Fernando Jose Rebelo. Do Couto et al.

Patent Trials and Appeals Board

Sep 18, 2019

14518977 - (D) (P.T.A.B. Sep. 18, 2019)

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.
14/518,977 10/20/2014 Fernando Jose Rebelo Do Couto EPIT-013DIV 3310
93726 7590 09/18/2019
EPA - BOZICEVIC FIELD & FRANCIS LLP
BOZICEVIC, FIELD & FRANCIS
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
EXAMINER
ALLEN, MICHAEL D
ART UNIT PAPER NUMBER
1642
NOTIFICATION DATE DELIVERY MODE
09/18/2019 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):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte FERNANDO JOSE REBELO DO COUTO, KRISTIN BETH
HENDRICKS, STACEY ELLEN WALLACE, and GUO-LIANG YU
__________

Appeal 2018-001243
Application 14/518,977
Technology Center 1600
__________

Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to a
method of screening for an antibody. The Examiner rejected the claims as
indefinite, as of improper dependent form, as directed to non-statutory
subject matter, and as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

1 Appellants identify the Real Party in Interest as Abcam plc. (see App. Br.
3).
2 We have considered and herein refer to the Specification of Oct. 20, 2014
(“Spec.”); Final Office Action of Dec. 28, 2016 (“Final Action”); Appeal
Brief of May 25, 2017 (“App. Br.”); Examiner’s Answer of Oct. 4, 2017
(“Ans.”); and Reply Brief of Nov. 17, 2017 (“Reply Br.”).
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Statement of the Case
Background
“Because of their ability to target virtually any molecule with
exquisite specificity, monoclonal antibodies have the potential to become
one of the main therapeutic agents of the future” (Spec. 1:10–12).
“[H]owever the first attempts to fulfill the potential were disappointing
because monoclonal antibodies used in therapy elicit a strong immune
response in patients” (id. at 1:12–14). “In order to decrease these responses,
efforts have been made to replace as much as possible of the non-human
sequence of an antibody with human sequences using recombinant DNA
technology” (id. at 1:27–29). “[M]any humanized antibodies are still highly
immunogenic to a large proportion of patients. This is thought to be because
the CDRs themselves are immunogenic” (id. at 2:15–17).
“[T]here is a need for humanization methods that reduce the
immunogenicity of CDR regions of a non-human antibody in humans” (id.
at 2:27–29).
The Claims
Claims 37, 39–43, 45–49, and 52 are on appeal. Claim 37 is sole
independent claim, is representative and reads as follows:
37. A method of screening for an antibody, the method
comprising:
(a) immunizing an animal with an antigen;
(b) obtaining the amino acid sequence of a plurality of
antibodies from the immunized animal that bind to the antigen:
(c) identifying a plurality of substitutable positions in the
antibodies by: (i) aligning the amino acid sequences: (ii)
grouping the antibodies according to their sequence similarity to
produce groups of related antibodies and (iii) identifying
positions at which the amino acid varies;
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(d) making a library of candidate antibodies, wherein the
variant antibodies comprise amino acid substitutions at the
substitutable positions; and
(e) screening the variant antibodies to identity an antibody
having a desirable activity.

The Rejections
A. The Examiner rejected claims 45 and 49 under 35 U.S.C. § 112(b) as
indefinite (Ans. 2).
B. The Examiner rejected claim 45 under 35 U.S.C. § 112(d) as being of
improper dependent form (Ans. 2–3).
C. The Examiner rejected claims 37, 39–43, 45–49, and 52 under 35
U.S.C. § 101 as directed to non-statutory subject matter (Ans. 3–4).
D. The Examiner rejected claims 37, 39–43, 45–49, and 52 under 35
U.S.C. § 103(a) as obvious over Rader,3 Moe,4 Watkins,5 and Wu6 (Ans. 4–
8).

