Ambrx, Inc. et al.

Patent Trials and Appeals Board

Sep 22, 2021

2020006147 (P.T.A.B. Sep. 22, 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.
16/165,813 10/19/2018 Anna-Maria A. HAYS PUTNAM X18746A 5736
159715 7590 09/22/2021
Elanco US Inc.
Patent Division
2500 Innovation Way
Greenfield, IN 46140
EXAMINER
ALLEN, MARIANNE P
ART UNIT PAPER NUMBER
1647
NOTIFICATION DATE DELIVERY MODE
09/22/2021 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):
patents@elanco.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ANNA-MARIA A. HAYS PUTNAM, NICK KNUDSEN, THEA
NORMAN, ALAN KODER, VADIM KRAYNOV, LILLIAN SKIDMORE,
and PETER C. CANNING

Appeal 2020-006147
Application 16/165,813
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
JAMIE T. WISZ, Administrative Patent Judges.

WISZ, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 68, 102, and 104–116. 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 ELANCO US INC. and AMBRX,
INC. as the real parties-in-interest. Appeal Br. 2.
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CLAIMED SUBJECT MATTER
The Specification describes “bovine granulocyte-colony stimulating
factor (bG-CSF) polypeptides optionally modified with at least one non-
naturally-encoded amino acid.” Spec. 2. In some embodiments, the non-
naturally encoded amino acid is linked to a water soluble polymer, such as a
poly(ethylene glycol) moiety. Id. ¶ 49. According to the Specification, “G-
CSF is capable of inducing an increase in the absolute number of circulating
neutrophils and enhances neutrophil function” and “bG-CSF polypeptides of
the invention may be used to ameliorate or prevent infections in animals.”
Id. ¶¶ 20, 215.
Claim 68 is illustrative of the claimed subject matter and is
reproduced below:
68. A method of treating an animal having a disorder
modulated by bG-CSF comprising administering to the animal
a therapeutically-effective amount of a bG-CSF polypeptide
comprising the sequence of SEQ ID NO: 1, wherein position
133 of SEQ ID NO: 1 is substituted with a non-naturally
encoded amino acid,
wherein the non-naturally encoded amino acid is para-
acetylphenylalanine, and
wherein the non-naturally encoded amino acid is linked
to a water soluble polymer comprising a poly(ethylene) glycol
moiety having a molecular weight of between about 1 kDa and
about 100 kDa.
Appeal Br. 19 (Claims App.).
REJECTIONS
The Examiner rejected claims 68, 102, and 104–116 under 35 U.S.C.
§ 112 for lack of enablement.
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The Examiner rejected claims 68, 102, and 104–116 under 35 U.S.C.
§ 103 as being unpatentable over Canning2 in view of Cho,3 Heidari,4
Lovejoy,5 Park,6 Kang,7 and Tonon.8
ISSUES AND ANALYSIS
Rejection of claims 68, 102, and 104–116 under 35 U.S.C. § 112 for lack of
enablement
The Examiner rejected claims 68, 102, and 104–116 because the
Examiner finds that the Specification does not provide enablement for all the
claimed methods. Final Act. 2. According to the Examiner, the claims do
not identify the animal, the disorder/infection, or the therapeutic effect that
must be achieved by the “therapeutically effective amount.” Id. at 3. The
Examiner further finds that, “the claims are broad and the amount of
experimentation would be large given the variety of animals to be treated
with a bovine G-CSF, the large number of conditions to be treated, and the
variety of therapeutic effects that must be achieved (prevention, cure,
amelioration or reversal of all symptoms).” Id. at 5. According to the
Examiner, there is little direction or guidance in the Specification compared

