Ex Parte Edelman et al

Board of Patent Appeals and Interferences

Oct 13, 2009

10059261 (B.P.A.I. Oct. 13, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte LENA EDELMAN,
ETIENNE DANIEL FRANCOIS JACOTOT, and JEAN-PAUL BRIAND
____________

Appeal 2009-003878
Application 10/059,261
Technology Center 1600
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Decided: October 13, 2009
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Before DONALD E. ADAMS, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims 85-90, 94, and 95.
Pending claims 57, 60, 61, 73-84, 91-93, and 96-105 have been withdrawn
(Ans. 2; App. Br. 4; Reply Br. 1). We have jurisdiction under 35 U.S.C. §
6(b).
Appeal 2009-003878
Application 10/059,261

STATEMENT OF THE CASE
The claims are directed to a chimeric, bifunctional molecule (claims
85-90) and a pharmaceutical composition comprising a chimeric
bifunctional molecule (claims 64 and 95). Claim 85 is illustrative:
85. A chimeric, bifunctional molecule that can enter into a cell to
induce death of the cell by apoptosis, wherein the chimeric, bifunctional
molecule comprises a first functional molecule covalently linked to a second
functional molecule, wherein the first functional molecule targets and enters
into the cell and the second functional molecule targets and induces the
death of the cell by apoptosis by regulating opening of a permeability
transition pore complex (PTPC) of mitochondria or a fragment of the PTPC,
wherein the chimeric, bifunctional molecule has the formula:
TARG-TOX,
wherein
TOX is a peptide chosen from Vpr 71-82 (SEQ ID NO: 225), Vpr 71-82
[R73, 77, 80K] (SEQ ID NO: 226), Vpr 71-96 (SEQ ID NO: 227), Vpr 71-
96 [R73, 77[,] 80K] (SEQ ID NO: 228), Vpr 52-96 (SEQ ID NO: 229), Vpr
52-96 [R73,77, 80K) (SEQ ID NO: 230), Vpr 52-96 [L60, 67A] (SEQ ID
NO: 231), Vpr 52-82 (SEQ ID NO: 232), Vpr 52-82 [R73, 77, 80K] (SEQ
ID NO: 233), Vpr 52-96 [C76S] (SEQ ID NO: 256), and
TARG is chosen from HIV-1 tat 48-59 transduction domain (SEQ ID NO:
269), HIV-1 tat 49-57 (SEQ ID NO: 270), and pep-1 (SEQ ID NO[:] 271),
and wherein the TARG peptide is optionally covalently linked to the TOX
peptide by a peptide linker of 2-18 amino acids.

The Examiner relies on the following evidence:
Sherman et al. US 6,664,040 B2 Dec. 16, 2003
Arunagiri et al., A C-terminal domain of HIV-1 accessory protein Vpr is
involved in penetration, mitochondrial dysfunction and apoptosis of human
CD4+ lymphocytes, 2 APOPTOSIS 69-76 (1997).

Kim et al., Introduction of soluble proteins into the MHC class I pathway by
conjugation to an HIV tat peptide, 159 J. IMMUNOL 1666-1668 (1997)
(PubMed Abstract No. 9257826).

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Application 10/059,261

Sela et al., Different roles of D-amino acids in immune phenomena, 11
FASEB J. 449-456 (1997) (PubMed Abstract No. 9194525).

The rejection presented by the Examiner is as follows:
Claims 85-90, 94, and 95 stand rejected under 35 U.S.C § 103(a) as
unpatentable over the combination of Sherman, Kim, Arunagiri, and Sela.
We reverse.

ISSUE

Have Appellants established error in the Examiner’s prima facie case
of obviousness?

FINDINGS OF FACT
FF 1. The Examiner finds that Sherman teaches “a chimeric, bifunctional
molecule that enters a cell and induces cellular death via apoptosis” (Ans. 5).
FF 2. “Because sVpr rapidly and strongly transduces freshly isolated
primary human cells at nanomolar concentrations, the methods of the
invention provide an attractive and effective means for delivery of a
molecule into a cell” Sherman’s “invention provides a method for delivering
a molecule into a cell . . . compris[ing] contacting the cell with a conjugate
comprising a Vpr polypeptide conjugated to the molecule” (Sherman, col. 7,
ll. 40-47).
FF 3. “Because sVpr can induce apoptosis, those cells which are more
susceptible than non-target cells to transduction by Vpr are selectively
killed,” therefore, “[i]n an alternative embodiment [of Sherman’s invention],
the method of killing a target cell population comprises administration of a
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Vpr polypeptide, without necessarily conjugating the Vpr polypeptide to a
toxin or other molecule” (Sherman, col. 8, ll. 6-12).
FF 4. Sherman defines “transduction” as “the ability to cross a biological
membrane in a receptor-, energy-independent process” (Sherman, col. 19, ll.
59-60).
FF 5. The Examiner finds that Arunagiri teaches “that the crucial peptide
sequence of Vpr required in order to evoke mitrochondrial dysfunction and
apoptotic death is a conserved H(F/S)RIG repeat motif” (Ans. 5).
FF 6. The Examiner finds that neither Sherman nor Arunagiri teach SEQ.
ID. NO. 232 of Appellants’ claimed invention. Nevertheless, the Examiner
finds that Appellants’ Specification “fails to disclose any unique or novel
contributions, such as, a change of function to the additional amino acids
that are adjacent to the . . . [H(F/S)RIG] essential motifs in SEQ ID NO[ ]:
232” (Ans. 5).
FF 7. Sherman teaches “that full-length sVpr, or at least more than only the
putative transducing domain, is necessary for efficient protein transduction”
(Sherman, col. 20, ll. 29-31). In this regard, Sherman teaches that “HIV-1
Vpr is optimized for protein transduction, including apparent receptor
independence and rapid uptake under conditions of limited energy”
(Sherman, col. 20, ll. 51-54).
FF 8. The Examiner finds that Kim teaches “the unique ability of HIV-1
tat to transport macromolecules into cells is well known in the prior art”
(Ans. 5).
FF 9. The Examiner finds that Kim teaches “the use of tat-conjugated
proteins for the treatment of tumors” (id.).
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FF 10. Kim teaches that “[p]rotection against most intracellular pathogens
requires T cells that recognize pathogen-derived peptides in association with
MHC class I molecules on the surface of infected cells” (Kim, PubMed
Abstract).
FF 11. Kim teaches a HIV-1 tat (residues 49-57) – OVA protein conjugate
and that “[w]hen APC were exposed in vitro to such protein conjugates, they
processed and presented the peptides in association with MHC class I
molecules and stimulated CD8+ Ag-specific T cells” (id.).
FF 12. The Examiner finds that Sela teaches “that ‘the inclusion of D-amino
acids may be an advantage in terms of both specificity and efficacy, the
latter because of longer persistence in an undigested form because they resist
enzymatic degradation’” (Ans. 5-6).

