Carlos Alberto. Guzman et al.

Patent Trials and Appeals Board

Jul 26, 2019

13848936 - (D) (P.T.A.B. Jul. 26, 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.
13/848,936 03/22/2013 Carlos Alberto Guzman 03100215CON 1788
30743 7590 07/26/2019
W&C IP
11491 SUNSET HILLS ROAD
SUITE 340
RESTON, VA 20190
EXAMINER
ZEMAN, ROBERT A
ART UNIT PAPER NUMBER
1645
MAIL DATE DELIVERY MODE
07/26/2019 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte CARLOS ALBERTO GUZMAN and PETER MÜHLRADT
____________

Appeal 2018-0054711
Application 13/848,9362
Technology Center 1600
____________

Before DONALD E. ADAMS, ULRIKE W. JENKS, and
JOHN E. SCHNEIDER, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
This Appeal under 35 U.S.C. § 134(a) involves claims 12–22 (Final
Act.3 2). Examiner entered rejections under 35 U.S.C. § 103(a) and
obviousness-type double patenting. We have jurisdiction under 35 U.S.C.
§ 6(b).
We REVERSE.

1 The record includes a transcript of the Oral Hearing held July 2, 2019.
2 Appellants identify “Helmholtz-Zentrum fuer Infektionsforschung GmbH”
as the real party in interest (Appellants’ November 8, 2017 Appeal Brief
(App. Br.) 3).
3 Examiner’s May 31, 2017 Final Office Action.
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STATEMENT OF THE CASE
Appellants’ disclosure “relates to the use of a lipopeptide or
lipoprotein as adjuvant in therapeutic or prophylactic vaccination, especially
via the mucous membranes, i.e. as mucosal adjuvant” (Spec. 1: 4–7).
Appellants’ claim 12 is representative and reproduced below:
12. A method of vaccinating an animal or human in need
thereof, comprising the steps of:
providing said animal or human, via mucous membranes
of said animal or human, with an antigen; and
providing said animal or human, via mucous membranes
of said animal or human, with an adjuvant in the form of a
lipopeptide or lipoprotein of the structure (I)

where
R1 and R2, which may be identical or different, are C7-25-
alkyl, C7-25-alkenyl or C7-25-alkynyl,
X is S, O or CH2,
R3 and R4 are independently of one another H or methyl and
Y is a physiologically tolerated amino acid sequence which
consists of 1 to 25 amino acid residues and is not immunogenic
per se in the species used,
and the asymmetric carbon atom marked with * as the absolute
R configuration, according to the Cahn-Ingold-Prelog rule,
when X is S (sulfur).
(App. Br. 30.)

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Grounds of rejection before this Panel for review:
Claims 12–22 stand rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Mühlradt ’2424 and Foss.5
Claims 12–22 stand rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Mühlradt ’1106 and Foss.
Claims 12–22 stand rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Mühlradt ’977 and Foss.
Claims 12, 13, 15, 16, 20, and 22 stand rejected under the judicially
created doctrine of obviousness-type double patenting as being unpatentable
over the claims of Mühlradt ’242 and Foss.

Obviousness:
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. There is no dispute on this record that each of Mühlradt ’242,
Mühlradt ’110, and Mühlradt ’97 “teach a [MALP–2] peptide that would be
encompassed by the claims” (Oral Hearing Transcript8 3: 18–20; see

