DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 143-156 are pending.
Claim 150 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions.
Claims 143-149 and 151-156 are examined on the merits with species, (antifolate): j. pemetrexed; and (targeting moiety): a. folate receptor alpha.
3. Applicants are put on notice that claims should note proper status identifiers. For instance, claim 150 should cite (withdrawn) instead of (previously presented), see page 3 of the Listing of the Claims submitted November 4, 2025.
Applicant should carefully review all claims and ensure the corresponding status identifier properly reflects the listing of the claim. Improper status identifiers or no status identifiers may result in the receipt of a Notice of Non-Compliant Amendment (37 CFR 1.121), see MPEP 714 for
further explanation of the amendment format.
4. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 102
5. The rejection of claim(s) 143-147, 151 and 154 under 35 U.S.C. 102(a)(2) as being anticipated by Lin et al., US 2014/0234210 A1 (effectively filed July 9, 2012) is withdrawn in light of Applicant’s arguments presented on pages 4 and 5 of the Remarks submitted November 4, 2025.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
6. 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.
7. The rejection of claim(s) 143-149 and 151-156 under 35 U.S.C. 103 as being unpatentable over Lin et al., US 2014/0234210 A1 (effectively filed July 9, 2012), and further in view of Shi et al., US 2013/0315831 A1 (published November 28, 2013) and Chang et al., US 2014/0120157 A1 (effective filing date September 18, 2013/ IDS reference US11 on sheet 1 submitted November 19, 2024) is maintained.
Initially, Applicant sets forth the tenets of establishing a proper prima facie case of obviousness, see Remarks submitted October 4, 2025, pages 5 and 6.
Applicant argues “…primary reference[,] Lin fails to teach the claimed liposomal composition comprising a liposome that has a zeta potential in the range of -1 to -50 mV. Lin is directed to metal-bisphosphonate nanoparticles” and “speculates that “[t]he nano particles can be coated with organic or inorganic polymers, single lipid layers, and/or lipid bilayers, and/or incorporated into liposomes.”, see page 6, 2nd paragraph (para.).
Applicant continues arguments stating the secondary references, “do not disclose each of the elements of the claimed invention, and this rejection should be withdrawn.”, see page 7, last sentence in 1st para.
In particular, Applicant argues “[a] person skilled in the art would be discouraged from combining Shi’s teachings with a goal of forming a liposomal composition, as the reference guides the art away from liposome structures.”, see page 6, 3rd para.
Applicant further argues, “Chang is purposefully and specifically limited to cationic liposome-based drug delivery—i.e., liposomes that have a zeta potential greater than zero. Chang refers to "cationic liposomes" more than 200 times but never mentions an anionic liposome. [see], Chang, Abstract and entire document. The Patent Office's failure to address this fundamental distinction between cationic liposomes (taught by Chang) and anionic liposomes (claimed by Applicant) constitutes an improper construction of Chang's relevance. As held in In re Wesslau, 353 F.2d 238, 241 (CCPA 1965), it is "impermissible within the framework of section 103 to pick and choose from any one reference only so much of it as will support a given position, to the exclusion of other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art." Chang's entire thrust suggests forming a cationic particle, and discourages a person skilled in the art from preparing the claimed anionic liposome.”, see bridging paragraph of pages 6 and 7.
Applicant’s arguments and assertions have been carefully considered, but fail to persuade.
Applicant’s claims read on open-ended language, comprising “…and does not exclude additional 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).” And while Lin teaches a metal-bisphosphonate nanoparticle, it is also disclosed “the nanoparticles can be coated with one or more coating agents or layers, such as, but not limited to, a metal oxide, a polymer …, a single lipid layer, a lipid bilayer, and combinations thereof, to provide coated nanoparticles. Thus, some of the nanoparticles can be coated with a … a lipid coating for stabilization and surface functionalization…Some of the nanoparticles can be directly encapsulated within liposomes”, see page 13, section 0228; page 4, section 0089. The pharmaceutical compositions including the said nanoparticles incorporated into liposomes is regarded by the Examiner a liposomal composition, see page 1, section 0003.
While Shi teaches particulate compositions including lipid and polymer components, this technology is not that distinct that it does not overlap with the claimed invention. Shi was relied upon to teach one of ordinary skill in the art could arrive at a liposome with the zeta potential in the range of -30 to -50 mV, the polydispersity index (PD1) of 0.007, as well as including sorbitol or mannitol in the pharmaceutical composition.
