Diamyd Medical AB

Patent Trials and Appeals Board

Jun 29, 2021

2020006074 (P.T.A.B. Jun. 29, 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.
15/315,557 12/01/2016 Anders ESSEN-M¿LLER ZACCO-008 9980
93726 7590 06/29/2021
EPA - BOZICEVIC FIELD & FRANCIS LLP
BOZICEVIC, FIELD & FRANCIS
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
EXAMINER
EWOLDT, GERALD R
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
06/29/2021 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):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD

Ex parte ANDERS ESSEN-MÖLLER and
JOHNNY LUDVIGSSON

Appeal 2020-006074
Application 15/315,557
Technology Center 1600
Before DONALD E. ADAMS, FRANCISCO C. PRATS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
STATEMENT OF THE CASE
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 87, 89–93, and 98–100. 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(a). Appellant identifies the real party in interest as Diamyd Medical
AB. Appeal Br. 3.
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CLAIMED SUBJECT MATTER
Appellant’s invention is directed to “to the prevention and/or
treatment of autoimmune diseases such as type 1 diabetes or autoimmune
diabetes.” Spec. 1. The Specification explains that, “[i]n autoimmune
disease, the adaptive immune system commonly reacts to at least one self-
antigen, (auto-antigen, aag).” Id.
The Specification discloses that “[l]arge clinical trials have been
performed and are currently being performed using different insulin derived
formulations in order to induce tolerance and stop or prevent the disease
progression.” Spec. 2. The Specification discloses that “[m]any other beta
cell antigen molecules and peptides thereof including but not limited to
GAD65 have been tried for the same purpose, and others, not limited to
insulin B-chain and pro-insulin and variations thereof, are being prepared for
clinical development.” Id.
The Specification explains that “GAD65 (the 65 kd isoform of
Glutamic Acid Decarboxylase), is a major beta cell auto-antigen, as it is
produced in the islets with increased release as response to beta cell
stimulation. This protein has been shown to deeply influence the
autoimmune immune process.” Spec. 7. In particular, “[n]umerous studies
have shown that GAD can prevent diabetes in experimental animals.” Id.
The Specification discloses that clinical trials involving “GAD-alum
(Diamyd)” led to the conclusion that “that while partly effective, GAD-alum
may need to be combined with other compounds in order to become part of a
clinically effective treatment regimen for type 1 diabetes.” Spec. 7.
Appellant’s claim 87 is representative of the appealed subject matter
and reads as follows:
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87. A method for treating at least one of type 1 diabetes,
autoimmune diabetes, and latent autoimmune diabetes,
comprising administering to a subject in need thereof a
therapeutic composition comprising at least one β cell
autoantigen and alum,
wherein the at least one β cell autoantigen is glutamic
acid decarboxylase (GAD), the administering is done by
injection directly into a lymph node and the subject has a serum
vitamin D level that is above 50 nanomole/litre.
Claims App. 2 (Claims Appendix entered May 1, 2020; indentation added).
REJECTION(S)
The sole rejection before us for review is the Examiner’s rejection of
claims 87, 89–93, and 98–100 under 35 U.S.C. § 103 as being unpatentable
over the Diamyd Press Release2 and Senti.3 Ans. 3–4.
DISCUSSION
The Examiner’s Prima Facie Case
The Examiner found that the Diamyd Press Release discloses a
process differing from the process recited in Appellant’s representative
claim 87 “only in that it does not teach administration of the GAD by intra-
lymph node injection.” Ans. 3.

