ASCENDIS PHARMA A/S

Patent Trials and Appeals Board

Feb 12, 2021

2020002976 (P.T.A.B. Feb. 12, 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.
14/786,456 10/22/2015 Ulrich HERSEL 514453-3996 5610
20999 7590 02/12/2021
HAUG PARTNERS LLP
745 FIFTH AVENUE - 10th FLOOR
NEW YORK, NY 10151
EXAMINER
COUGHLIN, MATTHEW P
ART UNIT PAPER NUMBER
1626
NOTIFICATION DATE DELIVERY MODE
02/12/2021 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@haugpartners.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ULRICH HERSEL, HARALD RAU, BURKHARDT LAUFER,
JOACHIM ZETTLER, and ROMY REIMANN
Appeal 2020-002976
Application 14/786,456
Technology Center 1600
Before JASON V. MORGAN, DEBORAH KATZ, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
SCHNEIDER, 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 1–12, and 16.2 See Final Act. 1. We
have jurisdiction under 35 U.S.C. § 6(b).
We Affirm.

1 We use the term “Appellant” to refer to “applicant” as defined in 37 C.F.R.
§ 1.42. Appellant identifies the real party in interest as Ascendis Pharma
A/S. Appeal Br. 1.
2 Claim 13–15 are pending in the application but have been withdrawn from
consideration. Final Act. 2.
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CLAIMED SUBJECT MATTER
The claims are directed to a modified hydrogels. Claim 1, reproduced
below, is illustrative of the claimed subject matter:
A process for the modification of a hydrogel suitable as carrier
in a hydrogel-linked prodrug comprising the steps of:
(a) providing a hydrogel having groups Ax0, wherein groups Ax0
represent the same or different functional groups;
(b) optionally covalently conjugating a spacer reagent of formula
(I) to Ax0 of the hydrogel from step (a), where the formula (I) is:
Ax1–SP2–Ax2 (I);
wherein:
SP2 is Cl-50 alkyl, C2-50 alkenyl, or C2-50 alkynyl,
which Cl-50 alkyl, C2-50 alkenyl and C2-50 alkynyl is
optionally interrupted by one or more group(s)
selected from the group consisting of –NH–,
–N(C1-4 alkyl)–, –O–, –S–, –C(O)–, –C(O)NH,
–C(O)N(C1-4 alkyl)–, –O–C(O)–, –S(O)–, –S(O)2–,
4-to 7-membered heterocyclyl, phenyl, and
naphthyl;
Ax1 is a functional group for reaction with Axo of the
hydrogel; and
Ax2 is a functional group;
(c) reacting the hydrogel of step (a) or step (b) with a reagent of
formula (II) such that at most 99 mol-% of Ax0 or Ax2 react with
Ax3, where the formula (II) is:
Ax3–Z (II)
wherein:
Ax3 is a functional group; and
Z is an inert polymer having a molecular weight ranging
from 5 kDa to 100 kDa.
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REFERENCES
The prior art relied upon by the Examiner is:
Name Reference Date
Rau et al. (Rau ’260) US 2012/0156260 A1 June 21, 2012
Rau et al. (Rau ’259) US 2012/0156259 A1 June 21, 2012
Zhu et al. (Zhu) PEGylated PAMAM
Dendrimer-Doxorubicin
Conjugates: In Vitro
Evaluation and In Vivo
Tumor Accumulation,
27 Pharm. Res. 161
Jan. 2010
Desai et al. (Desai) Synthesis and
Characterization of
Photocurable
Polyamidoamine
Dendrimer Hydrogels
as a Versatile Platform
for Tissue Engineering
and Drug Delivery, 11
Biomacromolecules 666
Mar. 8, 2010
REJECTIONS
Claims 1–12 and 16 have been rejected under 35 U.S.C. § 103 as
unpatentable over Rau ’259 in view of Zhu, Rau ’260 and Desai.
Claims 1–8, 10–12, and 16 have been rejected under 35 U.S.C. § 103
as unpatentable over Rau ’259 in view of Rau ’260.
The pending claims have also been rejected for non-statutory double
patenting over various claims of 24 pending applications and issued patents
in view of Rau ’259 in further view of Zhu, Rau ’260 and Desai. See Final
Act. 22–32. Appellant and the Examiner agree that these rejections stand or
fall for the reasons the obviousness rejections stand or fall. See Appeal Br.
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17–18. For this reason we do not list the individual rejection of non-statutory
obviousness double patenting here.
OPINION
Obviousness Based on Rau ’259 Combined with Zhu, Rau ’260, and Desai
Issue
The issue with respect to the rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter of
claims 1–12 and 16 would have been obvious to one of ordinary skill in the
