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 .
Amendments
In the reply filed 7/24/25, Applicant has amended Claims 46-47, 51, 53, 88, canceled claims 1-45, 57-87, and 91-94, and added new claim, Claim 98.
Election/Restrictions
Applicant’s election of the following invention without traverse in the telephonic reply by Applicant’s representative, David Kerr on 12/23/2024 has been acknowledged, and the requirement has been deemed proper and made FINAL.
Group IV, claims 46-56, 88-90, 95-98, drawn to a composition comprising and EV comprising a membrane protein coupled to a target molecule and to a first component of a split component system, and a second component of the split component system.
Applicant’s election of the following species has acknowledged, and the requirement has been deemed proper and made FINAL.
IV (A), Split GFP as the split complement system.
IV (B), Cas9 as the target molecule.
Election by Original Presentation
Newly amend Claim 88 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the target molecule coupled to the second component of the split complement system was elected as Cas9, while amended Claim 88 is directed to an unelected target molecule “presented on the surface of the EV and configured to elicit an immune response or a therapeutic response”, which despite a typographic error appears to be further limited to antibody peptide, tumor specific antigen peptides, therapeutic nucleic acids configured to target the EV to a specific cell type or tissue or tumors.
Since applicant has received an action on the merits for the originally presented invention (i.e., Cas9 as the target molecule), this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, Claims 88-90, 95-98 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) and MPEP § 821.03 as being drawn to a nonelected species of target molecule, there being no allowable generic claim.
Claims 46-56 are under consideration.
Priority
The instant application was filed 2/01/2021 and is a continuation-in-part (CIP) of national stage entry of PCT/US2019/044686 filed 8/01/2019, which claims priority to US provisional application 62/713,289 filed 8/1/2018.
The disclosure of the prior-filed application, PCT/US2019/044686, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Review of the application PCT/US2019/044686 did not reveal support for gectosome or extracellular vesicle comprising an HIV “p6Gag” peptide. Furthermore, searching of PCT/US2019/044686 did not reveal the recitation of “SEQ ID NO: 1” (correspond to the amino acid sequence of VSV-G) nor “SEQ ID NO:2” (correspond to the amino acid sequence of the HIV p6Gap peptide). Thus Claims 46-50, and 52, are being given the filing date of 2/1/2021.
Withdrawn Objection to Specification
The objection to the disclosure because of an embedded hyperlink and/or other form of browser-executable code has been withdrawn due to Applicant’s amendment.
New Objection to Specification
The disclosure is objected to because the figure legend for Figure 14 refer to “(E and F)”, as well as “Alignment of PCSK9 amplified region…”, which no longer appear in the amended Figure 14 filed 7/24/2025 because Applicant has removed Fig. 14E.
New Objection to Drawings
Figure 14 F of the drawings filed 7/24/2025 is objected to because the figure has not been re-lettered as Fig. 14 “E”. 37 CFR 1.437 states that different figures on the sheets of drawings must be numbered (and lettered) in the order in which they appear.
Maintained Objection to Drawings
Sequence Compliance
[AltContent: textbox ([img-media_image1.png])]The objection to Figure 14F (see nucleic acid sequences adjacent) of the Specification does not conform to sequence rules, requiring the use of “SEQ ID NO:” (37 CFR 1.821-1.825).
Where the description or claims of a patent application discuss a sequence that is set forth in the “Sequence Listing” in accordance with paragraph (c) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by “SEQ ID NO:” in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. 37 CFR 1.821 (d). Specifically, the cited section indicates that nucleotide and/or amino acid sequences are an unbranched sequence of 4 or more amino acids or an unbranched sequence of 10 or more nucleotides. Branched sequences are specifically excluded from this definition. Sequences with fewer than four specifically defined nucleotides or amino acids are specifically excluded from this section.
The applicant is reminded that the specification must be amended in order to comply with regulations cited above. All references to sequences in claims and specification should be referred to as “SEQ ID NO:1”, for example. To avoid all doubts of the examiner and to ensure correct interpretation of the claims and specification, the identification of sequences with proper sequence identifiers is required.
Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Withdrawn Claim Objections
The objection to Claims 46 and 95-96 have been withdrawn due to Applicant’s amendment.
New Claim Objections
Claim 46 is objected to because of the following informalities: instant claim recites the abbreviation “EV”, which should be properly defined as an “extracellular vesicle“. Appropriate correction is required.
Withdrawn 35 USC § 112(b)
The prior rejection of Claims 47-56 and 90 under 35 U.S.C. § 112(b) pre-AIA 2nd paragraph as being indefinite is withdrawn in light of Applicant’s amendments of instant claims to remove the trademark and describe the target molecule.
Maintained Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 52 stands rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 52 recites the broad recitation for the membrane-bound protein as comprising VSV-G, and the claim also recites that the membrane-bound protein comprises a protein according to SEQ ID NO:1, as well as 80% identical with SEQ ID NO:1, which are narrower statements of the limitation (albeit SEQ ID NO:1 is a 511 amino acid VSV-G protein). A broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In light of the specification and for the sake of compact prosecution, the membrane-bound protein of Claim 52 is being interpreted as being in the alternative, such that it is either a VSV-G or SEQ ID NO:1 or 80% of SEQ ID NO:1.
New Claim Rejections - 35 USC § 112(b)
Claim 49 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 49 recites the limitation "said gectosome" in regard to Claim 48. There is insufficient antecedent basis for this limitation in the claim because Claim 48 is directed to extracellular vesicles. Appropriate correction is required.
Withdrawn 35 USC § 112(d)
The prior rejection of Claim 96 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn in light of Applicant’s amendments of Claims 95 and 96 to place the limitations in the alternative.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 47 and 53 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Specifically, claims 47 and 53 draw to split complement systems comprising “a split ubiquitin system; a split beta-gal system;…and a split biotin system” that do NOT “emit” a detectable signal, and therefore do NOT narrow the scope of the split compliment systems of claims 46 and 51. Although Applicant’s specification does not define or have literal support for the phrase “emit a detectable signal”, it is clear from Applicant’s arguments and the working embodiments using the split GFP system, that the emission of a detectable light signal from the split system has inherent support. However, essentially, due to the Applicant’s own claim language, these non-light signal emitting embodiments of claims 47 and 53 are excluded from the scope of claims 46 and 51, respectively. Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Declaration under 37 CFR 1.130
The declaration under 37 CFR 1.130(a) filed on 7/24/2025 by Dr. Liu is sufficient to overcome the rejection of instant claims based on Zhang et al., (Dev Cell, 2020, 55:784-801, published 12/21/2020). Specifically, the filed declaration disqualifies the disclosure of Zhang as prior art because it was made by the inventor or a joint inventor, or the subject matter disclosed was obtained directly or indirectly from the inventor or a joint inventor.
Withdrawn 35 USC § 102
The prior rejection of Claims 46-50, 88 and 97 under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al., (Dev Cell, 2020, 55:784-801, published 12/21/2020) is withdrawn in light of the declaration under 37 CFR 1.130(a) filed on 7/24/2025 by Dr. Liu and the change the target molecule coupled to the second component of the split complement system to a non-elected species.
The prior rejection of Claims 51, and 54-56 under 35 U.S.C. 102(a)(2) as being anticipated by Hotta (US2021/0269790, filed 7/12/2019, with priority to JP2018-133682, filed 7/13/2018) is withdrawn in light of Applicant’s amendment of Claim 51 to limit the split complement system to emit a detectable signal when reconstituted, which is a limitation Hotta does not teach
Withdrawn 35 USC § 103
The prior rejection of Claims 51 with 52 under 35 U.S.C. 103 as being unpatentable over Zhang et al., (Dev Cell, 2020, 55:784-801, published 12/21/2020), in view of Nordin (US 2020/0062813, filed 1/19/2018) is withdrawn in light of the declaration under 37 CFR 1.130(a) filed on 7/24/2025 by Dr. Liu.