A. 35 U.S.C. § 112(b), indefiniteness
The Examiner finds “[c]laim 45 recites ‘directed amino acid
substitutions’. It is not clear what directed means in this phrase. There is no
special definition in the specification thereof. Therefore, the metes and
bounds of this claim are indefinite” (Ans. 2). The Examiner finds “[c]laim

3 Rader et al., The Rabbit Antibody Repertoire as a Novel Source for the
Generation of Therapeutic Human Antibodies, 275 (18) J. BIOL. CHEM.
13668–76 (2000).
4 Moe et al., US 2010/0260762 A1, published Oct. 14, 2010.
5 Watkins et al., US 2003/0099655 A1, published May 29, 2003.
6 Wu et al., Stepwise in vitro affinity maturation of Vitaxin, an αvβ3-specific
humanized mAb, 95 PROC. NATL ACAD. SCI. USA 6037–42 (1998).
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49 recites increased affinity but does not recite the comparison to be made to
get the increase and so this claim is indefinite” (Ans. 2).
Appellants contend “a person of ordinary skill in the art in light of the
present application would understand that a directed amino acid substitution
is ‘a substitution that make the amino acid sequence of an antibody more
similar to that of a related antibody’. Specification at page 12, lines 22-23”
(App. Br. 4). Appellants also contend regarding claim 49 that the
“comparison is made with the affinity of the related antibodies” (App. Br. 4).
We agree with Appellants. As to claim 45, the Specification identifies
four different types of substitutions: humanizing, directed, random, and
conservative (see Spec. 12:20–25) and as noted by Appellants, explains that
a directed substitution is “e.g., a substitution that makes the amino acid
sequence of an antibody more similar to that of a related antibody” (Spec.
12:22–23). The Specification also provides a more detailed discussion of
directed substitutions (see Spec. 20:13–21:4). We are not persuaded by the
Examiner’s argument that “the full breadth of the phrase is not defined by
the Specification” (Ans. 19). That claim 45 broadly encompasses any
substitutions that make an antibody more like some other antibody does not
render the claim indefinite, only broad. Even “undue breadth is not
indefiniteness.” In re Johnson, 558 F.2d 1008, 1016 n.17 (CCPA 1977).
As to claim 49, the claim expressly recites that the comparison is the
affinity of the desirable antibodies to a particular antigen relative to other
antibodies. Again, claim 49 may be broad because the comparison may be
to any antibody that is related in any way, but as already noted, “breadth is
not to be equated with indefiniteness.” In re Miller, 441 F.2d 689, 693, 169
USPQ 597, 600 (CCPA 1971).
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B. 35 U.S.C. § 112(d), improper dependent form
The Examiner finds that “[c]laim 45 recites directed substitutions.
However, there appears to be no difference between this phrase and the
substitutions of claim 37 on which claim 45 depends. Therefore, claim 45
does not further limit” (Ans. 3).
Appellants contend “directed amino acid substitution is a substitution
that makes the amino acid sequence of an antibody more similar to that of a
related antibody. As such, claim 45 further limits claim 37 on which claim
45 depends” (App. Br. 5).
We agree with Appellants. As already noted, claim 37 encompasses
at least four different types of substitutions including humanizing, directed,
random, and conservative (see Spec. 12:20–25) and claim 45 limits the
method to a particular one of these types, those that are “directed amino acid
substitutions.” We are not persuaded by the Examiner’s argument that
“whether the mutation is humanizing or making one antibody structurally
similar to a related antibody, for example, all would be considered directed”
(Ans. 21) because, at a minimum, directed substitutions limits claim 37 to
further exclude random substitutions, an alternative expressly discussed in
the Specification (see Spec. 12:23–24).