2 Diamyd Press Release, “New clinical study with Diamyd diabetes
vaccine,” (http://www.diamyd.com/docs/pressClip.aspx?section=investor&
ClipID=738265) (2013) (citation provided in Information Disclosure
Statement filed March 23, 2017).
3 Gabriela Senti et al., Intralymphatic allergen administration renders
specific immunotherapy faster and safer: A randomized controlled trial, 105
PNAS 17908–17912 (2008).
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The Examiner found, however, that Senti teaches “intra-lymph node
administration of an antigen for the induction of tolerance to said antigen.”
Ans. 3.
Based on the references’ combined teachings, the Examiner
concluded that it would have been obvious to treat type 1 diabetes “through
the method of the Diamyd Press Release wherein the administration of the
GAD65 antigen in combination with alum, ibuprofen, and vitamin D was by
intra-lymph node injection given the teachings of Senti et al. that intra-
lymph node injection of antigens facilitates tolerance to said antigens.” Ans.
3–4.
The Examiner reasoned that using intra-lymph node injection to
perform the process described in the Diamyd Press Release “is supported by
sound scientific reasoning as it was well known at the time of filing that
naïve T cells first encounter antigen in the lymph nodes thus, direct injection
therein would have been expected to have been more efficient.” Ans. 4.
The Examiner noted in particular that “[s]uch results were shown by Senti et
al. in that the tolerance was shown to result faster and be longer lasting.” Id.
As to the requirement in representative claim 87 for the subject to
have a serum vitamin D level above 50 nanomole/liter, the Examiner noted
“vitamin D’s tolerogenic properties (as cited in the specification)” as well as
the fact that the process of the Diamyd Press Release includes administration
of vitamin D, such that a subject of that process “would be expected to
achieve at least a 50 nmol/L serum concentration after a first treatment given
that a minimum recommended serum level of vitamin D is approximately
125 nmol/L.” Ans. 4.
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Analysis
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant in
response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992); see also In re Jung, 637
F.3d 1356, 1365 (Fed. Cir. 2011) (holding that requiring an applicant to
identify “reversible error” in an examiner’s rejection is consistent with long
standing Board practice).
Having carefully considered all of the evidence and argument
presented by Appellant and the Examiner, we are not persuaded that
Appellant has shown reversible error in the Examiner’s conclusion of
obviousness as to Appellant’s representative claim 87.
The Diamyd Press Release describes an FDA-approved clinical study
which “combines the diabetes vaccine Diamyd ® with relatively high doses
of vitamin D and the anti-inflammatory drug ibuprofen. The aim of
treatment is to preserve the body’s own ability to regulate blood sugar in
children and adolescents with recent-onset type 1 diabetes.” Diamyd Press
Release 1.4
The Diamyd Press Release explains that “[t]ype 1 diabetes . . . is an
autoimmune disease which means that the body’s own immune system
attacks and destroys the cells in the body that produce insulin, the so-called
beta cells in the pancreas leading to insulin deficiency and inability to