And while Chang teaches additional embodiments, including those noted by Applicant, the Chang reference is of record to teach optimization of ratios between ligands and liposome and achieving the desired pH, see Remarks, paragraph bridging pages 6 and 7. These characteristics can be accomplished regardless of the surface charge of the liposome.
It is well settled, however, that when considering the obviousness of claimed subject matter, “[a]ll the disclosures in a reference must be evaluated, including nonpreferred embodiments, a reference is not limited to the disclosure of specific working examples.” In re Mills, 470 F.2d 649, 651 (CCPA 1972) (emphasis added; citations omitted).
The combination of the three references continues to read on the claimed invention. One of ordinary skill in the art would have arrived at Applicant’s claimed invention with a reasonable expectation of success. Accordingly, the rejection is maintained.
Lin teaches liposomal compositions including nanoparticles incorporated into liposomes with a coating agent or layer comprising a targeting moiety, see page 1, section 0003; page 2, section 0070; and page 16, sections 0255 and 0256. “[T]he presently disclosed metal-bisphosphonate nanoparticles, including but not limited to those modified with a shell/coating layer or encapsulated within a single lipid layer or lipid bilayer, can be functionalized with biocompatible passivating molecules, such as polyethylene glycol [PEG],” page 16, section 0255. “In embodiments using a specific targeting or other additional moiety, the additional moiety can optionally be associated with the exterior (i.e., outer surface) of the particle. The targeting moiety can be conjugated (i.e., grafted or bonded) directly to the exterior via any useful reactive group on the exterior,”, see page 16, section 0256. One or more coating agents or layers may include 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)2000] (DPSE-PEG2k), cRGfK-derivatized silica, polyethylene glycol (PEG)-derivatized silica, and anisamide-PEG-derivatized silica, cholesterol, see page 14, section 0237; page 24, section 0338; and page 27, section 0361.
“[N]anoparticles can be coated with one or more coating agents or layers, such as, a polymer including PEG and polyvinylpyrrolidone (PVP), see page 8, sections 0166- 0169; and page 13, section 0228. The nanoparticle includes anticancer drugs including pemetrexed disodium, see page 15, section 0246.
This liposomal composition may have a diameter within the range of less than 1000 nm, as well as less than about 10 nm, see page 7, section 0162. The disclosed liposomal composition has zeta potential ranging from -0.92 to 29.4, see Tables 2 and 3 on page 22; Tables 4 and 5 on page 24; and page 27, Tables 6 and 7. Folate receptors were targeted by ligands including antibodies, see page 17, sections 0264 and 0267.
Absent evidence to the contrary the targeting moiety has specific affinity for the folate receptor alpha subtype.
Lin does not teach the liposomal composition comprises mannitol, trehalose, sorbitol and sucrose. the liposome encapsulates less than 200,000 molecules or between 10,000 to 100,000 molecules of the antifolate and the polydispersity index (PDI) of the composition is 0.007.
Lin does not teach the targeting moiety has specific affinity for folate receptor alpha and there are 30 to 200 targeting moieties.
Shi teaches lipid-polymer hybrid particles, wherein the “…particle has a surface zeta potential ranging from -80 mV to +50 mV” and the PDI of a population of particles is in the range of 0.6 to 0.05 or less, see page 1, section 0008; page 5, section 0052; and page 23, section 0221. Hence, one of ordinary skill in the art could arrive at the designated PDI. Pharmaceutically-acceptable carriers include sorbitol and mannitol, see page 21, section 0201.
Chang teaches the ratio of antibody can be optimized and any desired pH can be achieved with simple mixing, see page 8, section 0118; page 22, section 0302; and page 26, section 0386.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of all the references in order to formulate a pharmaceutical composition with the requisite PDI and necessary number of targeting moieties and bioactive antifolate agents in order to efficiently deliver therapeutic agents such as bioactive antifolate agent, pemetrexed in vivo to successfully target and treat cancer, see both references in their entirety, particularly Chang, page 11, section 0148. One of ordinary skill in the art would have been motivated to prepare and administer a targeted liposomal antifolate composition within a drug delivery system for the treatment of cancer because analogous compositions have been successfully manufactured and successfully implemented in anti-tumor treatment modalities, see all references.
Conclusion
8. THIS ACTION IS MADE FINAL. 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.
9. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached between the hours, 8AM-8PM, Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
Alana Harris Dent
December 8, 2025
/Alana Harris Dent/Primary Examiner, Art Unit 1643