The prior rejection of Claims 46, 48-50, 51-52, and 54-56 under 35 U.S.C. 103 as being unpatentable over Hotta (US2021/0269790, filed 7/12/2019, with priority to JP2018-133682, filed 7/13/2018), in view of Nordin (US 2020/0062813, filed 1/19/2018) is withdrawn in light of Applicant’s amendment of Claims 46 and 51 to limit the split complement system to emit a detectable signal when reconstituted, which is a limitation neither Hotta nor Nordin teach
The prior rejection of Claims 88-89, 95-97 under 35 U.S.C. 103 as being unpatentable over Hotta (US2021/0269790, filed 7/12/2019), in view of Nordin (US 2020/0062813, filed 1/19/2018) and Mangeot (US 8,697,439, filed 11/10/2010, patented 4/15/2014) is withdrawn in light of Applicant’s amendment of Claim 88 to (1) limit the split complement system to emit a detectable signal when reconstituted, which is a limitation neither Hotta, Nordin nor Mangeot teach, and (2) change the target molecule coupled to the second component of the split complement system to a non-elected species.
The prior rejection of Claim 90 under 35 U.S.C. 103 as being unpatentable over Hotta (US2021/0269790, filed 7/12/2019), Nordin (US 2020/0062813, filed 1/19/2018) and Mangeot (US 8,697,439, filed 11/10/2010, patented 4/15/2014), as applied to claims 88 & 89, in further view of Waldo et al. (US2015/0099271, filed 10/06/2014) is withdrawn in light of Applicant’s amendment of Claim 88 to change the target molecule coupled to the second component of the split complement system to a non-elected species.
New Claim Rejections - 35 USC § 103
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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 46-56 are rejected under 35 U.S.C. 103 as being unpatentable over Hotta (US2021/0269790, filed 7/12/2019, with priority to JP2018-133682, filed 7/13/2018, prior art of record), in view of Nordin (US 2020/0062813, filed 1/19/2018, prior art of record) and Waldo et al. (US2015/0099271, filed 10/06/2014, prior art of record)
[AltContent: textbox ([img-media_image2.png])]In regard to claims 46 and 51, Hotta teaches a multi-component extracellular virus-like vesicular particle comprising a split FKBP12/FRB system attached to a target molecule (see Fig. 6a excerpt adjacent from US20210269790, as well as Fig. 6a of JP2018133682 priority document).
Specifically, Hotta teaches the first component of the split system (i.e., FKBP12) is coupled to the membrane-bound envelope protein VSV-G, while the second component of the split system (i.e., FRB) is coupled with the target molecule of Cas9.
In regard to claims 46 and 51, as per the p6Gag peptide/peptide configured to increase delivery, Hotta teaches that in addition to the envelope protein of VSV-G that is responsible for membrane fusion, the vesicular particle can also comprises a Gag protein, such as the HIV-derived Gag protein of SEQ ID NO: 1 (see Fig. 6c, [0099-0100, 0103-0104] and Sequence Listings from US20210269790, as well as Figs. 6c, and Sequence Listings of JP2018133682 priority document). Importantly, the 533 amino acid SEQ ID NO:1 of Hotta comprises the p6Gag peptide of instant SEQ ID NO:2 as the last 52 amino acids.
Furthermore, Nordin (US 2020/0062813) teaches a composition comprising extracellular vesicles (EV) that combines a protein to improve transport and trafficking, wherein the protein is the HIV p6Gag of SEQ ID NO:86 [0024, 0072-0073], which comprises a sequence that is 100% identical to the 52 amino acid sequence of SEQ ID NO:2 (see SCORE search 1/15/2025, rapm.file, Result #3).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to prepare the VSV-G/FKBP12 and FRB/Cas9 vesicles as taught by Hotta and combine a p6Gag sequence comprising SEQ ID NO:2 with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because both Hotta and Nordin teach including a protein comprising the p6Gag HIV sequence improves vesicle trafficking and Cas9 delivery (Figs. 7-14 from US20210269790, as well as Figs. 7-15 of JP2018133682 priority document).
However, in regard to claims 46 and 51, as per the first and second components of the split compliment system emitting a detectable signal when reconstituted, although Hotta visualizes the vesicles by GFP fluorescence, they are silent to further including a split GFP.
[AltContent: textbox ([img-media_image3.png])]Nevertheless, Waldo teaches split GFP10/GFP11 system for in vivo real-time fluorescent visualization of FKBP12 binding to FRB in subcellular structures ([0018, 0108-0110, 0174, 0186], see Fig. 5A adjacent).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to prepare the VSV-G/FKBP12 and FRB/Cas9 vesicles as taught by Hotta and combine the split GFP system as taught by Waldo with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because Waldo teaches this addition would allow in vivo real-time visualization of FKB12 binding to FRB, and this would be particularly advantageous for seeing the real-time loading and/or release of the vesicles Cas9 cargo of Hotta.
In regard to claims 48-50 and 54-56, as stated supra, Hotta teaches the target molecule is Cas9 and that it is accompanied by a sgRNA (see Fig. 20, [0279] from US20210269790, as well as Fig. 20, [0169] of JP2018133682 priority document).
In regard to claims 47 and 53, as stated supra, Waldo teaches the split GFP complimentary system.
In regard to claim 52, as stated supra, Hotta and Nordin teach the p6Gag peptide of instant SEQ ID NO:2.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 7/24/2025 are acknowledged.
Applicant argues that the FKB12/FRB system of Hotta does not emit a detectable signal, and requires a small molecule such as rapamycin to induce dimerization, which is also not present in Applicant’s claimed system.
Furthermore, Applicant argues that Hotta in view of Nordin does not make the claimed invention obvious. Applicant argues that the claimed gectosome consists of a membrane fusugenic protein such as VSV-G coupled with a target molecule in a reversible manner via a split protein that emits a detectably signal. Applicant describes the system as including a VSV-G protein fused to a GFP11 protein, and a GFP1-10 protein fused to BlaM-vpr reporter. Applicant argues the observable light from the reconstituted split GFPs confirms the target molecules has been recruited and packaged in the EV, and also allows light based sorting and isolation of EV, as well as quantification of target molecule quantities.
Applicant's arguments have been fully considered but they are not persuasive.
In response to Applicant’s first arguments , the terms "comprising" and “having” are open-ended and allow for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). Applicant fails to specifically exclude the elements of FKBP12/FRB and rapamycin in either the claims or the specification.
In response to Applicant's second arguments, 37 CFR § 1.111(b) states, "A general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references does not comply with the requirements of this section." Applicant has failed to specifically point out how the language of the claims patentably distinguishes them from the references. In other words, Hotta makes clear it was already known that VSV-G can mediated the fusion of EV, and that split systems such as the FKBP12/FRB system allow the loading of target molecules in EV, while related split systems of Waldo such as FKBP12-GFP/GFP-FRB allow the real-time visualization of FKBP12/FRB binding, and that the p6Gag peptide of Nordin improves cargo delivery and trafficking of the EVs. In regard to the possible intended uses of the split GFP system for isolation and/or quantification of the EVs, the rejected claims do not require any quantitative amount of EVs or certain amount of cargo therein. Furthermore, instant claims encompass a genus of split system that “emit a detectably signal” but have no described nor art recognized ability to be used quantitatively. Similarly, the breadth of independent Claim 51 does not even require a VSV-G based “gectosome”, which has been argued by Applicant as being required for inventive features 1, 4-5, and 7 (pgs. 10-11 of Applicant’s arguments).
Furthermore, in response to Applicant's arguments, a 35 U.S.C. § 103(a) based 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). In instant case, Hotta teaches the vesicles comprise membrane bound VSV-G fused to FKBP12, and FRB fused to the target molecule Cas9, while Waldo teaches a split GFP system comprising FKBP12-GFP11 and GFP10-FRB that would have been predictably obvious to include in the vesicles of Hotta in order to conduct in vivo real-time fluorescent visualization of FKBP12 binding to FRB in subcellular structures.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Doug Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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