C. 35 U.S.C. § 101
The Examiner finds the claims
are directed to an abstract idea. This idea can be found in
claim 37c. Identifying substitutable positions via comparison
of at least two protein sequences through sequence alignment
and identification of varying residues is an abstract idea.
Addition of the step of grouping antibody sequences also adds
to this abstract idea. Furthermore, this abstract idea also
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contains a natural phenomenon/law of nature. This is the
correlation between sequence variation and substitutable
positions. Thus, the claims are clearly drawn to judicial
exceptions.
(Ans. 3). The Examiner further finds the “ordered combination of the active
steps of the instant claims is well-understood, routine and conventional. It is
routine in the art to immunize and animal to generate antibodies against the
immunogen/target antigen. It is routine to sequence the resulting antibodies
and to compare their sequences for differences” (Ans. 4).
Appellants contend that “claims are not directed to an abstract idea
because the claimed method for screening antibodies is implemented using a
set of limited rules specifically designed to improve existing technology for
identifying antibodies that have an improved activity” (App. Br. 7).
Appellants contend that
consistent with the court’s decision in Rapid Litigation
Management v. CellzDirect, the end result of the claimed
method is not simply an observation or detection of variant
antibodies, but instead, the claims recite a number of steps that
obtain and identify variant antibodies to achieve a desired
outcome (generating a library of antibodies and identifying a
novel antibody having a desirable activity).
(App. Br. 10). Appellants contend “the claims recite patent eligible subject
matter because the claims yield significantly more than the judicial
exception” (App. Br. 11).
The Alice Test
The Supreme Court has long interpreted 35 U.S.C. § 101 to include
implicit exceptions: “[l]aws of nature, natural phenomena, and abstract
ideas” are not patentable. See, e.g., Alice Corp. v. CLS Bank Int’l, 573 U.S.
208, 216 (2014).
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In determining whether a claim falls within an excluded category, we
are guided by the Supreme Court’s two-step framework, described in Mayo
and Alice. Id. at 217–18 (citing Mayo Collaborative Servs. v. Prometheus
Labs., Inc., 566 U.S. 66, 75–77 (2012)). In accordance with that framework,
we first determine if there is a judicial exception. See Alice, 573 U.S. at 219
(“On their face, the claims before us are drawn to the concept of
intermediated settlement, i.e., the use of a third party to mitigate settlement
risk.”) Although method claims are generally eligible subject matter, claims
that are directed only to abstract ideas, laws of nature, and/or natural
phenomena are directed to patent ineligible concepts. Ariosa Diagnostics,
Inc. v. Sequenom, Inc., 788 F.3d 1371, 1376 (Fed. Cir. 2015).
If the claim recites an abstract idea, we turn to the second step of the
Alice and Mayo framework, where “we must examine the elements of the
claim to determine whether it contains an ‘inventive concept’ sufficient to
‘transform’ the claimed abstract idea into a patent-eligible application.”
Alice, 573 U.S. at 221 (quotation marks omitted).
2019 Guidance
The United States Patent and Trademark Office published revised
guidance on the application of 35 U.S.C. § 101. USPTO’s 2019 Revised
Patent Subject Matter Eligibility Guidance (“Guidance”).7 Under the
Guidance, in determining what concept the claim is “directed to,” we first
look to whether the claim recites:
(1) any judicial exceptions, including “[l]aws of nature,
natural phenomena, and abstract ideas,” (quoting Alice, 573

