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 11/17/2025, Applicant has amended Claims 1, 5-8, 43, and 44, and cancelled Claim 45.
Claims 30-41 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-3, 5-8 and 42-44 are under consideration.
Priority
The instant application was filed 11/30/2020 and is a national stage entry of PCT/EP2019/064236 filed 5/31/2019 and claims foreign priority to EPO application EP18175634.7 filed 6/01/2018.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. EP18175634.7, 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 EP18175634.7 did not reveal support for a nucleic acid encoding a fusion protein between a RNA binding domain of a bacteriophage coat protein and a protein binding domain for an origin of replication. While cited priority document does disclose a “cas9-Rep fusion”, which supports a fusion protein between an endonuclease and a binding domain for an origin of replication (see also priority Claim 5 and Fig. 5c), and discloses an “exo1-MS2 fusion protein”, which supports a fusion protein between an exonuclease and a RNA binding domain of a bacteriophage coat protein (see also priority Claims 1, 2, and 14, and Fig. 6), there is no explicit, implicit nor inherent support for a between a RNA binding domain of a bacteriophage coat protein and a protein binding domain for an origin of replication (e.g,. Rep-MS2 fusion protein). Thus the instant claims are being given the filing date of 5/31/2019, wherein this claimed fusion protein (i.e., Rep-MS2 fusion protein) is recited once as an alternative embodiment on p. 9, section (iii) of the specification.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 11/17/2025 are acknowledged.
Applicant argues that the EP patent application provides support for a single fusion protein comprising (i) a RNA binding domain of a bacteriophage coat protein and (ii) a binding domain for an origin of replication (p. 12-13 of Remarks).
Applicant's arguments have been fully considered but they are not persuasive.
Priority is analyzed on a claim-by-claim basis. If a limitation added later is not supported, the entire claim loses priority. In instant case, although the claims have foreign priority for a fusion protein comprising (i) an endonuclease domain and (ii) a binding domain for an origin of replication, they do not appear to have support for the fusion protein comprising (i) a RNA binding domain of a bacteriophage coat protein and (ii) a binding domain for an origin of replication. No where in Applicant’s remarks was this fusion protein annotated, and nowhere in the foreign priority application does there appear explicit, implicit nor inherent support for said fusion protein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/09/2025 were filed after the mailing date of the non-final Office action on 7/15/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Withdrawn 35 USC § 112(b)
The prior rejection of Claims 43 and 44 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 describe the nucleic acid compositions.
Withdrawn 35 USC § 102
The prior rejection of Claims 1-3 and 5-8 under 35 U.S.C. 102(a)(1) as being anticipated by Konermann (US Patent 10,550,372, filed 6/10/2016) is withdrawn in light of Applicant’s amendment of Claim 1 to limit the nucleic acid to encoding a fusion protein comprising either a) a fusion protein between (i) a RNA binding domain of a bacteriophage coat protein and (ii) a binding domain for an origin of replication, or b) a fusion protein between (i) an endonuclease domain and (ii) a binding domain for an origin of replication, which is are limitations Konermann does not teach.
The prior rejection of Claims 1-3, 5, 7-8 and 42 under 35 U.S.C. 102(a)(1) as being anticipated by Konermann (Nature, 2015, 517:583-588), as evidenced by Addgene (Plasmid #61423, “MS2-P65-HSF_GFP”, available 2014) is withdrawn in light of Applicant’s amendment of Claim 1 to limit the nucleic acid to encoding a fusion protein comprising either a) a fusion protein between (i) a RNA binding domain of a bacteriophage coat protein and (ii) a binding domain for an origin of replication, or b) a fusion protein between (i) an endonuclease domain and (ii) a binding domain for an origin of replication, which is are limitations Konermann does not teach.
The prior rejection of Claims 1-3, 5, 7-8 under 35 U.S.C. 102(a)(1) as being anticipated by Joung (WO2014/152432, filed 3/14/2014, published 9/25/2014) is withdrawn in light of Applicant’s amendment of Claim 1 to limit the nucleic acid to encoding a fusion protein comprising either a) a fusion protein between (i) a RNA binding domain of a bacteriophage coat protein and (ii) a binding domain for an origin of replication, or b) a fusion protein between (i) an endonuclease domain and (ii) a binding domain for an origin of replication, which is are limitations Joung does not teach.
Withdrawn 35 USC § 103
The prior rejection of Claims 1-3, 5-8 and 42-44 under 35 U.S.C. 103 as being unpatentable over Aharoni (US2019/0048330, filed 8/22/2018, published 2/14/2019, which is a CIP of PCT/IL2017/051020, filed 9/11/2017), in view of Joung et al. (WO2016/054326, see IDS filed 6/02/2022) is withdrawn in light of Applicant’s amendment of Claim 1 to require the functional limitation that the fusion protein is for the replication of a nucleic acid comprising an origin of replication, which is a limitation neither Aharoni nor Joung teach for the BeYDV based Rep-MS2 fusion protein.
New Claim Rejections - 35 USC § 103
as necessitated by amendment
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.
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.
Claims 1-2, 6-8, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Gordon et al (WO2018/231999, filed 6/13/2018, with priority to US 62/518,960 filed 6/13/2017, see IDS filed 6/02/2022), in view of Harrach et al. (GenBank AY256460, deposited 3/14/2003) and Steinfeldt et al. (J Virol, 2007, 81, 5696-5704)
[AltContent: textbox ([img-media_image1.png])]In regard to claim 1, Gordon teaches a fusion protein comprising (i) a Cas9 endonuclease and (ii) a Rep protein for an origin of replication derived from PCV2 (Example 1, see excerpt from Fig. 3A).
However, in regard to a nucleic acid encoding a PCV2 fusion protein as per claim 1, although Gordon established that the nucleic acids that encode Cas9 nucleases were well-known (p. 14, 1st para., p. 16, 1st para., p. 21, Methods, 1st para., see also pgs. 10, 13, 15 of priority document), they are silent to a nucleic acid encoding the PCV2 Rep protein.
Nevertheless, the nucleic acid that encodes for the PCV2 Rep protein was known and had been deposited as GenBank AY256460 by Harrach et al. in 2003.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to prepare a Cas9-PCV2 fusion protein as taught by Gordon and choose the nucleic acid for doing so as taught by Harrach with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
However, in regard to the functional language directed to the ability of a Cas9-PCV2 being able to replicate a nucleic acid with an Ori as per claim 1, Gordon et al. are silent to this function. Nevertheless, Steinfeld teaches several PCV fusion proteins including GST, HIS, and Flag tagged versions of PCV1. Steinfeld evidences that the PCV1 fusion proteins are fully capable of replicating a nulceic acid comprising an Ori (see Fig. 5-7). Importantly, Steinfeld teaches that the 1,759 nt sequence of PCV1 is highly similar to the 1,768 nt sequence for PCV2, and evidences that the functional studies of PCV1 are corroborated by the functional studies of PCV2, thereby establishing a reasonable expectation of success that the nucleic acid encoding Cas9-PCV2 fusion protein as suggested by Gordon et al. would produce a fusion protein capable of replicating a nucleic acid with an Ori. It is noted that the use of a product for a particular purpose is not afforded patentable weight in a product claim where the body of the claim does not depend on the preamble for completeness but, instead, the structural limitations are able to stand alone. The MPEP states that,”.. in apparatus, article, and composition claims, intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art.” In re Casey, 152 USPQ 235 (CCPA 1967); In re Otto , 136 USPQ 458, 459 (CCPA 1963)(MPEP 2111.02).
In regard to claim 2, Steinfeldt evidences PCV2 Rep protein is a component of the replication initiation complex.
In regard to claims 6-8, as stated supra, Gordon teaches the endonuclease is Cas9, and demonstrates the Cas9-PCV fusion protein induced double stranded breaks in a target nucleic acid in a sequence specific manner (Example 1, Results).
In regard to claim 42, Steinfeldt teaches the PCV2 Rep protein is derived from porcine circovirus type 2, and the target sequence is a viral origin of replication.
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 11/17/2025 are acknowledged and have been addressed above.
Claims 3, 5, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Gordon et al (WO2018/231999, filed 6/13/2018, with priority to US 62/518,960 filed 6/13/2017, see IDS filed 6/02/2022), in view of Harrach et al. (GenBank AY256460, deposited 3/14/2003) and Steinfeldt et al. (J Virol, 2007, 81, 5696-5704), as applied to claim 1, in further view of Joung et al. (WO2016/054326, see IDS filed 6/02/2022) and Konermann (US Patent 10,550,372, filed 6/10/2016, prior art of record)
As stated supra, Gordon et al. suggest a nucleic acid encoding a fusion protein comprising (i) a Cas9 endonuclease and (ii) a PCV2 protein for binding of a DNA donor molecule to enhance HDR.
However, Gordon is silent to a nucleic acid that encodes a fusion protein comprising (i) a RNA binding MS2 bacteriophage coat protein and (ii) the PCV2 Rep protein that binds the DNA donor.
In regard to claim 3, Joung teaches a fusion protein comprising (i) a RNA binding domain that binds the Cas9 gRNA and (ii) a DNA binding domain (DBD) protein that binds and recruits a DNA donor molecule (p. 10, 2nd para.). Specifically, Joung teaches the RNA binding domain is MS2 (p. 10, 3rd para., see also p. 4, 3rd para., and p. 17, last para.).
[AltContent: textbox ([img-media_image2.png])]Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to prepare the nucleic acid encoding the fusion protein comprising (i) Cas9 and (ii) the PCV2 Rep protein that binds and recruits the DNA donor as suggested by Gordon et al. and substitute the (i) Cas9 with (i) a RNA binding MS2 bacteriophage coat protein that binds the gRNA of Cas9 as taught by Joung with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Joung because fusing the MS2 guide RNA binding domain to the PCV2 that binds the donor molecule increases HDR by increasing the local concentration of donor molecules near the site of the Cas9 nuclease-induced double strand break (p. 8, 2nd para., p. 17, last para, see also Fig. 1c and see modified Fig. 3d, adjacent).
[AltContent: textbox ([img-media_image3.png])]Furthermore, as alluded to by Joung (Fig. 3e), the gRNA can be engineered to bind multiple MS2 fusion proteins, which was well known in the prior art (see Fig. 44 and modified Fig. 48 of Konerman, adjacent), and an obvious extension of the teachings of Joung so as to increasing the local concentration of DNA molecules for HR by twice as much.
In regard to claim 5, as stated supra, both Gordon and Joung teach that the composition should further include a nucleic acid encoding the Cas9 nuclease, and the MS2-PVC2 fusion suggested by Gordon and Joung would require several nucleic acids encoding Cas9.
In regard to claim 44, Joung teaches the nucleic acid composition comprising a nucleic acid encoding the HDR-related protein EXO1 (p. 4, 4th para., p. 15, 1st para. see Claim 21 of Joung)
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to prepare the nucleic acid as suggested by Gordon et al. and combine the EXO1 sequence as taught by Joung with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Joung because EXO1 increases HDR (p. 15, 1st para.).
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 11/17/2025 are acknowledged.
Applicant argues that Joung alone does not teach or suggest a fusion protein comprising Rep protein and a MS2 binding domain.
Applicant's arguments have been fully considered but they are not persuasive.
In response to Applicant's argument, 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, Gordon et al. suggest a nucleic acid encoding the Cas9 fusion with PCV2 to bind and recruit DNA for homologous recombination, while Juong et al. make obvious to substitute the Cas9 for MS2 binding domains for gRNA so as to be able to recruit even more DNA to the Cas9 complex for homologous recombination.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Gordon et al (WO2018/231999, filed 6/13/2018, with priority to US 62/518,960 filed 6/13/2017, see IDS filed 6/02/2022), in view of Harrach et al. (GenBank AY256460, deposited 3/14/2003) and Steinfeldt et al. (J Virol, 2007, 81, 5696-5704), as applied to claim 1, in further view of Aharoni (US2019/0048330, filed 8/22/2018, published 2/14/2019, which is a CIP of PCT/IL2017/051020, filed 9/11/2017)
As stated supra, Gordon et al. suggest a nucleic acid encoding a fusion protein comprising (i) a Cas9 endonuclease and (ii) a PCV2 protein for binding of a DNA molecule to enhance HDR.
In regard to claim 43, although Gordon teaches the nucleic acids may be incorporated into vectors, and a “vector” is a replicon, they are silent to expressing the Cas9 fusion in a bean yellow dwarf virus (BeYDV) replicon system.
In regard to claim 43, Aharoni teaches a BeYDV replicon comprising a replicative double-stranded donor DNA encoding Cas9 flanked by viral origins of replication (i.e., geminiviral intergenic regions) ([0026-0028, 0052-0054] Figs. 5-7, see also Figs. 4-6 of PCT document). Note that Applicant’s specification does not provide a definition for “donor vector”.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to prepare nucleic acids encoding the Cas9-PCV2 fusion protein and gRNA system in a replicon vector as suggested by Gordon and choose the BeYDV replicon for the Cas9/gRNA expression as taught by Aharoni with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because Aharoni because the BeYDV replicon system generated high levels of Cas9 and gRNA copies ([0253], see also [0195] of PCT document).
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 11/17/2025 are acknowledged.
Applicant argues that Aharoni is not prior art because its earliest effective filing date in 8/22/2018, which is after the foreign priority date of present Application of 6/01/2018.
Applicant's arguments have been fully considered but they are not persuasive.
As state supra, Applicant’s foreign priority document does not support a fusion protein comprising (i) a RNA binding domain of a bacteriophage coat protein and (ii) a binding domain for an origin of replication (e.g., MS2-Rep fusion protein), and as priority is analyzed for the entire claim, the entire claim loses priority if a single limitation is unsupported.
Furthermore, even if Applicant was able to demonstrate foreign priority to 6/01/2018, the effective filing date of Aharoni extends to its PCT document filed 9/11/2017, and supports the Cas9 BeYDV replicon constructs disclosed in the CIP. Specifically, Aharoni’s PCT document conducts identical and/or similar experiments overexpressing Cas9 with BeYDV replicon system.
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1-3, 5-8 and 44 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-8 of copending Application No. 18/665,659. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the nucleic acid composition of cited application anticipates the nucleic composition of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that the cited application claims are much more specific with respect to the 5’ to 3’ DNA exonuclease being part of a fusion protein. Thus the invention of said claims of the cited application are in effect “species” of the “generic” invention of the instant claim. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Since the instant application claims are anticipated over cited application claims, said claims are not patentably distinct.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 11/17/2025 are acknowledged, and ask that the provisional double patenting rejection be held in abeyance.
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
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/ARTHUR S LEONARD/Examiner, Art Unit 1631