art at the time the invention was made over Rau ’259 combined with Zhu,
Rau ’260 and Desai.
The pending claims are subject to an election requirement. Final Act.
2–3. Appellant has elected that the hydrogel is formed between poly
amidoamines (PAMAM) dendrimers and PEG cross-linkers and where the
compound of formula (II) is a succinimidyl PEG. Id.
The Examiner finds that Rau ’259 teaches the preparation of
polyethylene based water-insoluble hydrogels having the functional groups
recited in claim 1. Id. at 4. The Examiner finds that Rau ’259 teaches that the
hydrogel may comprise PEG cross-linker moieties having a molecular
weight of from 0.5 to 5 kDa. Id. The Examiner also finds that Rau ’259
teaches that the hydrogel also comprises PAMAM. Id. at 5.
The Examiner finds that Rau ’259 does not explicitly each step (c) of
claim 1.
The Examiner finds that Zhu teaches the reaction of PAMAM
dendrimer with a PEG moiety having a functional group as shown in
Scheme 1 of Zhu, a portion of which is reproduced below. Id. at 6–7.
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The reproduced portion of Scheme 1 from Zhu page 164 illustrates part of
the synthetic route for PPCD and PPSD conjugates. Specifically, it shows
the reaction of PAMAM dendrimer and SCM-PEG-MeO to form a PEG-
PAMAM conjugate.
The Examiner finds that Zhu teaches that the PAMAM dendrimers
have terminal amine groups which meet the functional group limitation of
claim 1 step (a). Id. at 8. The Examiner also finds that Zhu teaches that the
PEG succinimidyl moiety has a molecular weight of about 5000 which
meets the limitation recited in step (c). Id.
The Examiner concludes:
a person having ordinary skill in the art in making hydrogels of
Rau [’259] that contain a poly(amidoamine) structure in the
hydrogel would have been motivated to modify the hydrogel
with PEG containing polymers as taught by Zhu et al. to reduce
cytotoxicity and then subsequently conjugate a prodrug as taught
by Zhu et al.
Id. at 7.
Appellant contends that Zhu teaches the use of a water soluble
hydrogel and that the claims require a water-insoluble hydrogel. Appeal Br.
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10–11. Appellant contends that one skilled in the art would not use a water
soluble hydrogel as a starting point to create a water-insoluble hydrogel. Id.
Appellant also contends that one skilled in the art would not use a
cytotoxic drug carrier to reduce immune reactions or inflammation. Appeal
Br. 12–13. Appellant contends that the purpose of the present invention is to
shield the biologically active groups to prevent exposure to enzymes that
might degrade or modify the active group. Id. at 12. Appellant contends that
this is different from the purpose of Zhu which is to reduce cytotoxicity. Id.
at 13.
Principles of Law
“[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting a prima facie case of unpatentability. If
that burden is met, the burden of coming forward with evidence or argument
shifts to the applicant.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
“Non-obviousness 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).
In determining whether the subject matter of a patent claim is
obvious, neither the particular motivation nor the avowed
purpose of the patentee controls. . . . [A]ny need or problem
known in the field of endeavor at the time of invention and
addressed by the patent can provide a reason for combining the
elements in the manner claimed.
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 419–20 (2007).
Analysis
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We adopt the Examiner’s findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Final Action and
Answer regarding this rejection. We find the Examiner has established a
prima facie showing that the subject matter of the claims would have been
obvious over Rau ’259 combined with Zhu, Rau ’260 and Desai to a person
of ordinary skill in the art at the time the invention was made. Appellant has
not produced evidence showing, or persuasively argued, that the Examiner’s
