DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. Claims 2, 5, and 7 have been cancelled. Claims 1, 3, 4, 6, 12, 13, 15, 18, 19, and 21 have been amended.
Claims 1, 3, 4, 6, and 8-21 are pending and under examination.
2. All rejections/objections pertaining to claims 2, 5, and 7 are moot because the claims were cancelled with the reply filed on 04/27/2026.
The objections to claims 1, 3, 4, 6, 12, 13, 15, 18, 19, and 21 are withdrawn un response to the amendments filed on 04/27/2026.
These obviousness-type rejections are maintained. However, they have been modified to address the newly added recitation of all E501A, W504A, Q530A, and E533A in the independent claims.
Claim Rejections - 35 USC § 103
3. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
4. Claims 1, 8, 9, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Witting et al. (Gene Therapy, 2013, 20: 997-1005), in view of both Buchholtz et al. (WO 08/037458) and Negrete et al. (J. Virol., 2007, 81: 10804-10814).
Witting et al. teach a lentiviral particle pseudotyped with Nipah virus (NiV) attachment (G) and fusion (F) proteins having a truncated cytoplasmic tails (NiV-G[Symbol font/0x44]34 and Niv-F[Symbol font/0x44]25, respectively); the combination of NiV-G[Symbol font/0x44]34 and F Niv-F[Symbol font/0x44]25 results in high lentiviral titers. Witting et al. teach that NiV-G is responsible for binding to the NiV cellular receptors ephrin-B2 and B3. Witting et al. teach using the pseudotyped lentiviral particle for gene delivery to cells expressing ephrin-B2 and B3 (claims 1 and 8) (see Abstract; paragraph bridging p. 997 and 998; p. 998, Fig. 1-2; paragraph bridging p. 998 and 1000; p. 999, Fig. 3; p. 1002, column 2, second full paragraph).
Fig. 1 and 2 in Witting et al. show that the cytoplasmic domain of NiV-G is located at the N-terminus, while that of NiV-F is located at the C-terminus.
As shown in Fig. 1, the cytoplasmic domains of NiV-G and NiV-G[Symbol font/0x44]34 are:
NIV-G NH2-MPAENKKVRFENTTSDKGKIPSKVIKSYYGTMDIKKINEGLLDSK
NiV-G[Symbol font/0x44]34 NH2-MKKINEGLLDSK (in bold below)
Thus, NiV-G[Symbol font/0x44]34 lacks the PAENKKVRFENTTSDKGKIPSKVIKSYYGTMDI sequence, i.e., amino acids 2-34 of SEQ ID NO: 9 (underlined below) (claim 1).
Claimed SEQ ID NO: 9 (wild type NiV-G; see the attached alignment)
MPAENKKVRF ENTTSDKGKI PSKVIKSYYG TMDIKKINEG LLDSKILSAF NTVIALLGSI 60
VIIVMNIMII QNYTRSTDNQ AVIKDALQGI QQQIKGLADK IGTEIGPKVS LIDTSSTITI 120
PANIGLLGSK ISQSTASINE NVNEKCKFTL PPLKIHECNI SCPNPLPFRE YRPQTEGVSN 180
LVGLPNNICL QKTSNQILKP KLISYTLPVV GQSGTCITDP LLAMDEGYFA YSHLERIGSC 240
SRGVSKQRII GVGEVLDRGD EVPSLFMTNV WTPPNPNTVY HCSAVYNNEF YYVLCAVSTV 300
GDPILNSTYW SGSLMMTRLA VKPKSNGGGY NQHQLALRSI EKGRYDKVMP YGPSGIKQGD 360
TLYFPAVGFL VRTEFKYNDS NCPITKCQYS KPENCRLSMG IRPNSHYILR SGLLKYNLSD 420
GENPKVVFIE ISDQRLSIGS PSKIYDSLGQ PVFYQASFSW DTMIKFGDVL TVNPLVVNWR 480
NNTVISRPGQ SQCPRFNTCP EICWEGVYND AFLIDRINWI SAGVFLDSNQ TAENPVFTVF 540
KDNEILYRAQ LASEDTNAQK TITNCFLLKN KIWCISLVEI YDTGDNVIRP KLFAVKIPEQ CT 602
As shown in Fig. 2 of Witting et al., the cytoplasmic tails of NiV-F and NiV-F[Symbol font/0x44]25 are:
NiV-F EKKRNTYSRLEDRRVRPTSSGDLYYIGT-C00H
NiV-F[Symbol font/0x44]25 EKK-COOH (in bold below).
