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 .
Applicants' arguments, filed December 23, 2025, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112 – Indefiniteness
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.
Claims 89 – 91 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. Each of claims 89 and 90 depends from now cancelled claim 88. Claim 91 depends from claim 88 via claim 90. Therefore the complete set of limitations for each of these claims cannot be determined.
Please clarify.
In the interest of compact prosecution, given that now cancelled claim 88 was a duplicate of claim 22, for the purposes of applying art below, claims 89 and 90 are being interpreted as depending from claim 22.
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, 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 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.
Claim(s) 1, 8, 15, 39, 86, 87 and 92 were rejected under 35 U.S.C. 103 as being unpatentable over Xiong et al. (US 2014/0127287) in view of Monshipouri et al. (US 5,626,870), Nograles et al. (J Biosci Bioeng, 2012), Yin et al. (WO 2015/191693) and Guo et al. (Theranostics, 2016). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed September 26, 2025 and those set forth herein.
Independent claim 1 and new claim 92 contain new claim language regarding higher polynucleotide encapsulation when a hydrogel is encapsulated within the liposome compared to a liposome without such a hydrogel (claim 1) and that at least 20% more polynucleotide is encapsulated (claim 92). "A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim." Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1172 (Fed. Cir. 1993; MPEP 2111.04). The higher polynucleotide encapsulation in the wherein clauses necessarily flows from the presence of the hydrogel within the liposome. Xiong et al. discloses high drug loading and sustained release achieved with liposome-encapsulated hydrogels (lipogels) and that interactions between the hydrogel polymer and drug molecules increase drug loading (¶ [0009]). Figure 1 compared the in vitro release of 17-DMAPG (17-dimethylaminopropylamino-17-demethoxy-geldanamycin, a weakly basic drug, ¶ 0029]) from a bulk hydrogel, liposome and lipogel so each material was loaded with 17-DMAPG. ¶ [0070] indicates about 60% loading of 17-DMAPG into a bulk hydrogel, with the liposomes showing a relatively low loading efficiency of about 15% (¶ 0072]). The lipogel which encapsulates the hydrogel inside the liposome showed quantitative loading (100%) of the 17-DMAPG (¶ 0074]). There is no evidence of record as to unexpected results arising from the claimed composition such that the enhanced encapsulation observed is greater than would be expected given the presence of a liposome around a hydrogel as is present in a lipogel particle.
Applicants traverse this rejection on the grounds that one of ordinary skill in the art would not have predicted or recognized the higher loading efficiency based on the applied prior art. The numbers in Xiong et al. are attributed to the unique properties of 17-DMAPG that changes charge based on the acrylic acid hydrogel to form stable ion pairs. This would lead one of ordinary skill to not predict that the higher encapsulation of polynucleotides in non-cationic lipogels compared to liposomes without the hydrogel. Polynucleotides are acidic and would not form a stable ion-pair with carboxylic acid side chains and enhanced loading. Monshipouri’s disclosure would not have made the encapsulation any more predictable since Xiong’s explanation only applied to a select group of drugs that does not include polynucleotides. Monshipouri does not load any drug molecules despite disclosing that many types of drug types can be loaded into a lipogel. The skilled person would have no reason to predict higher polynucleotide encapsulation when a hydrogel is present. Microspheres like those in Nograles were known in the art to have different loading properties than the claimed nanoparticles. The Kohane reference is provided which states that the access of a drug dispersed in a smaller particle to the external aqueous phase is greater as particles get smaller, which can lead to substantial loss of payload or lower maximal drug loading than for larger particles. The size difference between Nograles of 30 – 40 microns and the claimed nanoparticles would have a substantial effect on the drug loading, predicting the claimed nanoparticles would have a lower maximal drug loading. Nograles does not provide the skilled artisan with a reason to predict the higher encapsulation as recited in the claims. Yin does not load any drug molecules into a non-cationic liposome much less one encapsulating a hydrogel and does not provide the skilled person with a reason to predict the higher encapsulation as recited in the claims. Guo does not load any drug molecules into a nanoparticle lipogel and does not provide the skilled person with a reason to predict the higher encapsulation as recited in the claims. The combination of reference cannot render predictable the claimed nanoparticle with higher encapsulation.