determinations on obviousness are incorrect. Only those arguments made by
Appellant in the Briefs have been considered in this Decision. Arguments
not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv). We
have identified claim 1 as representative; therefore, all claims fall with claim
1. We address Appellant’s arguments below.
Appellant contends that Zhu relates to water-soluble hydrogels and
that one skilled in the art would not look to water-soluble hydrogels as a
starting material for water-insoluble hydrogels. Appeal Br. 10–11. Appellant
contends that the water-soluble hydrogels of Zhu achieve systemic
circulation of the complex whereas the water-insoluble complexes of the
invention have limited or no systemic circulation. Id. at 11. Appellant
contends that the complexes of the present invention serve a different
purpose than those of Zhu. Id.
We have considered Appellant’s arguments and are not persuaded that
the Examiner erred in rejecting the claims. We begin by noting that claim 1
is directed to a process of modifying a hydrogel and not the hydrogel itself.
See Appeal Br. 18 (Claim App.). The properties of the hydrogel are
irrelevant to the patentability of the method use to make the hydrogel.
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With respect to the use of a water-soluble hydrogel as the starting
material, the rejection is based on the combination of Rau ’259 and Zhu with
the water insoluble hydrogel of Rau as the starting material. Final Act. 3–4.
Rau ’259 specifically teaches that the hydrogels are water insoluble and may
include PAMAM. Rau ’259 Abstr. ¶ 184. Zhu is cited for teaching the
reaction of PAMAM with a succinimidyl reagent and as providing the
motivation to modify the PAMAM hydrogel. Final Act. 5–7.
Appellant next contends that one skilled in the art would not use a
cytotoxic drug carrier as a starting point to reduce immune reactions or
inflammation. Appeal Br. 12. Appellant contends that the purpose of the
present invention is to shield the biologically active moieties to reduce
degradation and reduce immune reactions or inflammation. Id. Appellant
contends that Zhu is directed to achieving a different purpose, namely
reducing cytotoxicity. Id. at 13. Appellant contends that one skilled in the art
would not have been motivated to modify the hydrogels of Rau ’259 to
shield the active moieties. Id.
Again, we are unpersuaded by Appellant’s argument. Rau teaches that
the water insoluble hydrogel can contain PAMAM. Rau ’259 ¶ 184. Rau
teaches that PAMAM hydrogels exhibit cytotoxicity and that the addition of
PEG reduces cytotoxicity and improves biocompatibility. Zhu, 161. We
agree with the Examiner that this teaching in Zhu serves as a sufficient
motivation to modify the hydrogels of Rau ’259 as taught by Zhu. Final Act.
7, Ans. 34. That Appellant may have had a different motivation to modify
the PAMAM containing hydrogel is irrelevant. KSR, 550 U.S. at 419–20.
Conclusion
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Based on the foregoing we conclude that a preponderance of the
evidence supports the Examiner’s finding that the subject matter of claim 1
would have been obvious to one of ordinary skill in the art at the time the
invention was made over Rau ’259 combined with Zhu, Rau ’260 and Desai.
Claims 2–16 and 16 have not been argued separately and therefore fall with
claim 1. 37 C.F.R. § 41.37(c)(iv).
Obviousness Based on Rau ’259 and Rau ’260
Issue
The issue with respect to this rejection is whether the subject matter of
claims 1–8, 10–12, and 16 would have been obvious to one of ordinary skill
in the art at the time the invention was made over Rau ’259 combined with
Rau ’260.
The Examiner finds that Rau ’259 teaches polyethylene glycol based
water-insoluble hydrogels prepared from a hydrogel having an amine group
meets the requirements of step (a) of claim 1. Final Act. 14. The Examiner
finds that Rau ’259 also teaches reacting the amine group containing
hydrogel with a compound with the formula disclosed in Rau ’259 paragraph
555. This structure is reproduced below.