4 The Diamyd Press Release does not include page numbers. We cite to
document as if the pages were numbered consecutively starting with page 1.
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control blood sugar levels.” Diamyd Press Release 2. The Diamyd Press
Release explains that the clinical trial’s treatment with the GAD-containing
Diamyd vaccine “is designed to prevent, delay, or stop the autoimmune
attack on beta cells.” Id.
It is undisputed on this record that the Diamyd vaccine contains alum
as well as GAD, as recited in Appellant’s claim 87. See Spec. 7 (describing
previous clinical trials involving “GAD-alum (Diamyd)”). It is also
undisputed on this record that patients receiving the vitamin D dosage
described in the Diamyd Press Release will have a serum vitamin D level
that is above 50 nanomole/liter, as also recited in Appellant’s claim 87.
As required by Appellant’s claim 87, the Diamyd Press Release
discloses that the Diamyd is administered by injection. See Diamyd Press
Release 2 (describing different treatment groups receiving “an injection of
Diamyd ®”).
Thus, as the Examiner found, and Appellant does not dispute, the sole
difference between the process described in the Diamyd Press Release and
the process recited in Appellant’s claim 87 is that the Diamyd Press Release
does not disclose that the GAD-alum composition (the Diamyd vaccine) is
injected directly into the lymph node. We agree with the Examiner that,
when performing the process taught in the Diamyd Press Release, it would
have been obvious to inject the Diamyd vaccine directly into the lymph
node.
As the Examiner found, Senti discloses that direct injection into the
lymph node of hay fever-causing antigens induced superior tolerance as
compared to standard subcutaneous (“s.c.”) injections, and also had several
other advantages:
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Three low-dose intralymphatic allergen administrations
increased tolerance to nasal provocation with pollen already
within 4 months (P < 0.001). Tolerance was long lasting and
equivalent to that achievable after standard s.c. immunotherapy
(P = 0.291 after 3 years). Intralymphatic immunotherapy
ameliorated hay fever symptoms (P < 0.001), reduced skin
prick test reactivity (P < 0.001), decreased specific serum IgE
(P < 0.001), caused fewer adverse events than s.c.
immunotherapy (P = 0.001), enhanced compliance (P < 0.001),
and was less painful than venous puncture (P = 0.018). In
conclusion, intralymphatic allergen administration enhanced
safety and efficacy of immunotherapy and reduced treatment
time from 3 years to 8 weeks.
Senti 17908; see also id. at 17910–17911 (“We demonstrated that
intralymphatic allergen administration enhanced safety, efficacy, and
compliance of s.c. immunotherapy and allowed reduction of the number of
injections from 54 to 3, and reduction of the cumulative allergen dose by
more than 1000-fold.”)
Senti goes on to teach that, beyond the allergic tolerance examined in
its study, “intralymphatic injection appears to generally enhance the efficacy
of vaccination and immunotherapy. The explanation is that only a small
fraction of s.c.-injected biomolecules reaches the draining lymph nodes to
stimulate the immune response, whereas direct injection into a lymph node
delivers all of the vaccine to the lymphatic organ.” Senti 17911.
Thus, on the current record, the Diamyd Press Release describes
injecting patients with the GAD-containing Diamyd vaccine to prevent an
attack by the patients’ immune system on its own pancreatic beta cells, that
is, to induce immune tolerance to the GAD protein so that the patients’
immune system does not attack its own beta cells. Senti, in turn, teaches that
intralymphatic injection is useful for inducing immune tolerance to hay fever
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antigens, has a number of advantages as compared to standard s.c. injections
of antigens for immunotherapy, and generally enhances the efficacy of
vaccination and immunotherapy. Given these teachings, we agree with the
Examiner that a skilled artisan, injecting the Diamyd vaccine into patients as
taught in the Diamyd Press Release, had a good reason for, and a reasonable
expectation of success in, injecting the Diamyd vaccine directly into the
patients’ lymph nodes, as taught in Senti.
We therefore also agree with the Examiner that a skilled artisan would
have considered the process recited in Appellant’s claim 87 prima facie
obvious. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007) (“[I]f a
technique has been used to improve one device, and a person of ordinary
skill in the art would recognize that it would improve similar devices in the
same way, using the technique is obvious unless its actual application is
beyond his or her skill.”). Appellant’s arguments do not persuade us to the
contrary.
Appellant argues that allergies and autoimmune diseases are entirely
different phenomena, and therefore “there is no reasonable expectation that
something that might work for allergies (e.g., Senti’s intra-lymph node
administration method) would also be expected to work for Type I diabetes.”
Appeal Br. 9; see also Reply Br. 2 (“There is simply no nexus between
treatment of allergies and treatment of autoimmune disease in the cited prior
art and, as such, there is no reason to expect that Senti’s method would work
for an aut[o]immune disease.”). We are not persuaded.
We first note, as the Examiner contends, and as Appellant does not
dispute, “any immunologist of ordinary skill in the art would have known at
the time of filing, lymph nodes are where immune responses happen. As
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taught by Senti et al., they employed lymph node injection because it had
worked in other immunological contexts.” Ans. 6; see also Senti 17910
(disclosing that “[e]nhanced efficacy of targeted lymph node immunization
has also been found for immunostimulatory complexes, bacteriophages, and
a recombinant simian immunodeficiency virus vaccine” and therefore that
“intralyrnphatic injection appears to generally enhance the efficacy of
vaccination and immunotherapy,” the explanation being that “only a small
fraction of s.c.-injected biomolecules reaches the draining lymph nodes to
stimulate the immune response, whereas direct injection into a lymph node
delivers all of the vaccine to the lymphatic organ”).
Given the variety of useful immunological contexts of intralymphatic
injection, and given Senti’s teaching that intralymphatic injection generally
enhances vaccine and immunotherapy efficacy, Appellant does not persuade
us that a skilled artisan lacked a reasonable expectation of success in using
intralymphatic injection in the process described in the Diamyd Press
Release. As our reviewing court has explained, “[o]bviousness does not
require absolute predictability of success. . . . For obviousness under § 103,
all that is required is a reasonable expectation of success.” In re Kubin, 561
F.3d 1351, 1360 (Fed. Cir. 2009) (quoting In re O’Farrell, 853 F.2d 894,
903–04 (Fed. Cir. 1988) (emphasis removed) (alteration in original).
Moreover, as discussed above, the nexus between treating type 1
diabetes as taught in the Diamyd Press Release, and treating allergies as
taught in Senti, is that both treatments involve administration to a patient, by
injection, of an antigen that causes an undesired immune/inflammatory
response. See Diamyd Press Release 2 (explaining that the clinical trial’s
treatment with the GAD-containing Diamyd vaccine “is designed to prevent,
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delay, or stop the autoimmune attack on beta cells”); see also Senti generally
(injecting extracts of hay fever allergens to inhibit allergies).
Indeed, in discussing the background state of the art, Appellant’s own
Specification explains that the art-recognized objective of administering
GAD was to induce tolerance. See Spec. 2 (disclosing that “[l]arge clinical
trials have been performed and are currently being performed using different
insulin derived formulations in order to induce tolerance and stop or prevent
the disease progression” and that “[m]any other beta cell antigen molecules
and peptides thereof including but not limited to GAD65 have been tried for
the same purpose”) (emphasis added).
We are also not persuaded that Appellant has advanced evidence
sufficient to support its contention that a skilled artisan would have believed
that Senti’s intralymphatic injection technique “does not work even for
treating allergies.” Appeal Br. 12; see also id. at 10–11 (citing Witten);5
Reply Br. 3.
We acknowledge Witten’s teaching, identified by Appellant, that in its
experiments intralymphatic injection “for grass pollen allergy revealed no
improvement in patients’ registered symptoms and use of rescue medication
or in quality-of-life or intradermal test scores in spite of weak signs of
immune modulation of IgE and IgG4.” Witten 1251.
As the Examiner points out, however, rather than stating that
intralymphatic injection does not work, Witten ultimately concludes that
more study of the technique is required:

5 Marianne Witten et al., Is intralymphatic immunotherapy ready for clinical
use in patients with grass pollen allergy?, 132 J. ALLERGY CLIN. IMMUNOL.
1248–1251 (Letter to the Editor) (2013).
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Even though the number of treated patients in our study
exceeds the sum of the 2 previous placebo-controlled studies, it
was small, and further adequately performed large-scale,
double-blind, placebo-controlled studies focusing on optimizing
allergen extracts, dose regimens, or both are required before
ILIT [intralymphatic immunotherapy] is ready for clinical use.
Witten 1251(emphasis added).
We are not persuaded that a study whose ultimate conclusion advises
further study of a technique, that is, trying it again, is sufficient to teach
away from performing the technique. See DePuy Spine, Inc. v. Medtronic
Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009) (“A reference
does not teach away . . . if it merely expresses a general preference for an
alternative invention but does not criticize, discredit, or otherwise discourage
investigation into the invention claimed.”) (citation and internal quotation
marks omitted). Indeed, by advising further study, Witten encourages
investigation into the invention claimed, rather than discourages it.
Moreover, to properly consider the record evidence of obviousness as
a whole, Witten’s teaching as to the desirability of further study of
intralymphatic injection must be considered alongside the teachings
discussed above in Senti, that intralymphatic injection is useful for inducing
immune tolerance to hay fever antigens, has a number of advantages as
compared to standard injections used in immunotherapy, and generally
enhances the efficacy of vaccination and immunotherapy. Thus, viewing the
evidence of record as whole, while Witten might have suggested that a
skilled artisan would not have been absolutely certain whether Senti’s
intralymphatic injection technique would work in the process of the Diamyd
Press Release, absolute certainty is not the criterion of obviousness. See
Kubin, 561 F.3d at 1360 (“Obviousness does not require absolute
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predictability of success. . . . [A]ll that is required is a reasonable
expectation of success.”) (citation and internal quotation marks omitted)
(emphasis removed).
In addition, we find that Appellant’s argument in relation to Witten is
generally inconsistent with its initial arguments. Specifically, as seen above,
Appellant initially argues that a skilled artisan lacked a reasonable
expectation of success in using Senti’s intralymphatic injection technique in
the process of the Diamyd Press Release because autoimmune disorders and
allergies are entirely different phenomena. Yet, in the arguments relating to
Witten, Appellant contends that any alleged negative teachings in Witten
about allergy treatment should be credited as being predictive in relation to
treating autoimmune diabetes.
In sum, for the reasons discussed, Appellant does not persuade us of
reversible error in the Examiner’s conclusion that the process recited in
Appellant’s representative claim 87 would have been obvious to a skilled
artisan. We therefore affirm the Examiner’s rejection of claim 87 over the
Diamyd Press Release and Senti. Because they were not argued separately,
claims 89–93 and 98–100 fall with claim 87. 37 C.F.R. § 41.37(c)(1)(iv).
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
87, 89–93,
98–100
103 Diamyd Press
Release, Senti
87, 89–93,
98–100

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TIME PERIOD FOR RESPONSE
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