4 Muhlradt, US 6,573,242 B1, issued June 3, 2003.
5 Dennis L. Foss et al., Role of Macrophage Cytokines in Mucosal
Adjuvanticity, 41 ADVANCES IN VETERINARY MEDICINE 83–104 (1999).
6 Mühlradt, WO 98/27110, published June 25, 1998.
7 Peter F. Mühlradt et al., Isolation, Structure Elucidation, and Synthesis of a
Macrophage Stimulatory Lipopeptide from Mycoplasma fermentans Acting
at Picomolar Concentration, 185 J. EXP. MED. 1951–58 (1997).
8 Transcript for Oral Hearing held July 2, 2019.
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generally Ans.9 3 (discussing Mühlradt ’242); Ans. 4 (discussing Mühlradt
’110); Ans. 5 (discussing Mühlradt ’97); see Spec. 8: 16–17 (“The
lipopeptides of [Appellants’] . . . invention are also referred to as MALP,
namely as ‘macrophage-activating lipopeptides’. These include . . .
MALP–2”)).
FF 2. Mühlradt ’242 discloses a composition comprising a peptide within
the scope of Appellants’ claimed invention “together with a conventional
carrier and/or adjuvant” (Mühlradt ’242 1: 64–67).
FF 3. Mühlradt ’242’s composition “can be used for stimulating the
synthesis of antibodies . . . for activating [macrophages], . . . or as a vaccine
adjuvant (admixture with a vaccine)” (Mühlradt ’242 1: 67 – 2: 7; see also
Mühlradt ’242 4: 39–47 (Mühlradt ’242 discloses a method of stimulating
the synthesis of antibodies comprising the step of administering a
composition for activating macrophages comprising a peptide within the
scope of Appellants’ claimed invention together with: (a) an excipient or
additive or excipient and in admixture with a known vaccine to humans or
animals or (b) a conventional excipient or additive or excipient and additive
in admixture with a vaccine); see Mühlradt ’97, Abstract; Ans. 3 (discussing
Mühlradt ’242); Ans. 4 (discussing Mühlradt ’110); Ans. 5 (discussing
Mühlradt ’97)).
FF 4. Mühlradt ’242’s peptide “has the property of stimulating
macrophages of mice and humans to release cytokines and prostaglandins,
with all the consequences of indirect stimulation of T and B lymphocytes”