The structure relied on by the Examiner is a more preferred species of
N-hydroxysuccinimide ester, one of a genus of N-hydroxysuccinimide esters
also disclosed by Rau ’259. The Examiner finds this compound meets the
cross-linker limitation of the claims. Id. at 14–15. The Examiner finds that
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Rau ’260 teaches various elements found in the dependent claims including
the limitation that the linking compound comprise a protein. Id. at 15–17.
Appellant contends that the combination of references does not teach
or suggest the claimed invention as the methods disclosed in the art do not
result in stable linkages. Appeal Br. 14–15. Appellant contends that stable
linkages are required to shield the biologically active moieties. Id. Appellant
also contends that Rau ’259 does not teach or suggest shielding of
biologically active moieties. Id at 15–16.
Legal Principles
[I]t is the language itself of the claims which must particularly
point out and distinctly claim the subject matter which the
applicant regards as his invention, without limitations imported
from the specification . . . Limitations in the specification not
included in the claims may not be relied upon to impart
patentability to an otherwise unpatentable claim.
In re Lundberg, 244 F.2d 543, 548 (CCPA 1957).
Analysis
We adopt the Examiner’s findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Final Action and
Answer regarding this rejection. We find the Examiner has established a
prima facie showing that the subject matter of the claims would have been
obvious over Rau ’259 combined with Rau ’260 to a person of ordinary skill
in the art at the time the invention was made. Appellant has not produced
evidence showing, or persuasively argued, that the Examiner’s
determinations on obviousness are incorrect. Only those arguments made by
Appellant in the Briefs have been considered in this Decision. Arguments
not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv). We
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have identified claim 1 as representative; therefore, all claims fall with claim
1. We address Appellant’s arguments below.
Appellants contend that the references do not teach the formation of a
stable bond which shield a biologically active moiety. Appeal Br. 14–15.
Appellant contends that Rau ’259 discloses forming a transient linker
formed by an auto-cleavable functional group. Id. Appellant also contends
that Rau ’259 does not teach shielding a biologically active moiety. Id. at
15–16.
We are not persuaded by Appellant’s arguments. Claim 1 does not
include a limitation calling for shielding a biologically active moiety nor
does it specify the type of bond formed between the PEG liner either the
PAMAM dendrimer or the prodrug. See Appeal Br. 18 (Claims App.).
Appellant’s argument address limitations that are not in the rejected claims
and therefore cannot serve as the basis for overcoming the present rejection.
In re Lundberg, 244 F.2d at 548.
Conclusion
Based on the foregoing we conclude that a preponderance of the
evidence supports the Examiner’s finding that the subject matter of claim 1
would have been obvious to one of ordinary skill in the art at the time the
invention was made over Rau ’259 and Rau ’260. Claims 2–8, 10–12, and
16 have not been argued separately and therefore fall with claim 1. 37 C.F.R.
§ 41.37(c)(iv).
Non-statutory Double Patenting
As noted above the Examiner has rejected claims 1–12 and 16 for
non-statutory double patenting over the claims of 24 allowed patents and
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pending applications combined with the teachings of Rau ’259 Zhu, Rau
’260, and Desai. Final Act. 22–32. Appellant has not presented separate
arguments for the rejections other than to contend that the rejections stand or
fall with obviousness rejection based on Rau ’259 combined with Zhu, Rau
’260 and Desai. Appeal Br. 16–18.
As discussed above we affirm the rejection based on Rau ’259
combined with Zhu, Rau ’260 and Desai. We therefore affirm the rejections
for non-statutory double patenting.
CONCLUSION
The Examiner’s rejections are affirmed.
More specifically,
The Examiner’s rejection of claims 1–12 and 16 under 35 U.S.C.
§ 103 as unpatentable over Rau ’259 combined with Zhu, Rau ’260 and
Desai is affirmed.
The Examiner’s rejection of claims 1–8, 10–12, and 16 under 35
U.S.C. § 103 as unpatentable over Rau ’259, Rau ’260 is affirmed.
The Examiner’s rejection for non-statutory double patenting is
affirmed
DECISION SUMMARY
In summary:
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Claims
Rejected
35 U.S.C. § References/Basis Affirmed Reversed
1–12, 16 103 Rau ’259, Zhu,
Rau ’260, Desai
1–12, 16
1–8, 10–12,
16
103 Rau ’259, Rau
’260
1–8, 10–12,
16

1–12, 16 Non-statutory
Double Patenting
1–12, 16
Overall
Outcome
1–12, 16

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).

AFFIRMED