7 2019 Revised Patent Subject Matter Eligibility Guidance, 84 Fed. Reg.
50–57 (January 7, 2019).
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U.S. at 216) and/or including certain groupings of abstract ideas
(i.e., mathematical concepts, certain methods of organizing
human activity such as a fundamental economic practice, or
mental processes) (Guidance Step 2A, Prong 1); and
(2) additional elements that integrate the judicial
exception into a practical application (see MPEP § 2106.05(a)–
(c), (e)–(h)) (Guidance Step 2A, Prong 2).
Only if a claim (1) recites a judicial exception and (2) does not
integrate that exception into a practical application, do we then look to
whether the claim contains an “‘inventive concept’ sufficient to ‘transform’”
the claimed judicial exception into a patent-eligible application of the
judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82).
In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial
exception that are not “well-understood, routine and
conventional in the field” (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine,
conventional activities previously known to the industry,
specified at a high level of generality, to the judicial exception.
(Guidance Step 2B). See Guidance, 84 Fed. Reg. at 54–56.
Analysis
Applying the Revised Guidance to the facts on this record, we find
that Appellants’ claims recite patent-eligible subject matter. Because the
same issues are present in each of the claims, we focus our consideration on
representative claim 37. The same analysis applied below to claim 37 also
applies to the other rejected claims.
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I. Guidance Step 2A, Prong 1
The Revised Guidance instructs us first to determine whether any
judicial exception to patent eligibility is recited in the claim. The Revised
Guidance identifies products of nature as having been identified by the
courts as judicial exceptions. 84 Fed. Reg. at 54.
We therefore look to see if the claim recites any judicial exceptions.
The Examiner, as already noted, finds that step (c) of the claim that recites
aligning and identifying substitutable positions in antibodies, grouping the
antibodies, and identifying varying amino acid positions is an abstract idea
and a law of nature (Ans. 3–4).
The Specification teaches that “sequences may be aligned by eye, or
by employing an alignment program such as one of the CLUSTAL suite of
programs” (Spec. 16:23–24). The Specification teaches using the aligned
sequences
to identify a substitutable position of an antibody, the amino
acid sequence of that antibody is compared to the sequences of
other antibodies belonging to the same group as that antibody.
If the identity of that amino acid varies between the different
related antibodies of a group at any particular position, that
position is a substitutable position of the antibody.
(Spec. 17:19–22). In the context of humanization of antibodies, the
Specification teaches that “[b]uilt-in searching engines can be used to search
for most similar sequences in terms of amino acid sequence homology”
(Spec. 23:6–7).
These computations used to align and group the sequences, along with
the use of mathematical operations or mental steps reasonably support the
Examiner’s finding that the claims recite the judicial exception of a
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mathematical concept. See SAP America, Inc. v. InvestPic, LLC, 898 F.3d
1161, 1166 (Fed. Cir. 2018) (“The court concluded that the claims . . . are
directed to ‘performing statistical analysis,’ specified using words in the
claims and using more technical, mathematical notation in the written
description”).
Also, we find that claim 37 recites methods and a system for obtaining
(step b), aligning (step (c)(i)), grouping (step (c)(ii)), and identifying (step
(c)(iii)) biological data associated with antibody sequences. While these
methods and system may be performed by a computer (see Spec. 16:23–24),
they ultimately represent mental processes that a biochemist would
undertake to generate a new antibody. As explained by our reviewing court,
“analyzing information by steps people go through in their minds, or by
mathematical algorithms, without more, [are treated] as essentially mental
processes within the abstract-idea category.” Elec. Power Grp., LLC v.
Alstom S.A., 830 F.3d 1350, 1354 (Fed. Cir. 2016). Because claim 37 recites
steps involving analyzing information by mathematical algorithms, we find
claim 37 recites a mental process in the abstract idea category of judicial
exceptions.