2 Canning et al., US 2005/0232898 A1, published Oct. 20, 2005
(“Canning”).
3 Cho et al., WO 2005/074650 A2, published Aug. 18, 2005 (“Cho”).
4 Heidari et al., “Cloning, sequencing, and analysis of cDNA encoding
bovine granulocyte-colony stimulating factor,” Elsevier 73 (2000), 183–191
(“Heidari”).
5 Lovejoy et al., “Crystal Structure of Canine and Bovine Granulocyte-
Colony Stimulating Factor (G-CSF),” J. Mol. Biol. (1993) 234, 640–653
(“Lovejoy”).
6 Park, Myung-Ok, US 7,557,195 B2, issued Jul. 7, 2009 (“Park”).
7 Kang et al., US 2008/0200657 A1, published Aug. 21, 2008 (“Kang”).
8 Tonon et al., WO 2008/017603 A1, published Feb. 14, 2008 (“Tonon”).
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to the scope of the claims and “[t]he prior art of record does not disclose that
bG-CSF could ameliorate or reverse any symptom of any disease or
infection.” Id.
Appellant argues that “a person of skill in the art would easily
recognize the disorder or infection to be treated and the therapeutic effect to
be achieved.” Appeal Br. 9. Appellant points to page 9, lines 10–16 of the
Specification, which states:
Administration of a compound that treats or modulates the
incidence, recurrence, duration, and/or severity of mastitis or
respiratory disease in cattle or other infections in non-human
animals, including but not limited to, cattle, poultry, swine,
horses, dogs, and cats would be useful in veterinary medicine.
Examples of such infections include but are not limited to,
neonatal septicemia in horses, pleuropneumaonia in pigs, and
pneumonia in non-human animals. Such compounds may restore
or modulate neutrophil function in the animal.
Spec. 9, ¶ 17.
Appellant also cites to Examples 2, 25, 26, 27, 28, and 29 as support
for the claims. Appeal Br. 11–13. Appellant contends that the Examiner
failed to properly analyze the state of the art, particularly as cited in the
Specification. Id. at 13 (citing Spec. 10, 12–21, 11, 13–14, 14:27–15:6;
226:28–227:2).
We find that Appellant has the better position. The Examiner alleges
that “the broadest reasonable interpretation of a claim directed to treating
without a specific therapeutic effect recited in the claim includes preventing,
curing, and ameliorating or reversing any and all symptoms of the disorder
in all animals embraced by the claims.” Final Act. 3. However, the term
“treating” is defined in the Specification as referring to “either prophylactic
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and/or therapeutic treatments” and “effective amount” is defined as the
“amount of the modified non-natural amino acid polypeptide being
administered which will relieve to some extent one or more of the symptoms
of the disease, condition or disorder being treated.” Spec. ¶¶ 184, 193.
Therefore, the method of treatment claims do not require that the recited
diseases be cured but, rather, that the symptoms are “relieve[d] to some
extent.”
While the Examiner acknowledges that the Specification includes
examples of administration of bG-CSF polypeptides to cows and steers and
that “[t]reatment with a therapeutic goal of reducing the incidence of mastitis
is enabled,” the Examiner finds that “[t]here is no evidence of record or
reason to believe that administration of a bG-CSF polypeptide of the claims
will treat all aspects or symptoms of all disorders modulated by bG-CSF in
all animals embraced by the claims.” Final Act. 4. First, as discussed above,
the claims do not require that the bG-CSF polypeptides “treat all aspects” of
the claimed disorders but, rather, that symptoms are “relieve[d] to some
extent.” Second, while acknowledging that there are examples of methods
of treatment in the Specification, the Examiner does not cite to any evidence
to support the contention that “[i]t is not considered to be so predictable that
the results disclosed in the specification would have been predictive or could
have been extrapolated to enable the breadth of the claims.” Id. at 6.
Therefore, we find that the Examiner has not made a prima facie case
of lack of enablement and we reverse the enablement rejection of claims 68,
102, and 104–116.