These arguments are unpersuasive. Prior art is relevant for all that is taught and while the examples of Xiong et al. use the model drug 17-DMAPG which is not the same as polynucleotides, there are also broader teachings as to the agents that can loaded and the type of interactions that can occur between the hydrogel and drug molecules. That a reference does not, for example, explicitly load any drug molecules is insufficient to patentably distinguish the instant claims over the prior art when the knowledge of one of ordinary skill in the art and the explicit, implicit and inherent teachings of the applied prior art are considered. The relevant question for obviousness is would one of ordinary skill in the art before the effective filing date of the claimed invention been motivated to prepare non-cationic lipogels as in Xiong et al. with alginate as the hydrogel material and polynucleotides such as that encoding a Cas9 protein and a guide RNA in that lipogel. Nograles loads such polynucleotides into an alginate hydrogel and Monshipouri et al. discloses that alginate can be used as the hydrogel portion of the lipogels. Thus one of ordinary skill in the art would reasonably expect that non-cationic liposomes as in Xiong et al. encapsulating an alginate hydrogel loaded with polynucleotides could be prepared. Explicit appreciation of the enhanced polynucleotide loading for the lipogel compared to the liposome only is not required to render the claims obvious. The discussion in the Remarks as to the effect of particle size from one sentence in Kohane on loadings ignores the fact that the claim language does not relate to particle size, absolute encapsulation efficiency, payload amount or maximal drug loading. The compared conditions in the claim are the presence and absence of the hydrogel inside the liposome and the relative effect (e.g., increased or decreased) on polynucleotide encapsulation. The cited portions of Kohane postulates that the greater access to the external aqueous phase leading to substantial payload loss or lower maximal possible loss of payload. The hydrogel portion of lipogels as in Xiong et al. is not directly exposed to the external environment because of the liposome which encapsulates the hydrogel portion of the lipogel even if one of the parameters mentioned by Kohane were recited in the claims. While hybrid/composite systems are mentioned on p 208, col 1, ¶ 4 of Kohane et al., there is no discussion as to how such hybrid/composite systems might alter these parameters. A person ordinary skill in the art need not have an expectation of enhanced loading to render obvious the claimed particles when it would have been otherwise obvious to prepare non-cationic lipogels comprising an alginate hydrogel loaded with the specific polynucleotides claimed. “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). Unexpected results must outweigh prima facie case of obviousness and the evidence of record in support of the alleged unexpected results does not outweigh the prima facie case of obviousness.
Applicants also argue that while they do not concede that the combined references would provide a skilled person with a reason to predict the enhanced encapsulation, the skilled person would not have predicted that the resultant nanoparticles could achieve over 80% encapsulation efficiency. The encapsulation efficiency from Table 1 of applied Guo reference is 42 – 47.1%, which is well below what was achieved by the instantly claimed nanoparticles. The other cited references do not make this any less expected. Plain liposomes in Xiong only achieved 10% loading of a cationic drug and attributes this to ionic interactions. The same information from Nograles, Monshipouri and Yin as referenced above are reiterated in this section. No additional arguments regarding the dependent claims are set forth as each claim is believed to be patentable as depending from a base claim that is in condition for allowance.
These arguments are unpersuasive. The instant claims contain no limitations on the encapsulation efficiency other than the relative limitation of encapsulation amount in the presence and absence of the hydrogel portion. Applicants cite data for completely different systems and provides no explanation as to why the same results would be expected for all of these systems obtained from different labs and at different time points that could also affect the results. The Examiner once again inserts this table from previous Office Actions.
Instant Application
Guo et al.
Yin et al.
Delivery system
85:5:10 DOPC:DODAP:DSPE-PEG-COOH liposome encapsulating alginate hydrogel with ICAM1 antibody conjugated to surface (no seq. given)
85:5:10 DOPC:DODAP:DSPE-PEG-COOH liposome with no hydrogel and with ICAM1 antibody conjugated to surface (no seq. given)
Nanoparticles of 50:20:10:10 C12-200, cholesterol, C14-PEG and DSPC (¶ [00130])
Gene editing system
CRISPR Cas9 with gRNA (no seq given)
Lcn2 siRNA (no seq given)
Cas9 mRNA chemically modified to reduce TLR response (no seq given)
Targeted protein
Lcn2
Lcn2
GFP (green fluorescent protein)
Cell line
MDA-MB-231, MDA-MB-436 and MDA-MB-157
MDA-MB-231
HEK293T reporter cell line stably expressing GFP (¶ [00135])
Efficiency
60-98%
78.3 ± 1.7%
77.1 ± 2.6%
The additional arguments do not result in persuasive evidence of record as to unexpected results that outweigh the prima facie case of obviousness and the independent claim is not patentably distinguished over the applied prior art.
Claim(s) 22 and 89 – 91 were rejected under 35 U.S.C. 103 as being unpatentable over Xiong et al., Monshipouri et al., Nograles et al. and Yin et al. further in view of Gunawan et al. (Biomaterials, 2011). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed September 26, 2025 and those set forth herein.
Applicants do not mention Gunawan et al. at all so there are no arguments regarding this reference for the Examiner to address herein.
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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8, 15, 22, 39, 86, 87 and 89 – 92 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 15 of U.S. Patent No. 11,260,132 in view of Xiong et al. (US 2014/0127287), Monshipouri et al. (US 5,626,870), Nograles et al. (J Biosci Bioeng, 2012), Yin et al. (WO 2015/191693) and Guo et al. (Theranostics, 2016). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed September 26, 2025 and those set forth herein.
PASTE STUFF ABOUT LOADING HERE
Applicants reference the arguments set forth above regarding Xiong et al., Monshipouri et al, Nograles et al., Yin et al. and Guo et al. which are not persuasive as discussed above.
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 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 Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618