9 Examiner’s March 8, 2018 Answer.
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(Mühlradt ’242 2: 58–61; see Ans. 3 (discussing Mühlradt ’242); Ans. 4
(discussing Mühlradt ’110)).
FF 5. Examiner finds that each of Mühlradt ’242, Mühlradt ’110, and
Mühlradt ’97 fail to disclose, inter alia, a peptide, within the scope of
Appellants’ claimed invention, as a mucosal adjuvant and relies on Foss to
make up for this deficiency (Ans. 3–5).
FF 6. Foss discloses:
The mucosal immune system is in constant contact with
vast numbers and varieties of antigens, both living and dead,
dangerous and benign. The ability to selectively mount
appropriate immunity to potentially harmful antigens and
organisms, while at the same time tolerating beneficial ones, is
essential to the maintenance of homeostasis. This conflict in
function is especially problematic in the immune system of the
intestinal tract (gut-associated lymphoid tissue or GALT),
where immunity to pathogens must coexist with a need to
control inflammatory responses to the lumenal flora and dietary
antigens. Understanding the molecular basis of this decision
will aid the rational development of mucosally delivered
vaccines.
(Foss 83–84.)
FF 7. Foss discloses that “[t]here are a wide variety of potential
mechanisms for adjuvants to enhance mucosal immunity,” including
“[a]lterations in delivery of antigen to the GALT,” “[e]ffects on antigen
presentation,” “B-cell antibody isotype switching,” “[c]ytokine production
by antigen-specific lymphocytes, induction of Th2 phenotype,” and
“[l]ymphocyte proliferation” (Foss 92–93 (emphasis omitted)).
FF 8. Foss discloses that the “[d]elivery of protein antigens to the GALT
can result in immunity or oral tolerance depending on the circumstances of
the encounter,” wherein “[o]ne mechanism by which mucosal adjuvants can
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affect these circumstances is by the induction of macrophage cytokines,
including IL-1 and IL-12” (Foss 98 (emphasis added); see id. at 99 (“the
mucosal adjuvanticity of [cholera toxin (CT)] involves a variety of
mechanisms,” including “a role for the induction of the macrophage
cytokines IL-1 and IL-12”)).
FF 9. Foss discloses:
There are significant differences between species in the
adjuvanticity of CT and [cholera toxin’s B subunit (CT-B)]. In
humans oral CT-B is generally considered to be immunogenic.
Oral cholera vaccine containing CT-B results in systemic and
local (intestinal) antibody response . . . , but inconsistent
response in distant mucosal sites including vaginal washes . . .
or in saliva . . . and no detectable secretory antibodies in breast
milk. . . . While immunogenic orally in humans, CT-B shows
no adjuvant effect for the coadministered, whole-cell portion of
the cholera vaccine as measured by vibriocidal antibodies. . . .
In contrast to oral administration, intranasally administered CT-
B results in systemic (serum) as well as distant mucosal
(vaginal) anti-CT-B responses.
(Foss 86; see id. (“species differ in the mucosal immunogenicity and
adjuvanticity of CT-B and CT”).)
FF 10. Foss discloses that although “parenterally administered [keyhole
limpet hemocyanin (KLH)] resulted in a robust [immune] response,”
“[i]ntragastric administration of . . . [KLH, alone,] results in little or no
response,” KLH in combination with “CT results in both local (intestinal
wash) and systemic (serum) anti-KLH IgA and IgG” (Foss 87).
FF 11. Guzman declares that Foss “focused [its] . . . work in the study of a
single and well-established[,] at the time[,] mucosal adjuvant. Thus, the
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assumptions made cannot be extrapolated to adjuvants in general and/or
mucosal adjuvants in particular” (Guzman Decl.10 ¶ 5).
FF 12. Guzman declares that Foss
specifically mentioned a long list of “potential” underlying
mechanisms (i.e. activation of macrophages is just one of the
multiple proposed mechanisms), which might explain the
adjuvanticity of the tested compound/toxin. The authors are not
providing in this publication solid experimental evidence,
which can be useful for ruling out or conforming the specific
contribution of any of the hypothesized mechanisms for the
adjuvant effect. Thus, by and large, all the proposed
mechanisms represent as a whole just an informative
compendium of potential mechanisms of action, for which
backing evidence is overdue (i.e. just putative roles are
described or associations are made). None of them can be
seriously proposed as the underlying mechanism of adjuvancity
in general, and even less as the mechanism explaining the
mucosal adjuvanticity of cholera toxin, A-B moiety toxins or
their derivatives and/or other compounds exerting activity as
mucosal adjuvants.
(Guzman Decl. ¶ 5; see id. (Guzman declares that “not every macrophage
stimulating molecule is a ‘mucosal adjuvant’”).)
FF 13. Guzman identifies several mucosal adjuvants and declares that “there
are no overall macrophage-driven mechanisms responsible for mucosal
adjuvancity, that specific interactions with macrophages could be
dispensable and that several distinct mechanisms can be in part leading to
mucosal adjuvanticity” (Guzman Decl. ¶ 5).
FF 14. Guzman declares that “it is not a reasonable expectation that
molecules which are able to activate macrophages are generally acting as
mucosal adjuvants” (Guzman Decl. ¶ 5).

10 Declaration of Carlos A. Guzman, signed July 4, 2011.
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FF 15. Guzman declares that
every compound, before it can be determined to be an adjuvant
(particularly a mucosal adjuvant), needs to be tested for its
efficiency as [a] mucosal adjuvant even when it is able to
interact with macrophages and/or DCs, because[, inter alia,] . . .
an activator of macrophages and/or DCs cannot be considered a
priori an adjuvant (or, more particularly, a mucosal adjuvant).
(Guzman Decl. ¶ 5; see also Mühlradt Decl.11 ¶ 4 (Mühlradt declares “that a
macrophage stimulator such as MALP-2 is not a priori an adjuvant, and in
particular, is not necessarily a mucosal adjuvant”); Mühlradt Decl. ¶ 6
(Mühlradt declares that “one of ordinary skill in the art would know that the
effectiveness of a known adjuvant in a new experimental setting cannot be
foreseen”).)
FF 16. Guzman distinguishes the CT protein, addressed in Foss, from the
MALP-2 peptide set forth in Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97
(Guzman ¶ 5).
ANALYSIS
Based on Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97 in
combination with Foss, Examiner concludes that, at the time Appellants’
invention was made, it would have been prima facie obvious to utilize a
peptide within the scope of Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97
as a mucosal adjuvant (see Ans. 3–5). We are not persuaded.
The consistent criterion for determination of obviousness
is whether the prior art would have suggested to one of ordinary
skill in the art that this process should be carried out and would
have a reasonable likelihood of success, viewed in the light of
the prior art . . . . Both the suggestion and the expectation of