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Rejection of claims 68, 102, and 104–116 under 35 U.S.C. § 103 as being
unpatentable over Canning in view of Cho, Heidari, Lovejoy, Park, Kang,
and Tonon
The Examiner finds that Canning discloses treating or preventing
infections in mammals such as cows (bovine) by administering bovine G-
CSF (bG-CSF). Final Act. 8 (citing Canning abstract, claims, ¶¶ 9, 11, 13).
The Examiner also finds that Canning discloses the treatment of mastitis,
intrauterine infections, and bovine respiratory disease and also discloses the
need for stable protein compositions. Id. The Examiner acknowledges that
Canning does not disclose the PEGylated bG-CSF of the instant claims but
finds that this limitation is suggested by other references. Id. at 9.
The Examiner finds that Cho discloses “non-natural amino acid
modification and PEGylation of human G-CSF.” Id. (citing Cho Examples
36–39). According to the Examiner, the three-dimensional structure of G-
CSF would have been well known as well as PEGylation of mutated G-CSF.
Id. (citing Cho ¶¶ 14, 22, Figures 1, 5). The Examiner further finds that Cho
discloses the non-natural amino acid, para-acetylphenylalaninne (pAF) and
also discloses using PEG polymers of 0.1 to 50 kD, 0.1 or 100 kD or 5–20
kD. Id. (citing Cho ¶¶ 254, 261, 455, claims 27–28, 54). The Examiner also
finds that Cho discloses the sequence of mature human G-CSF as SEQ ID
NO: 29 and mutation of amino acid position 134 of SEQ ID NO: 29. Id.
(citing Cho Examples 36–39, ¶ 734). According to the Examiner, Cho
“suggests that glycosylation sites may be useful sites for introducing non-
naturally-occurring amino acid substitutions into the proteins” and that
“[a]mino acids that comprise O-linked glycosylation sites in the proteins
may be sites for non-naturally-occurring amino acid substitutions because
these amino acids are surface-exposed.” Id. The Examiner acknowledges
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that Cho does not disclose the polypeptide sequence of claimed SEQ ID
NO: 1 for bovine G-CSF (bG-CSF) but finds that this limitation is suggested
by Heidari Id. at 10.
The Examiner finds that Heidari discloses the polypeptide of bG-CSF
corresponding to the claimed SEQ ID NO: 1 and also discloses an O-linked
glycosylation site at Thr-133. Id. (citing Heidari 185, Abstract, Figure 1,
Table 1). According to the Examiner, the human and bovine G-CSF
sequences have high homology. Id. The Examiner also finds that Lovejoy
discloses the 3D structure of bovine G-CSF and its close similarity to the 3D
structure of human G-CSF. Id. (citing Lovejoy Abstract, Figs. 1, 6).
According to the Examiner amino acid position 133 of the claimed SEQ ID
NO: 1 corresponds to amino acid position 134 of SEQ ID NO: 29 of Cho
and, as evidenced by Heidari, this is an O-linked glycosylation site, which is
suggested by Cho for modification. Id.
The Examiner also finds that Kang “discloses substituting the
threonine at amino acid 134 of human G-CSF (corresponding to position 133
of instant SEQ ID NO: 1 . . . ) with cysteine and monoPEGylating this
position with a 20 kD water soluble PEG polymer” and also discloses that
this “PEGylated polypeptide is biologically active.” Id. at 10 (citing Kang
abstract, ¶¶ 63, 91, 97–98, Example 5, Figure 5, Tables 1, 5, 6). The
Examiner further finds that Tonon “discloses substituting individual G-CSF
amino acids within the range of amino acid positions 132-137 with
glutamine and monoPEGylating the position with a 20 kD water soluble
PEG polymer.” Id. at 11 (citing Tonon 7–8, 17–19, Example 6, claims).
According to the Examiner, Park discloses PEGylation of G-CSF and makes
clear that non-human G-CSF from recombinant mouse, bovine, or dog can
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also be PEGylated in the same way. Id. (citing Park 5:60–65, Example 17,
Table 1).
The Examiner concludes that “[i]t would have been obvious to modify
bovine G-CSF (using the sequence provided by [Heidari]) in the manner
taught by [Cho] to arrive at modified bG-CSF compounds containing non-
naturally encoded amino acids that are then PEGylated” by “[u]sing the non-
natural amino acid para-acetylphenylalanine [which] is taught by [Cho].”
Id. at 11. The Examiner also finds that Kang and Tonon teach the
desirability of using a 20 kDa PEG to PEGylate G-CSF and mutation of the
particularly claimed amino acid position of G-CSF is disclosed by Cho. Id.
According to the Examiner, amino acid 134 of Cho corresponds to amino
acid 133 of instant SEQ ID NO: 1 and this amino acid position is a
glycosylation site. Id. The Examiner finds that Cho specifically suggests