II. Guidance Step 2A, Prong 2
A claim that recites a judicial exception requires further analysis to
determine if any additional elements integrate the judicial exception into a
practical application. See 84 Fed. Reg. 54. The 2019 Guidelines explain
that additional elements that integrate the judicial exception into a practical
application include applying the judicial exception in some meaningful way
beyond generally linking the use of the judicial exception to a particular
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technological environment. (See 84 Fed. Reg. 55, citing Diamond v. Diehr,
450 U.S. 175, 184 (1981)).
As Appellants correctly note
the end result of the claimed method is not simply an
observation or detection of variant antibodies, but instead, the
claims recite a number of steps that obtain and identify variant
antibodies to achieve a desired outcome (generating a library of
antibodies and identifying a novel antibody having a desirable
activity).
(App. Br. 10).
That is, the claimed steps of aligning the amino acid sequences,
grouping the antibodies based on sequence similarity and identifying varying
positions is integrated into a specific method that requires forming a library
of variant antibodies that are screened to identify antibodies having desirable
activity (see Claim 37). We find these final steps analogous to the claims in
Diehr that recited a method for operating a rubber-molding press including
the step of “opening the press automatically when said comparison [of
calculated cure time vs. elapsed time] indicates equivalence.” See Diehr,
450 U.S. at 179 n.5.
We determine that the “making a library” and “screening the variant
antibodies” steps represent manufacturing steps that integrate the judicial
exceptions into the practical application of obtaining an “antibody having a
desirable activity” as required by claim 37. This integration occurs because,
as in Diehr, the mathematical concepts and abstract ideas recited in claim 37
result in a physical construct, a desirable antibody that has improved
properties relative to the starting antibody sequence, such as increased
antigen affinity (see, e.g., Claim 49). Specifically, the claimed method is
analogous to the Diehr step of opening the press because both require a
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specific, practical physical act in a particular technological environment that
extends the methods beyond mental steps or mathematical analysis. In the
instant case, the method does not merely inform the artisan about possible
changes in amino acid sequence that might improve the antibody obtained
immunization, but actually require the generation of particular improved
variant antibodies. Because we conclude that the judicial exceptions recited
in claim 37 are integrated into the practical application of methods for
creating antibodies with desirable activities, we conclude that claim 37 is
directed to patent-eligible subject matter.
We recognize the Examiner’s argument that “even the ordered
combination of steps in the instant claims does not add significantly more to
the exceptions. This is because the steps are well-understood, routine, and
conventional” (Ans. 24). However, simply because “a mathematical
equation is required to complete the claimed method and system does not
doom the claims to abstraction.” Thales Visionix Inc. v. United States, 850
F.3d 1343, 1349 (Fed. Cir. 2017). The instant claims seek to protect the
detailed, and presumably unobvious,8 method for identifying substitutable
positions in antibody, making a library, and screening that library, in order to
obtain antibodies having desirable activities.
Therefore, rather than claiming solely an abstract idea or law of
nature, claim 37 specifies a particular unobvious approach to such design
that results in particular designed and desirable antibodies. See Thales, 850
F.3d at 1349 (“The claims specify a particular configuration of inertial
sensors and a particular method of using the raw data . . . Far from claiming

8 We note that the Examiner’s obviousness rejection below is reversed.
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the equations themselves, the claims seek to protect only the application of
physics to the unconventional configuration of sensors as disclosed.”)
Alice Step Two
We are persuaded by the Appellants’ position that the Examiner does
not establish sufficiently that the claims on appeal satisfy Alice step one. As
such, we need not proceed to Alice step two in order to conclude that, on the
record before us, it has not been established sufficiently that the claims on
appeal fail the Alice Test for patent eligibility.
Conclusion of Law
We conclude that claims 37, 39–43, 45–49, and 52 are not directed to
patent-ineligible subject matter.

D. 35 U.S.C. § 103(a)9 over Rader, Watkins, and Wu
The Examiner finds that Rader teaches a process where “Rabbits are
immunized with target antigen, antibody genes are isolated, rabbit antibody
library is constructed, selection for binding to antigen occurs, humanization
via CDR grafting is performed, and finally humanized antibodies are
selected for target antigen binding” (Ans. 4–5). The Examiner finds Rader
teaches alignment and comparison of “3 rabbit antibody clone sequences” as
well as issues about anti-idiotypic response (Ans. 5).
The Examiner acknowledges that Rader “does not teach use of the
noted CDR variations to identify substitutable positions and use the amino

