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 5-9, 11, 12, 14-16, 20-26,and 28 have been amended.
Claims 1-28 are pending and under examination.
Claim Objections
2. Claim 1 is objected to because of the recitations “a miRNA”; “a membrane of the exosome”; and “a HER2 protein”. Correction to “an miRNA”; “the membrane of the exosome”; and “the HER2 protein” is required.
3. Claim 5 is objected to because of the recitations “has a sequence of”. Correction to “has the sequence” is required.
4. Claims 7, 21, and 22 are objected to because of the recitations “a mature form” and “has a nucleotide sequence as shown in”. Correction to “the mature form” and “has the nucleotide sequence set forth by” is required.
5. Claims 8, 9, 23, and 24 are objected to because of the recitations “a precursor” and “has a nucleotide sequence as shown in”. Correction to “the precursor” and “has the nucleotide sequence set forth by” is required.
6. Claim 10 should be rewritten as follows:
The engineered exosome of claim 1, wherein the ligand is a peptide.
7. Claims 13 and 16 are objected to because of the recitation “a group consisting of”. Correction to “the group consisting of” is required.
8. Claim 17 is objected to because of the recitations “synthesis” (line 2) and “the miRNA has a seed sequence having a nucleotide sequence as shown in”. Correction to delete the term “synthesis” and to “the seed sequence of the miRNA is set forth by” is required.
9. Applicant is advised that should claims 10 and be found allowable, claim 11 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two
claims in an application are duplicates or else are so close in content that they both
cover the same thing, despite a slight difference in wording, it is proper after allowing
one claim to object to the other as being a substantial duplicate of the allowed claim.
See MPEP § 706.03(k).
Claim Rejections - 35 USC § 103
10. 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.
11. Claims 1-9 and 14-28 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Mol. Ther., 2018, 26: 1032-1039), in view of all McSwiggen et al. (WO 03/070912), Gomari et al. (OncoTargets and Therapy, 2018, 11: 5752-5762), and Dweep et al. (RNA Mapping: Methods and Protocols in Molecular Biology, 2014, Chapter 25: 289-305).
Wang et al. teach engineered MSCs exosomes comprising an miRNA targeting ICP4 for blocking HSV-1 replication, where the exosomes efficiently deliver the miRNA the cytoplasm of to the HSV-1-infected cells; the miRNA comprises a seed sequence and a downstream UGCGGAC EXO-motif operably linked to the seed sequence (claims 1, 3, 4, 18, 19) (see Abstract; p. 1033, column 1 and Fig. 1). Since UGCGGAC is an EXO-motif, it is an equivalent of the GGAG and GGAGGAG (claims 5 and 20). Wang et al. teach designing several miRNAs by using BLOCK-iT RNAi Designer and selecting the most efficient one (see Abstract; p. 1032, paragraph bridging columns 1 and 2; p. 1033, paragraph bridging columns 1 and 2; p. 1036, column 1 and column 2, third paragraph).
Wang et al. do not teach targeting HER2 (claims 1 and 17). However, based on Wang et al., one of skill in the art would have reasonably concluded that exosomes could be used to deliver any miRNA to any cell of interest. McSwiggen et al. teach using miRNAs to inhibit HER2 in cancer cells overexpressing HER2 (which depend on HER2 for their survival); delivery could be targeted; the miRNAs could be encapsulated into a delivery vehicles such as a liposome (see Abstract; p. 8, lines 12-15; p. 38, lines 23-28; p. 39, lines 5-10; p. 57, lines 16-24; p. 59, lines 23-28; p. 86, lines 23-28; p. 94, lines 5-10; p. 98, lines 18-26; p. 99, line 23 through p. 100, line 9). Based on these teachings, one of skill in the art would have found obvious to use BLOCK-iT RNAi Designer to obtain anti-HER2 miRNAs, select the most efficient ones, and further modify Wang et al. by replacing the anti-ICP4 miRNA with the selected anti-HER2 miRNAs with the reasonable expectation of obtaining exosomes suitable to treat HER2-overxpressing cancers such as breast cancer (claim 14-16). By doing so, one of skill in the art would have obtained miRNAs having: seed sequences equivalent to SEQ ID NOs: 1 and 2; mature forms equivalent to SEQ ID NOs: 3-6; precursor forms equivalent to SEQ ID NOs: 7-10 (claims 2, 6-9, 17, and 21-24). The term “equivalent” recited in claims 2, 6-9, 17, and 21-24 is reasonably interpreted as meaning functional equivalents; the specification does not provide any definition to the contrary. Conversely, Dweep et al. teach generating all possible miRNAs-binding sites by walking the genes (see p. 290). Thus, one of skill in the art would have found obvious to us BLOCK-iT RNAi Designer and walk the HER2 gene, with the reasonable expectation that doing so would identify the most potent amti-HER2 miRNAs. By doing so, one of skill in the art would have obtained the miRNAs having the limitations recited in claims 2, 6-9, 17, and 21-24. The specification does not teach more than this, as it discloses that the claimed miRNAs were obtained by using the BLOCK-iT RNAi Designer tool
(see [0067]; [0081]). Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed sequences was other than routine or that the results should be considered unexpected in any way as compared to the closest prior art (see MPEP 2144.05 II).