Thus, NiV-F[Symbol font/0x44]25 lacks amino acids RNTYSRLEDRRVRPTSSGD, i.e., amino acids 522-546 of SEQ ID NO: 11 (underlined below) (claim 1).
Claimed SEQ ID NO: 11 (wild type NiV-F, see the attached alignment)
MVVILDKRCY CNLLILILMI SECSVGILHY EKLSKIGLVK GVTRKYKIKS NPLTKDIVIK 60
MIPNVSNMSQ CTGSVMENYK TRLNGILTPI KGALEIYKNN THDLVGDVRL AGVIMAGVAI 120
GIATAAQITA GVALYEAMKN ADNINKLKSS IESTNEAVVK LQETAEKTVY VLTALQDYIN 180
TNLVPTIDKI SCKQTELSLD LALSKYLSDL LFVFGPNLQD PVSNSMTIQA ISQAFGGNYE 240
TLLRTLGYAT EDFDDLLESD SITGQIIYVD LSSYYIIVRV YFPILTEIQQ AYIQELLPVS 300
FNNDNSEWIS IVPNFILVRN TLISNIEIGF CLITKRSVIC NQDYATPMTN NMRECLTGST 360
EKCPRELVVS SHVPRFALSN GVLFANCISV TCQCQTTGRA ISQSGEQTLL MIDNTTCPTA 420
VLGNVIISLG KYLGSVNYNS EGIAIGPPVF TDKVDISSQI SSMNQSLQQS KDYIKEAQRL 480
LDTVNPSLIS MLSMIILYVL SIASLCIGLI TFISFIIVEK KRNTYSRLED RRVRPTSSGD 540
LYYIGT 546
While NiV-F[Symbol font/0x44]25 is three amino acids shorter than the claimed Fv[Symbol font/0x44]22, it is noted that there is no evidence of record that the presence of extra three amino acids results in unexpected properties. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). A difference of three amino acids is not patentably relevant if it does not provide a novel feature.
Witting et al. do not teach retargeting the retroviral particle by using a fusion between NiV-G[Symbol font/0x44]34 and a targeting ligand (claim 1). Buchholtz et al. teach that lentiviral particles pseudotyped with attachment and fusion proteins could be retargeted for selective gene transfer into a cell of interest by modifying the attachment protein via: (1) fusing it with a ligand (such as an scFv) targeting the cell of interest (such as a CD4 or CD8 T-cell); and (2) mutating it such that it is not capable of interacting with its natural cellular receptor (see Abstract; paragraph bridging p. 1 and 2; p. 2, lines 12-19; p. 3, lines 14-17; paragraph bridging p. 26 and 27; p. 27, lines 4-28; p. 28; p. 33, lines 8-14). Negrete et al. teach that the mutation E533Q in NiV-G completely abrogates binding to ephrin-B2 and ephrin-B3 (see Abstract; p. 10810, column 1, second full paragraph and Fig. 6 D). Based on these teachings, one of skill in the art would have found obvious to modify NiV-G[Symbol font/0x44]34 by fusing it with an scFv targeting CD4 or CD8 on T-cells and introducing the E533Q mutation, to achieve the predictable result of specifically retargeting the pseudotyped lentiviral particle to CD4 or CD8 T-cells. One of skill in the art would have also found obvious to further administering the resultant pseudotyped lentiviral particle to T-cells to achieve the predictable result of obtaining T-cells expressing genes of interest, when obtaining T-cell expressing genes of interest was needed (claims 9, 11, and 12).
The cited prior art teaches the E533Q mutation, not E501A, W504A, Q530A, and E533A (claim 1). However, as per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, the E533Q mutation enables retargeting to cells of interest by abolishing binding to both ephrin-B2 and ephrin-B3. There is no evidence of record that E501A, W504A, Q530A, and E533A together provide for more than E533Q with respect to retargeting, as the single E533Q mutation abrogates binding to ephrin-B2 and ephrin-B3. Using E501A, W504A, Q530A, and E533A is not patentably relevant if it does not produce a novel feature when compared to E533Q.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
5. Claims 1, 3, 4, 6, and 8-21 are rejected under 35 U.S.C. 103 as being unpatentable over Witting et al. taken with both Buchholtz et al. and Negrete et al., in further view of Hurton et al. (Blood, 2008, 112, Abstract 3035).
