tissue is extracted from deceased individuals whose organs may have
very limited timeframes available for transplant (see, e.g., Buelow 3:24–26).
But even in the case of living donors, where time is less of a concern, the
Examiner provides no persuasive basis explaining why this assay would
allow the artisan “to more easily test and interpret the test results of
alloantibodies to a panel of HLA class II molecules” (Final Act. 10).
We therefore reverse this obviousness rejection.

D.–E. 35 U.S.C. § 103(a) Rejections
Having reversed the obviousness rejection of claim 42 over Buelow,
Kalandadze, Prilliman, and Chicz for the reasons given above, we also find
that the further combinations do not provide persuasive reasons to combine
addressing those missing in the above rejection. We therefore reverse these
rejections for the same reasons as given above.

F. Provisional Obviousness-Type Double Patenting
We decline to reach this provisional rejection. See In re Moncla, 95
USPQ2d 1884, 1885 (BPAI 2010) (precedential). The rejection is
provisional and US Application No. 13/860,897 remains copending and not
allowed; accordingly, the issues are not ripe for decision.

Appeal 2021-001720
Application 12/859,002

22
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
42–45, 47,
48, 50, 51,
53, 64–70
112 Written Description 42–45, 47,
48, 50, 51,
53, 64–70

42–45, 47,
48, 50, 51,
53, 64–70
112 Enablement 42–45, 47,
48, 50, 51,
53, 64–70

42–45, 47,
48, 50, 51,
53, 64–70
103 Buelow, Kalandadze,
Prilliman, Chicz
42–45, 47,
48, 50, 51,
53, 64–70
44, 50, 67 103 Buelow, Kalandadze,
Prilliman, Chicz,
Harlow
44, 50, 67
70 103 Buelow, Kalandadze,
Prilliman, Chicz,
Harlow, Hakim
70
48, 50, 53,
67–70
Nonstatutory Double
Patenting,
13/860,89711

Overall
Outcome
42–45, 47,
48, 50, 51,
53, 64–70

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

11 As indicated above, we decline to address the merits of this
rejection at this time.
Appeal 2021-001720
Application 12/859,002

23
AFFIRMED