Wang et al., McSwiggen et al., and Dweep et al. do not specifically teach targeting via a ligand binding HER2 (claim 1). Gomari et al. teach exosomes having on their surface Designed Ankyrin Proteins (DARPins) specifically binding HER2 for efficient and specific delivery to the HER2-overexpressing breast cancer cells (see Abstract; p. 5754, column 1, fourth paragraph; paragraph bridging p. 5757 and 5658). One of skill in the art would have found obvious to modify the exosomes of Wang et al. and McSwiggen et al. by adding a DARPin to achieve the predictable result of obtaining an efficient therapeutic composition for HER2-overexpressing breast cancers.
With respect to claims 26-28, since the prior art teaches that the exosomes are suitable to treat HER2-overexpressing cancers, one of skill in the art would have found obvious to formulate the exosomes as a pharmaceutical composition for intravenous for intravenous administration, especially in view of McSwiggen et al. teaching that the miRNAs could be formulated for intravenous administration (see p. 90, lines 18-27).
While the cited prior art does not teach that the exosomes are derived from HEK-293 cells (claim 25) it is noted that there is no evidence of record indicating that the exosomes derived from the HEK-293 cells exhibit unexpected properties over the exosomes derived from MSCs taught by the cited prior art. 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).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
12. Claims 1-11 and 14-28 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. taken with all McSwiggen et al., Gomari et al., and Dweep et al., in further view of Geng et al. (Theranostic, 2016, 6: 1261-1273).
The teachings of Wang et al., McSwiggen et al., Gomari et al., and Dweep et al. are applied as above for claims 1-9 and 14-28. Wang et al., McSwiggen et al., Gomari et al., and Dweep et al. do not teach a peptide ligand (claims 10, 11). Geng et al. teach peptides having nanomolar affinity and high specificity for HER2 for improved delivery to HER-positive (see Abstract). One of skill in the art would have found obvious to modify the teachings of Wang et al., McSwiggen et al., Gomari et al., and Dweep et al. by replacing DARPin with one of these peptides, to achieve the predictable result of obtaining a composition capable of mediating efficient therapy.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
13. Claims 1-9 and 12-28 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. taken with all McSwiggen et al., Gomari et al., and Dweep et al., in further view of Wang et al. (Mol. Cancer Ther., 2018, 17: 1133-1142; Wang2).
The teachings of Wang et al., McSwiggen et al., Gomari et al., and Dweep et al. are applied as above for claims 1-9 and 14-28. Wang et al., McSwiggen et al., Gomari et al., and Dweep et al. do not teach an scFV as a targeting ligand (claims 12 and 13). Wang2 teaches that exosomes carrying an anti-HER2-scFv (ML39) on their surface are capable of delivering therapeutics to HER2-positive tumors (see Abstract). One of skill in the art would have found obvious to modify the teachings of Wang et al., McSwiggen et al., Gomari et al., and Dweep et al. by replacing DARPin with one ML39, to achieve the predictable result of obtaining a composition capable of mediating efficient therapy.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
14. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Chakravarthy et al. (PGPUB 2013/0330279) teach targeted nanoparticles comprising an anti ERBB2 (HER2) miRNA, where the nanoparticles have a targeting moiety on their surface (see [0020]). However, this reference does not anticipate claim 1 because it teaches nanoparticles and not exosomes.
15. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633