PRINCIPLES OF LAW
“In proceedings before the Patent and Trademark Office, the
Examiner bears the burden of establishing a prima facie case of obviousness
based upon the prior art.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir.
1992). On appeal to this Board, Appellants must show that the Examiner
has not sustained the required burden. See Ex parte Yamaguchi, 88 USPQ2d
1606, 1608 and 1614 (BPAI 2008) (precedential); Ex parte Fu, 89 USPQ2d
1115, 1118 and 1123 (BPAI 2008) (precedential).
“The combination of familiar elements according to known methods is
likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). However,
it can be important to identify 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
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does . . . because inventions in most, if not all, instances rely
upon building blocks long since uncovered, and claimed
discoveries almost of necessity will be combinations of what, in
some sense, is already known.
Id. at 418-419.

ANALYSIS
Appellants contend that “the type of chimeric, bifunctional molecules
envisioned by . . . [Sherman] relate to linking unspecified molecules with
Vpr in order to deliver the molecules into the cell by exploiting Vpr’s ability
to pass through cell membranes” (App. Br. 14). Appellants contend that
“the cited art does not consider whether the three-dimensional structure of
the Targ component of the claimed bifunctional molecule would interfere
with the three-dimensional structure of the Tox component, and thus disturb
the function of the Tox component” (App. Br. 13-14). Further, Appellants
contend “that there is no teaching in Arunagiri [or Sherman] . . . that links
apoptosis of cells to regulation of PTPC by Vpr-derived peptides” (App. Br.
12). We agree.
The Examiner finds that neither Sherman nor Arunagiri teach SEQ.
ID. NO. 232 of Appellants’ claimed invention. Nevertheless, the Examiner
finds that Appellants’ Specification “fails to disclose any unique or novel
contributions, such as, a change of function to the additional amino acids
that are adjacent to the . . . [H(F/S)RIG] essential motifs in SEQ ID NO[ ]:
232” (FF 6). However, Sherman teaches that “HIV-1 Vpr is optimized for
protein transduction, including apparent receptor independence and rapid
uptake under conditions of limited energy” (FF 7).
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Nevertheless, Sherman teaches that Vpr can: (1) be used to deliver
molecules conjugated to Vpr into a cell in a receptor independent manner
(FF 2); and (2) induce apoptosis without necessarily conjugating the Vpr
polypeptide to a toxin or other molecule (FF 3). Sherman teaches that when
conjugated to another molecule, Vpr is the targeting component of the
conjugate and is responsible for taking the conjugate into a cell where the
other component of the conjugate will exhibit its function (see e.g., FF 2).
Notwithstanding this teaching in Sherman, the Examiner asserts that a
person of ordinary skill in the art would have found it prima facie obvious to
conjugate tat to Vpr effectively producing a conjugate with two targeting
components. The Examiner reasons that in such a conjugate the tat
component of the conjugate will be responsible for delivering the conjugate
into a cell where Vpr will induce apoptosis. We do not find, and the
Examiner failed to identify, a teaching in Sherman or Arunagiri of Vpr’s
ability to induce apoptosis when conjugated to another molecule,
particularly another “delivery” molecule.
Further, it is unclear from the Examiner’s statement of the rejection
why a person of ordinary skill in this art would modify Vpr, which can
induce apoptosis on its own (FF 3) and is “optimized for protein
transduction” in a receptor independent manner (FF 7), by conjugating it to
tat. Kim teaches that a tat based conjugate is processed and presented in
association with MHC class I molecules (FF 11). The Examiner fails to
explain why a person of ordinary skill in the art would have expected the
Vpr component of such a conjugate to induce apoptosis when it is processed
and presented in association with MHC class I molecules as taught by Kim.
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For the foregoing reasons we find that the Examiner failed to provide
the evidence necessary to establish a prima facie case of obviousness.

CONCLUSION OF LAW
Appellants established error in the Examiner’s prima facie case of
obviousness.

REVERSED

cdc

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