The teachings of Witting et al., Buchholtz et al., and Negrete et al. are applied as above for claims 1, 8, 9, 11, and 12. Although the combination of Witting et al., Buchholtz et al., and Negrete et al. teaches retargeting to introduce genes of interest into to a CD4 or CD8 T-cell, the combination does not specifically teach that the genes of interest are CD19 CAR and membrane-bound IL-7 (mIL-7) (claims 3, 4, 6, 10, and 12-17). Hurton et al. teach genetically modifying T-cells with CD19 CAR and mIL-7, where IL-7 improves the survival and proliferation of CAR T-cells. Hurton et al. teach the need to evaluate the therapeutic potential of the resulting T-cells in clinical trials (see Abstract). Based on these teachings, one of skill in the art would have found obvious to modify the pseudotyped lentiviral particles by using a nucleic acid encoding the CD19 CAR and a nucleic acid encoding the mIL-7 as the genes of interest to achieve the predictable result of obtaining a composition suitable for cancer therapy. One of skill in the art would have found obvious to further administer the T-cells expressing CD19 CAR and mIL-7 to subjects affected by CD19-expressing cancers with the reasonable expectation that doing so would treat the cancer in these subjects. By doing so, one of skill in the art would have practiced the methods of claims 18-20.
With respect to claim 21, Buchholtz et al. teach obtaining the pseudotyped lentivirus by co-transfecting HEK293 cells with a packaging plasmid encoding the lentiviral GAG and POL (i.e., core proteins), a plasmid encoding the fusion scFv-attachment protein, a plasmid encoding the F proteins, and a transfer plasmid encoding a gene of interest (see p. 66, lines 20-25). One of skill in the art would have found obvious to obtain the pseudotyped lentiviral particles by co-transfecting the HEK293 cells with a packaging plasmid, a plasmid encoding the fusion of CD4/CD8 scFv/NiV-G[Symbol font/0x44]34, a plasmid encoding NiV-F[Symbol font/0x44]25, a plasmid encoding the CD19 CAR, and a transfer plasmid encoding mIL-7.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
6. The arguments addressing the references individually are not found persuasive because none of the references has to teach every claim limitation.
The argument that Buchholtz provides no teaching or suggestion regarding pseudotyping the lentivirus with the NiV-G and NiV-F is not found persuasive. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Morbillivirus and Nipah viruses belong to the genus Paramyxoviridae and both utilize the same mechanisms for transducing cells: a fusion protein and an attachment protein which recognizes the respective natural receptor present on the cell surface. See Buchholtz (Abstract; paragraph bridging p. 1 and 2) and Witting (p. 997, column 2, last paragraph).
Buchholtz teaches lentiviral particles pseudotyped with Morbillivirus attachment and fusion proteins retargeted for selective gene transfer into a cell of interest; retargeting takes place via mutating the attachment protein to render it incapable of interacting with its natural cellular receptor and further fusing the mutant with a ligand. Witting reaches that results with other Paramyxoviridae could be extrapolated to the Nipah virus (see p. 997). Based on these teachings, one of skill in the art would have reasonably concluded that retargeting as disclosed by Buchholtz is extrapolatable to the Nipah virus taught by Witting. MPEP 2141.03 states:
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
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The "hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art." Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988).
The argument that, based on Witting and Negrete, one of skill in the art would expect that eliminating ephrin binding would abolish infectivity is not found persuasive because it do not address the teachings and suggestions provided by the combination of all cited references.
It was known in the prior art that the expression of ephrins B2 and B3 is not restricted to a particular cell type (see for example Witting, p. 997, column 2, last paragraph), and thus, transduction by using the wild type NiV-G would not achieve selective binding. The combination of Buchholtz and Negrete suggests that introducing mutation abolishing ephrin binding is necessary for selective gene transfer into a target cell; selective gene transfer is achieved by further fusing a ligand specific for the target cell. Doing so would not abolish infectivity because the virus would be capable of using the specific ligand to bind and transduce the target cell.
The applicant argues that the cited references do not teach or suggest introducing the claimed mutations.
However, the rejection is not based on the cited prior art teaching or suggesting the claimed mutations. The rejection is based on the E533Q mutation, which abolishes binding to ephrins B2 and B3. The rejection states that using the claimed mutations is not patentably relevant because there is no evidence that they produce a novel feature over E533Q.
The argument of unexpected results is not found persuasive because the data in Fig. 2 does not compare the claimed mutant (E501A, W504A, Q530A, and E533A) with the E533Q mutant taught by the prior art.
While the data in Fig. 2 demonstrates that the mutant comprising all four E501A, W504A, Q530A, and E533A is superior to the single E533A mutant, the rejection is not based on the E533A mutation. The rejection is based on E533Q, which completely abolishes infectivity mediated by ephrins B2 and B3 (see Fig. 6 D in Negrete, for example). Thus, the data in the specification does not demonstrate superior or unexpected results over the cited prior art.
Conclusion
7. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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