9 The Examiner acknowledges that the Moe patent does “not receive the
priority date of 06/23/2004 with respect to the taught sections, and, in view
of Applicant’s arguments above over their own priority, should be removed
as prior art” (Ans. 26).
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acids represented to construct an antibody library for screening for any
purpose” (Ans. 5).
The Examiner finds Watkins teaches the ordinary artisan “routinely
made and used libraries of antibody CDR variants and screened them to
optimize activity” (Ans. 6). The Examiner finds Wu teaches the “use of
CDR variant combinatorial antibody libraries to optimize antibody function”
(Ans. 7). The Examiner finds Wu “aligned and assessed differences
between related antibody CDRs” (Ans. 7). The Examiner acknowledged
that Wu “uses a less sequence-guided approach in their screening process
than the method of instant claims” but finds “smaller library size allowed for
easier screening and so contribution of all six CDRs could be assessed and
beneficial mutations were found in all six CDRs” (Ans. 7).
The Examiner finds the combination obvious because the artisan
would have been “motivated to apply the sequence comparison and library
screening techniques in the prior art above in order to find improved
therapeutic humanized antibodies” (Ans. 8).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that Rader,
Watkins, and Wu render claim 37 obvious?
Findings of Fact
1. Rader teaches the use of “phage display technology to select
and humanize antibodies from rabbits that were immunized with human A33
antigen which is a target antigen for the immunotherapy of colon cancer”
(Rader 13668, abstract).
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2. Figure 1 of Rader is reproduced below:

Figure 1 is a “[f]low chart outlining the process of generating and
humanizing rabbit antibodies directed to a target antigen” (Rader 13670, col.
2).
3. Figure 2 of Rader is reproduced, in part, below:

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Figure 2 depicts “frameworks (FRs) . . . [of] VH sequences. Dashes indicate
identical amino acids. The humanized library with diversified human FRs . .
. is shown in the center. Diversified positions are shown in bold type.
Underlined positions indicate a coupled diversification that limits the
selection to either all human or all rabbit sequence” (Rader 13671).
4. Rader teaches:
Analysis of sera from the patients revealed evidence for an anti-
idiotypic immune response, i.e. the sera contained antibodies
that recognized the antigenbinding site of humanized antibody
A33. Administration of an equally potent humanized antibody
that is unreactive to the anti-idiotypic immune response
generated by humanized antibody A33 would allow therapy to
continue.
(Rader 13675, col. 1).
5. Rader teaches “our humanized antibodies derived from the
rabbit antibody repertoire complement humanized antibody A33 derived
from the mouse antibody repertoire” (Rader 13675, col. 2).
6. Watkins teaches:
Libraries of CDR variants containing single amino acid
substitutions were generated (Example II). The libraries were
screened for binding to a cryptic collagen site, and single amino
acid mutations having beneficial activity were identified.
Combinatorial mutants, in which two or more variant CD Rs
containing at ieast one amino acid substitution relative to
parental HUIV26 or HUI77 CDRs were combined and screened
for activity (Example III). A number of combinatorial mutants
having optimized activity for binding to a cryptic collagen site
were identified.
(Watkins ¶ 44).
7. Wu teaches a “protein engineering strategy based on efficient
and focused mutagenesis implemented by codon-based mutagenesis was
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developed” (Wu 6037, abstract).
8. Wu teaches “phage-expressed antibody libraries for all six
lg heavy and light chain complementarity-determining regions
were expressed and screened . . . variants in these libraries each contained a
single mutation, and all 20 amino acids were introduced at each
complementarity-determining region residue, resulting in the expression
of 2,336 unique clones” (Wu 6037, abstract).
9. Wu teaches “variants with enhanced affinity were identified
rapidly and required the synthesis of only 2,592 unique variants” (Wu 6037,
abstract).
10. Wu teaches:
Construction of CDR Libraries. Using the numbering system
of Kabat et al. . . . the residues chosen for mutagenesis of the
CDRs (see Table 2) were: Gln24-Tyr36 in light chain CDRl (L1);
Leu46-Ser56 in light chain CDR2 (L2); Gln89-Thr97 in light chain
CDR3 (L3); Gly26-Ser35 in heavy chain CDR1 (H1); Trp47-Gly65
in heavy chain CDR2 (H2); and Ala93-Tyr102 in heavy chain
CDR3 (H3). Libraries were created for each CDR, with the
oligonucleotides designed to mutate a single CDR residue in
each clone.
(Wu 6038, col. 1).
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11. Table 2 of Wu is reproduced below:

Table 2 shows the antibody “variants all displayed a lower Ka than the
Vitaxin parent molecule” (Wu 6039–40).