modifying this particular amino acid position as well as glycosylation sites.
Id. The Examiner also finds that “[m]onoPEGylation at position 133 of G-
CSF with a 20 kD water soluble PEG polymer would have been known in
the art to be biologically active, particularly in the proliferation of
neutrophils as taught by [Kang].” Id. at 12.
The Examiner further finds that “[i]t would have been obvious to use
the PEGylated bG-CSF suggested by the combination of [Cho, Heidari,
Lovejoy, Park, Kang, and Tonon] in the methods of treatment and prevention
disclosed by [Canning]” which discloses treatment of mastitis, intrauterine
infections, and bovine respiratory disease (also known as shipping fever) in
periparturient dairy cows. Id. at 14. According to the Examiner, Canning
“suggests using stabilized forms of bovine G-CSF (bG-CSF) and the
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PEGylated bG-CSF suggested by the combination of [Cho, Heidari,
Lovejoy, Park, Kang, and Tonon] would have been stabilized.” Id.
Appellant argues that the art cited by the Examiner disclose “a variety
of modifications to a G-CSF molecule,” but “do not provide a motivation to
combine their disclosures to arrive at the claimed molecule and using it in
the claimed methods of treatment” and that the Examiner is using
impermissible hindsight. Appeal Br. 14. Appellant further argues that there
would have been no expectation of success and points to Table 9 of the
Specification to support their assertion that selecting an amino acid position
for PEGylation is unpredictable. Id. (citing Spec. 243). Appellant also
submits data related to the generation of porcine G-CSF variants to
demonstrate the unpredictability of generating G-CSF variants with
substitutions of non-natural amino acids. Id. at 15 (citing Exhibits H and I).
Appellant further asserts that there is no motivation to combine the
cited references and “Cho fails to provide sufficient direction to arrive at the
claimed method comprising the claimed bG-CSF variant with a reasonable
expectation of success.” Id. at 18.
We find that the Examiner has the better position. Canning discloses
treating or preventing infections in mammals such as cows by administering
bovine G-CSF and also discloses the need for stable protein compositions.
See Canning abstract, ¶ 13. In looking for stable therapeutic G-CSF
compositions, one of ordinary skill in the art would have looked to Cho,
which discloses using human G-CSF and its homologs as pharmaceutical
compositions. See Cho ¶¶ 136, 556–559. It was known from Heidari and
Lovejoy that bovine G-CSF has a highly homologous amino acid sequence
to human G-CSF and has a similar 3D structure to human G-CSF. See
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Heidari 185, 187; Lovejoy 641, 647. Thus, we agree with the Examiner that
it would have been obvious to modify bovine G-CSF (using the sequence
provided by Heidari), as taught by Cho to arrive at modified bG-CSF
compounds containing non-naturally encoded amino acids that are
PEGylated because “PEGylated proteins show lower renal clearance rates,
as well as higher stability and reduced immunogenicity” Tonon 4. Further,
one of skill in the art would have been motivated to use the non-natural
amino acid para-acetylphenylalanine as well as a PEG moiety having a
molecular weight of between about 0.1 kDa to about 100 kDa as taught by
Cho. See Cho ¶¶ 254, 261, claim 54.
Cho also teaches mutation of amino acid 134 of SEQ ID NO: 1
(which corresponds to amino acid 133 of Cho). Id. at ¶ 734. A person of
ordinary skill in the art would have been motivated to monoPEGylate
position 133 of bG-CSF in order to provide an improved therapeutic
composition because Kang taught that monoPEGylation of the
corresponding position in human G-CSF with a 20 kD water soluble PEG
polymer resulted in a biologically active PEGylated polypeptide that
increased neutrophil numbers and had increased plasma half-life. See Kang
¶¶ 63, 91, 97–98, Example 5, Figure 5, Tables 1, 5, 6. Thus, one of skill in
the art would have been motivated to use the PEGylated bG-CSF taught by
Cho, Heidari, Lovejoy, and Kang in the methods of treatment and prevention
disclosed by [Canning], which discloses treatment of mastitis, intrauterine
infections, and bovine respiratory disease (also known as shipping fever) in
cattle.
Appellant argues the references individually but does not persuasively
argue a lack of motivation to combine these references. “Non-obviousness
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cannot be established by attacking references individually where the
rejection is based upon the teachings of a combination of references. . .