11 Declaration of Peter F. Mühlradt, signed May 10, 2009.
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success must be founded in the prior art, not in the applicant’s
disclosure.
In re Dow Chemical Co., 837 F.2d 469, 473 (Fed. Cir. 1988) (citations
omitted). Although Examiner finds, on this record, that a person of ordinary
skill in this art would “have had a reasonable expectation of success” using
MALP-2 peptides, such as those disclosed by Mühlradt ’242, Mühlradt ’110,
or Mühlradt ’97 “as a mucosal adjuvant,” because “mucosal adjuvants
function by activating macrophages and [the peptides disclosed by Mühlradt
’242, Mühlradt ’110, or Mühlradt ’97] . . . are disclosed to activate
macrophages,” the evidence of record establishes “that a macrophage
stimulator such as MALP-2 is not a priori an adjuvant, and in particular, is
not necessarily a mucosal adjuvant” (see Ans. 3–5; cf. FF 15; App. Br.12 20
(“One of skill in the art would recognize that adjuvants in general are not
necessarily useful for mucosal administration”); see generally Reply Br. 2
(“one of ordinary skill in the art would not have had a reasonable
expectation of success from the proposed combination of Mühlradt and
Foss”)). To the contrary, Foss discloses that there is “a wide variety of
potential mechanisms for adjuvants to enhance mucosal immunity” and that
the “[d]elivery of protein antigens to the GALT can result in immunity or
oral tolerance depending on the circumstances of the encounter” (FF 7–8;
see App. Br. 25 (“Foss does not provide a unifying theory that could be used
to predict whether or not a substance could be successfully used as an
adjuvant, let alone whether it would be successful for a particular route of
administration, for a particular antigen”)). In this regard, the evidence of
record establishes that “there are no overall macrophage-driven mechanisms