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Principles of Law
A prima facie case for obviousness “requires a suggestion of all
limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003) and “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).
Analysis
Appellants contend that the Examiner acknowledges Rader doesn’t
teach “(a) identifying substitutable positions and (b) substituting those
positions to produce a library” (App. Br. 12; cf. Ans. 5). Appellants contend
Watkins and Wu fail to provide what Rader lacks. Specifically,
Watkins and Wu do not actually teach identifying substitutable
positions and substituting those positions to produce a library.
Rather, those publications simply show that one of ordinary
skill in the art can make a library of variants by random
methods and then screen the library. Steps (c) and (d) of claim
37, i.e., identifying substitutable positions using sequence
alignments and making a library of candidate antibodies that
comprise substitutions at the substitutable positions are not
taught or suggested by either of the publications.
(App. Br. 12–13).
The Examiner responds that “Wu clearly shows beneficial mutations
identified via screening in all three light chain CDRs, again, totaling to more
than five potential substitutions” (Ans. 26). The Examiner finds the
resulting
antibodies discussed in Table 3 of Wu were not made by
random mutagenesis. This is clear just from the table's title
identification of optimal combinatorial mutations. In a
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combinatorial approach, the changes are previously known.
Therefore, the mutants of Table 3 of Wu do not carry random
mutations but the beneficial mutations identified in the first
screen of Wu (Table 2). Said another way, Applicant must
consider that Wu teaches both a primary screen and a secondary
screen after recombining beneficial mutation identified in the
primary screen.
(Ans. 27).
We agree with Appellants. Claim 37, step (c) requires a step of
grouping aligned antibodies and “identifying positions at which the amino
acid varies” followed by step (d) of making substitutions at those variant
positions in a library of candidate antibodies. While Rader and Wu both
show alignments of antibodies, and these alignments have positions that vary
(FF 3, 11), neither Rader nor Wu teaches varying the positions based on
variant positions in the disclosed alignment as recited in step (c) of the
claim. Rader clearly simply performs an alignment, but does not teach the
step of “grouping the antibodies according to their sequence similarity to
produce groups of related antibodies” (FF 3). Wu teaches generating a
candidate antibody library, but generates this library by introducing
mutations at every position in the CDR, rather than restricting the introduced
mutations to variant positions as required by claim 37 (FF 10).
Table 2 of Wu shows the results of the random screening of every
position in the CDR (FF 11). The Examiner provides no persuasive reason
why the ordinary artisan would use Wu’s alignment of the experimental
results to perform a further mutation process at the specific positions
identified. That is, Table 2 of Wu is the end of the process, not an
intermediate step as in claim 37. We therefore agree with Appellants that
“there is no clear path from those references to toward the claimed method”
Appeal 2018-001243
Application 14/518,977

21
(Reply Br. 4).
Conclusion of Law
A preponderance of the evidence of record does not support the
Examiner’s conclusion that Rader, Watkins, and Wu render claim 37
obvious. The Examiner’s obviousness rejection with respect to claims 39–
43, 45–49, and 52, which depend from claim 37, is reversed for the same
reasons. In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992) (“[D]ependent
claims are nonobvious if the independent claims from which they depend are
nonobvious.”).

CONCLUSION
In summary:
Claim(s) Rejected Basis Affirmed Reversed
45, 49 § 112(b) 45, 49
45 § 112 (d) 45
37, 39–43, 45–49,
and 52
§ 101 37, 39–43, 45–
49, and 52
37, 39–43, 45–49,
and 52
§ 103(a) 37, 39–43, 45–
49, and 52
Overall Outcome 37, 39–43, 45–
49, and 52

REVERSED