. [The reference] must be read, not in isolation, but for what it fairly teaches
in combination with the prior art as a whole.” In re Merck & Co., 800 F.2d
1091, 1097 (Fed. Cir. 1986).
We are also not persuaded by Appellant’s arguments regarding no
reasonable expectation of success. We agree with the Examiner that one of
ordinary skill in the art would have had an expectation of success in
producing a biologically active product given the knowledge in the prior art
concerning highly related products such as the PEGylated G-CSF proteins of
Kang and Tonon, which exhibited increased neutrophil numbers and
increased plasma half-life. See Kang abstract, ¶¶ 63, 91, 97–98, Example 5,
Figure 5, Tables 1, 5, 6; Tonon 4, 7–8, 17–19, Example 6. As discussed
above, given the sequence similarity and 3D structural similarity between
human and bovine G-CSF, one of ordinary skill in the art would have
expected to obtain stable products that could treat the claimed disorders, as
taught in Channing.
Appellant argues that the Examiner engaged in impermissible
hindsight; however, “[a]ny judgment on obviousness is in a sense
necessarily a reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level of ordinary
skill at the time the claimed invention was made and does not include
knowledge gleaned only from applicant’s disclosure, such a reconstruction is
proper.” In re McLaughlin, 443 F.2d 1392, 1395, (CCPA 1971). Based on
the teachings of the prior art discussed above, one or ordinary skill in the art
at the relevant time would have found it obvious to use the modified bG-
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CSF polypeptide in the claimed methods and would have had a reasonable
expectation of success in doing so.
With regard to Appellant’s arguments regarding Table 9, we agree
with the Examiner that the fact that one of the modified bG-CSF variants
had better activity than the claimed variant does not teach away from the
claimed variant. A teaching away requires a reference to actually criticize,
discredit, or otherwise discourage the claimed solution. See In re Fulton,
391 F.3d 1195, 1201 (Fed. Cir. 2004) (“The prior art’s mere disclosure of
more than one alternative does not constitute a teaching away from any of
these alternatives because such disclosure does not criticize, discredit, or
otherwise discourage the solution claimed”). Also, as shown in Table 9, the
claimed variant still retained activity and the claims do not require any
particular level of activity. See Spec. 253.
We also agree that Appellant’s submission of Exhibits H, I, and J is an
improper submission of new evidence after the filing of an appeal pursuant
to 37 C.F.R. § 41.33(d)(2). However, even if we were to consider such
evidence, we do not find it to be persuasive. Appellant contends that data
regarding the porcine G-CSF variants described in the Exhibits provide
evidence of the unpredictable nature of variant molecules. Appeal Br. 15.
First, this data does not indicate any surprising or unexpected results
regarding the claimed bovine G-CSF variant and it is unclear how these
particular porcine variants relate to the claimed bovine variant. “It is well
established that the objective evidence of nonobviousness must be
commensurate in scope with the claims.” In re Lindner, 457 F.2d 506, 508,
(CCPA 1972). Furthermore, the data does not indicate that the generated
porcine variants would lack efficacy. In fact, Exhibit I indicates that eight of
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the nine variants had a similar activity profile, including the selected H43
variant. See Exhibit I, 3. Thus, the evidence submitted by Appellant is not
persuasive, when weighed with the Examiner’s strong prima facie case of
obviousness, to support a finding of nonobviousness.
For the reasons explained above, we affirm the Examiner’s rejection
of claims 68, 102, and 104 as being obvious over Canning in view of Cho,
Heidari, Lovejoy, Park, Kang, and Tonon. Claims 105–116 are not argued
separately apart from the independent claims, and, therefore, fall with claims
68, 102, and 104. See 37 C.F.R. § 41.37(c)(1)(iv).
CONCLUSION
For the reasons described herein and those already of record, we
reverse the Examiner’s enablement rejection of 68, 102, and 104–116 and
affirm the obviousness rejection of claims 68, 102, and 104–116.
DECISION SUMMARY
In summary:
Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
68, 102,
104–116
112 Enablement 68, 102,
104–116
68, 102,
104–116
103 Canning, Cho, Heidari,
Lovejoy, Park, Kang,
Tonon
68, 102,
104–116

Overall
Outcome
68, 102,
104–116

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No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED