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 .
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on October 16, 2025.
Currently, claims 26-28, 30-51, and 53-55 are pending and under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 112
Claims 26-28, 30-51, and 53-55 remain rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement for the reasons as set forth in the Office action mailed on April 16, 2025 and for the reasons set forth below.
Applicant's arguments filed on October 16, 2025 have been fully considered but they are not persuasive. Applicant argues the claims as currently amended comply with the written description requirement because the cited prior art references of record in the last Office action pertain to intravascular hydrodynamic injections, whereas the instant claims as amended recite liver-specific delivery without involving intravascular injection. In response, it is noted that whether or not the cited references in the last Office action used intravascular delivery to the liver is irrelevant to show that the instant specification itself describes the instantly claimed genus, which now broadly encompasses the polynucleotide in any form - with or without any type of vector/delivery vehicle - as evidenced by the recitation of “independent of any delivery vehicle”. That is, “it is the specification itself that must demonstrate possession” of the claimed genus as of the filing date sought in the instant application. See Ariad Pharmaceuticals Inc. v. Eli Lilly & Co. 593 F3d 1336, 94 USPQ2d 1161 (Fed. Cir. 2010).
Now, note that the instant claims do require that the delivery of the polynucleotide in any form should provide at least 60 days of gene product expression in the hepatocytes as evidenced by the limitation “wherein the delivery [of the polynucleotide] yields expression of the gene product in the hepatocytes for at least 60 days.” It is noted that the non-vascular hydrodynamic DNA delivery into the liver is not new but was performed by relevant artisans as evidenced by Sendra et al. (PLOS ONE, 2016, 11(10):e016898, of record), who teach a “closed surgical procedure” or “complete” vasculature closure procedure comprising “vascular inflow and outflow perfusion occlusion”, wherein all liver vasculature (inferior vena cava, portal vein, and hepatic artery) is clamped “to secure total hepatic vascular exclusion”, wherein a solution containing the hAAT plasmid (20 mg/ml) is retrogradely injected by inserting the perfusion cannula onto the anterior surface of the cava vein, wherein the basal pressure is about 61-87 mmHg, wherein the hAAT is effectively expressed in the liver tissue on day 7 after the procedure. See pages 4-7; Figures 1B, 4A. The liver expression of the plasmid DNA of Sendra, however, is not tested or demonstrated to last up to at least 60 days as required by the instant claims. Furthermore, the non-vasculature hydrodynamic DNA delivery into hepatocytes of a subject is also practiced by relevant artisans after the filing date as evidenced by Chan et al. (Molecular Therapy: Methods & Clinical Development, 2022, 24:268-279), who also do not show the hepatocyte expression lasting up to at least 60 days as they tested only up to 10 days in swine liver using a “nanovector platform” comprising a liver-specific P3 promoter, wherein the protein expression (luciferase) of the transgene “dropped” over the 10-day period. See pages 274-275. As such, it is clear from both the prior art and post-filing art references that the instantly claimed method with all of its limitations was not known in the relevant art.
For achieving at least 60-day duration of the polynucleotide product (e.g., protein) expression in hepatocytes by performing the method steps claimed in the instant case, the instant specification describes use of a sleeping beauty expression system that aids long-lasting expression of the polynucleotide, which is not sufficient to adequately and sufficiently support the instantly claimed genus that broadly claims the polynucleotide in any form, especially in view of applicant’s asserted nascent level of the relevant technology pertaining to the claimed subject matter, which is thus allegedly novel. Note that the specificity of the disclosure is inversely correlated with the state of the prior art and the level of knowledge/predictability in the prior art. See MPEP §2163. The instant inventors’ purposeful use of the sleeping beauty expression system for achieving “stable gene expression in target liver of swine” such that the gene expression persisted at least up to day 60 after the procedure as expressly disclosed in the instant specification is not representative or descriptive of the entire genus of the unspecified polynucleotide structure that is “independent of any delivery vehicle”. See page 32 of the instant specification for the following disclosure: “For the purposes of stable gene expression in target liver of swine, the inventors chose target plasmids combined with Sleeping Beauty-mediated somatic integration.” (emphasis added). As such, it remains unknown and undisclosed whether the hepatocytes of the swine would express the gene product (e.g., protein) of the delivered polynucleotide in the absence of the sleeping beauty expression system as broadly encompassed by the instant claims. It is found that the specification also discloses use of an expression cassette comprising “a liver-specific promoter” “to enhance expression”, wherein the expression cassette is mixed with “hyperPB transposase” (“Hyperactive piggyBac transposase”) for “affording stable production” of the expression cassette in hepatocytes of the swine, wherein the expression duration up to at least 60 days was not assessed but only the blood was collected on “Day 4 post procedure.” (emphasis added). See pages 39-40. Interestingly, it is noted that a post-filing reference, Kruse et al. (Gastrointestinal Endoscopy, 2021, applicant’s citation) submitted by applicant on October 16, 2025, appears to disclose a more complete description of the incomplete, curtailed disclosure pertaining to the experiments disclosed at pages 39-40 of the instant specification, wherein the post-filing reference at best teaches the target expression in liver lobes at 3 weeks, not 60 days as claimed in the instant case, after the ERCP-hydrodynamic delivery procedure. In fact, the post-filing reference expressly teaches it needs to be experimentally determined as to whether or not an expression cassette comprising the liver-specific promoter and the concurrent use of the hyperPB transposase provide a long-term expression. See pages 1125-1126 for the following: “Of note, a similar hyperactive piggyBac transposon experiment in mice showed stable hFIX expression for 1 year. Although there is reason to hypothesize that the expression in pigs could be observed at similarly long time points, a future sturdy is needed to obtain experimental proof.” (emphasis added). As such, the instantly claimed method with all of its recited limitations was far from well known or predictable as of the filing date sought in the instant application and therefore, the use of the “transposon plasmid pCMV-SB” to achieve at least the 60-day expression duration in the swine liver is not predictive/representative of the methods as generically claimed in the instant case.
In view of the foregoing, the instant specification fails to reasonably convey that the instant co-inventors had possession of the entire genus as now claimed as of the filing date sought in the instant application.
Claims 26-28, 30-51, and 53-55 remain rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement for the reasons as set forth in the Office action mailed on April 16, 2025 and for the reasons set forth below.
Applicant's arguments filed on October 16, 2025 have been fully considered but they are not persuasive. Applicant argues that the claims as amended are fully enabled as corroborated by Figures 31-32 of WO 2024/050039. It is noted that applicant did not submit a legible copy of the WO document for examiner’s consideration, nor is the document cited in any of the prior-filed IDS. For completeness of the record, the examiner cites the WO document in the attached PTO-892 (no copy attached). It is noted that the ‘039 WO document’s Figures 31-32 showing at least 60 days of expression in the swine liver pertain to the use of a “nanoplasmid”, which “was hypothesized to mediate long-term expression in liver compared to a regular plasmid” (emphasis added; see page 42) and the use of the “piggyBac transposon system” comprising “15 mg transposon and 5 mg transposase”, which “is maintained long-term in pigs” so much so that the inventor of the WO document concludes that “transposons can mediate stable expression over time” (emphasis added; see page 43). Interestingly, the post-filing WO document discloses that the “nanoplasmid” used in Figure 31 is a “novel DNA vector platform” comprising a “liver-specific promoter, LP1.” (emphasis added). See pages 42 and 169. Even more interestingly, the WO document discloses that the nanoplasmid “can greatly increase the observed transfection efficiency from biliary hydrodynamic injection, when combined with the other optimized procedural methods and promoter. This result is both surprising and unexpected since a recent study with the nanoplasmid and biliary hydrodynamic injection found that the plasmid could not yield any immunohistochemical staining.” (emphasis added). See page 168. Hence, the post-filing reference pointed out by applicant as allegedly corroborating the data and teachings in the application as originally filed is not practiced in accordance with the instant specification’s disclosure as evidenced by the fact that the WO document utilized the “novel” nanoplasmid comprising the LP1 promoter that is not disclosed in the instant specification and also used the transposon (15 mg) and transposase (5 mg) in the amounts that drastically differ from the amounts (e.g., 0.4 mg or 0.6 mg hyperBP transposase) disclosed in the instant specification. Hence, there is nothing in the WO document, in particular the data in Figures 31-32 pointed out by applicant, that practiced the teachings provided in the instant specification thus cannot corroborate that the instant specification fully enables the entire scope of the claims. Moreover, the fact that the post-filing WO document discloses the data as “both surprising and unexpected” clearly underscores the lack of predictability pertaining to the claimed subject matter, thereby supporting the examiner’s position as set forth in the last Office action. Furthermore, the purposeful use of various, required elements (e.g., liver-specific promoter, nanoplasmid, transposase) to enhance liver-specific delivery and prolonged liver expression as disclosed in the post-filing WO document does suggest that only a specifically designed polynucleotide, not the entire scope of any polynucleotide in any delivery vehicle, can be expressed at least up to 60 days in hepatocytes when delivered by the methodology claimed in the instant case.
Accordingly, this rejection is maintained.
Double Patenting
Claims 26-28, 30-51, and 53-55 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16, 18, 20-21, and 43 of copending Application No. 18/284,040 for the reasons as set forth in the Office action mailed on April 16, 2025 and for the reasons set forth below.
Applicant's arguments filed on October 16, 2025 have been fully considered but they are not persuasive. Applicant argues that the ‘040 claims have not been examined. In response, it is noted that the examination status in the ‘040 reference application is not a factor in establishing a provisional nonstatutory double patenting. It is noted that the ‘040 claims are drawn to a method that delivers a nucleic acid solution via a catheter that is advanced into the small intestine/stomach then into the common hepatic duct, wherein the nucleic acid is administered within the liver of a subject, wherein the nucleic acid claimed in the ‘040 claims is not specified to be naked or in a specific delivery carrier thus is structurally indistinguishable from the nucleic acid that is “independent of any delivery vehicle” as claimed in the instant case. Since applicant did not point out how the instant claims and the ‘040 claims do not overlap in scope thus the two conflicting claims are patentably distinct from each other, this rejection is maintained.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 27, 35, 41-44, and 46 are 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 27 and 42 recite the limitation "the delivering" in line 1. There is insufficient antecedent basis for this limitation in the claims.
Claims 35 and 41 recite the limitation "administering" in line 1. There is insufficient antecedent basis for this limitation in the claims.
Claims 43-44 recite “prior to administering the composition.” Since claim 26 does not recite “administering” as currently amended, the time point pertaining to “prior to administering” cannot be ascertained.
Claim 46 recites “after administering the composition.” Since claim 26 does not recite “administering” as currently amended, the time point pertaining to “after administering” cannot be ascertained.
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635