12 Appellants’ November 8, 2017 Appeal Brief.
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responsible for mucosal adjuvancity, that specific interactions with
macrophages could be dispensable and that several distinct mechanisms can
be in part leading to mucosal adjuvanticity” (FF 13). Thus, taken as a
whole, the evidence of record establishes that there “is not a reasonable
expectation that molecules which are able to activate macrophages are
generally acting as mucosal adjuvants” (FF 14).
Thus, although we agree with Examiner that, at the time of
Appellants’ claimed invention, the prior art provided a general approach that
seemed to be a promising field of experimentation (see FF 1–10), the prior
art, on this record, gave only general guidance relating to one, of several,
possible mechanisms for achieving mucosal immunity, with an adjuvant that
differs from Appellants’ claimed peptide (see generally FF 16; App. Br. 22
(“There is no reason to assume that results obtained with protein adjuvants
such as CT . . . , especially given the inconsistent adjuvanticity of CT, would
be indicative of results that could be expected with MALPS”); Reply Br. 2
(“Foss relates to cholera toxin, a large molecule, while MALP2 represents a
small molecule comparable to other small molecule adjuvants not suitable
for mucosal administration”)). As Appellants explain:
No common chemical structure, mechanism of action, or other
properties that could predict adjuvanticity with surety,
especially mucosal adjuvanticity, are taught by Foss, that could
have been reliably used by one of skill in the art to predict, with
a reasonable expectation of success, that the
lipopeptides/lipoproteins taught by Mühlradt would be
efficacious as mucosal antigens.
(App. Br. 26 (emphasis omitted).) To the contrary, the evidence on this
record supports a conclusion that
every compound, before it can be determined to be an adjuvant
(particularly a mucosal adjuvant), needs to be tested for its
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efficiency as [a] mucosal adjuvant even when it is able to
interact with macrophages and/or DCs, because[, inter alia,] . . .
an activator of macrophages and/or DCs cannot be considered a
priori an adjuvant (or, more particularly, a mucosal adjuvant).
(FF 15; see also App. Br. 20 (“to establish efficacy as a mucosal adjuvant, a
substance must be tested in one or more art recognized systems”)).
[A]n invention is not obvious to try where vague prior art does
not guide an inventor toward a particular solution. A finding of
obviousness would not obtain where “what was ‘obvious to try’
was to explore a new technology or general approach that
seemed to be a promising field of experimentation, where the
prior art gave only general guidance as to the particular form of
the claimed invention or how to achieve it.” . . . This expresses
the same idea as the KSR requirement that the identified
solutions be “predictable.”
Bayer Schering Pharma AG v. Barr Laboratories, Inc., 575 F.3d 1341, 1347
(Fed. Cir. 2009) (citations omitted).
For the foregoing reasons, Examiner has, at best, established that it
would have been obvious to try the methodology set forth in the
combination of Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97, with Foss in
order to arrive at Appellants’ claimed invention. “‘[O]bvious to try[,’
however,] is not the standard under § 103.” In re O’Farrell, 853 F.2d 894,
903 (Fed. Cir. 1988).
CONCLUSION
The preponderance of evidence relied upon by Examiner fails to
support a conclusion of obviousness.
The rejection of claims 12–22 under 35 U.S.C. § 103(a) as
unpatentable over the combination of Mühlradt ’242 and Foss is reversed.
The rejection of claims 12–22 under 35 U.S.C. § 103(a) as
unpatentable over the combination of Mühlradt ’110 and Foss is reversed.
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The rejection of claims 12–22 under 35 U.S.C. § 103(a) as
unpatentable over the combination of Mühlradt ’97 and Foss is reversed.

Obviousness-type Double Patenting:
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness-type double patenting?
ANALYSIS
Examiner finds that although “the adjuvant compositions are the same
in both [Mühlradt ’242] . . . and [Appellants’] claims, the [Mühlradt ’242]
. . . claims differ from [Appellants’ claimed invention] . . . in that they do not
explicitly disclose the mucosal administration of the adjuvant composition”
(Ans. 2). Examiner reasons, however,
given that the [Mühlradt ’242] . . . composition is a macrophage
activator . . . and Foss . . . disclose[s] that mucosal adjuvants
function by activating macrophages . . . , it would have been
[prima facie] obvious[, at the time of Appellants’ claimed
invention,] for one of ordinary skill in the art to use the
composition of [Mühlradt ’242] . . . as a mucosal adjuvant.
(Id.) We are not persuaded.
As Appellants explain, for the reasons discussed in their response to
Examiner’s obviousness rejections, “Foss does not teach that substances as
described by [Mühlradt ’242] should or could successfully be used as
mucosal adjuvants” and the evidence of record, as discussed above with
respect to the obviousness rejection, establishes that this “art is
unpredictable” (see App. Br. 29). We agree.
Thus, for the reasons set forth above, with respect to the obviousness
rejections on this record, we find that Examiner failed to establish an
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evidentiary basis to support the obviousness-type double patenting rejection
on this record.
CONCLUSION
The preponderance of evidence relied upon by Examiner fails to
support a conclusion of obviousness-type double patenting.
The rejection of claims 12, 13, 15, 16, 20, and 22 under the judicially
created doctrine of obviousness-type double patenting as being unpatentable
over the claims of Mühlradt ’242 and Foss is reversed.

REVERSED