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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 6/19/2024 is acknowledged.
Claim 16-21 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II-III, there being no allowable generic or linking claim.
Election was made without traverse in the reply filed on 6/19/2024.
The restriction requirement of Group II (Claim 15) is hereby withdrawn.
The updated groups of inventions are as follows;
Group I, claim(s) 1-15 and 22-25, drawn to a lipid-based nanocarrier and pharmaceutical composition comprising the lipid based nanocarrier.
Group II, claim(s) 16-21, drawn to a method for treating a disease, disorder, or condition comprising administering a lipid-based nanocarrier.
Status of Claims
Cancelled: 1, 9-14, 22-25
Withdrawn: 16-21
Examined Herein: 2-8, 15
Priority
Priority to PRO 62/798,137 filed on 1/29/2019 and PCT/US2020/015677 filed on 1/29/2020 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/3/2022 and 12/11/2023 is in
compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is
being considered by the examiner.
Drawings
The drawings filed on 7/13/2021 are accepted.
Withdrawn Rejections
All rejections of claim 1, 9-14, and 22-25 are hereby withdrawn; the cancellation of the claims moots the rejection.
The rejection of claims 1-8 under 35 U.S.C. 103 over Dhar and Auguste are hereby withdrawn in view of Applicant’s cancellation of claim 1, substantial amendments to claim 2, and persuasive arguments that the references do not teach the claims as amended. [Remarks 7/28/2025, Page 5]
The rejection of claims 1-10 and 15 under 35 U.S.C. 103 over Dhar, Auguste, and Li are hereby withdrawn in view of Applicant’s cancellation of claim 1, substantial amendments to claim 2, and persuasive arguments that the references do not teach the claims as amended. [Remarks 7/28/2025, Page 5-6]
The rejection of claims 1-10 and 12-15 under 35 U.S.C. 103 over Dhar, Auguste, Li, and Emelianov are hereby withdrawn in view of Applicant’s cancellation of claim 1, substantial amendments to claim 2, and persuasive arguments that the references do not teach the claims as amended. [Remarks 7/28/2025, Page 6-7]
The rejection of claims 1-10 and 22-25 under 35 U.S.C. 103 over Dhar, Auguste, and Peterson are hereby withdrawn in view of Applicant’s cancellation of claim 1, substantial amendments to claim 2, and persuasive arguments that the references do not teach the claims as amended. [Remarks 7/28/2025, Page 7]
The rejection of claims 1-11 and 22-25 under 35 U.S.C. 103 over Dhar, Auguste, Peterson, and Sgouros are hereby withdrawn in view of Applicant’s cancellation of claim 1, substantial amendments to claim 2, and persuasive arguments that the references do not teach the claims as amended [Remarks 7/28/2025, Page 8]
Claim Objections
Claims 2 and 8 are objected to because of the following informalities:
Claim 2 recites the term “tritratable,” which appears to be a misspelling of the term “titratable.” If this is the case, appropriate correction is required.
In claim 8, the structure depicting the compound of formula (I) is blurry and illegible, such that the elements of the structure cannot be clearly discerned. The structure must be replaced with a clear and legible replacement.
Claim 5 recites the limitation “…the polyethylene glycol linker is… [PEG(2000)]” but claim 6 recites the limitation “…the polyethylene glycol linker comprises PEG(2000).” Applicant should amend claim 6 by replacing the term “comprises” with “is” so the language of claim 6 is consistent with claim 5.
Specification
The disclosure is objected to because of the following informalities:
The specification recites the terms “titratable” and “tritratable,” which are used interchangeably. It is unclear whether this is intentional or whether the term “tritratable” is a misspelling of the term “titratable.” The specification should be amended to clarify that these terms are synonymous or to correct the misspelling of “titratable.”
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.
Claims 2, 5-7 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Lam (US 2002/0072121 A1, Published 6/13/2002), in view of Petersen (US 2013/0251630 A1, Published 9/26/2013) and Miller (Liposome−Cell Interactions in Vitro: Effect of Liposome Surface Charge on the Binding and Endocytosis of Conventional and Sterically Stabilized Liposomes, 8/26/1998, Biochemistry, Vol 37/Issue 37, 12875-12883).
With respect to claim 2, Lam discloses a lipid-based nanocarrier of formula (I) having the following structure:
PNG
media_image1.png
271
1407
media_image1.png
Greyscale
[Lam, Figure 21A]
wherein:
n is an integer of about 77;
R1 is lysinamide, which is a moiety having a protonizable (titratable) cationic charge that becomes positively charged at pH 6.7, which is the physiological pH of a tumor interstitium;
R2 and R3 are each independently the same fatty acid residue;
wherein:
the lipid-based nanocarrier adheres to a target cell. [Lam, 0006, 0007, 0095-0099, 0109, 0110]
With respect to claim 5 and 6, Lam disclose the polyethylene glycol linker is PEG(3400). [Lam, 0109]
With respect to claim 7, Lam discloses R2 and R3 are each independently stearic acid. [Lam, Figure 21A]
With respect to claim 15, Lam discloses a pharmaceutical formulation comprising the lipid-based nanocarrier and a pharmaceutically acceptable carrier, saline. [Lam, 0202]
Lam does not explicitly disclose the lipid-based nanocarrier comprises a DOTA chelating agent comprising 225-Actinium or the internalization of the lipid-based nanocarrier by the target cell is minimized. (Claim 2) Lam does not disclose the polyethylene glycol linker is PEG(2000). (Claim 5 and 6)
However, with respect to claim 2, Lam discloses a chelating moiety can be attached, linked or coupled to the lipid-based nanocarrier, wherein the chelating moiety is DOTA or a metal chelate ligand. [Lam, 0112]
With respect to claim 5 and 6, Lam discloses the PEG moiety of the lipid-based nanocarrier may have a molecular weight of 250 to 7000 Da. [Lam, 0098]
Furthermore, with respect to claim 2, Petersen discloses 225Ac is a radionuclide/metal that chelates with DOTA. [Petersen, Page 28, Claim 49-50] Petersen further discloses 225Ac is an ideal radioisotope for therapeutic applications because it emits low penetrating radiation. When the low energy emitting radioisotope, in the form of a radiopharmaceutical, reaches the target site, the energy emitted is only deposited at the target site, so nearby normal tissues are not irradiated. [Petersen, 0007]
Moreover, Miller discloses sterically stabilized liposomes reduce interactions with and uptake by the reticuloendothelial system (RES). Grafted PEG, like negatively charged PEG lipids, reduce the interaction of liposomes with systemic cells because they present an electrostatic and steric barrier. [Miller, Page 12876, Col. 2, Paragraph 1] Furthermore, Miller discloses negatively charged PEG lipids are hardly endocytosed by cells, like HeLa cells. [Miller, Abstract and Page 12881, Figure 6]
Modifying the lipid-based nanocarrier disclosed by Lam by adding 225Ac-DOTA thereto and combining the teachings of Lam and Miller and concluding that the internalization of the lipid-based nanocarrier by the target cell is minimized due the presence of DSPE-PEG, results in the lipid-based nanocarrier of claim 2.
Further modifying the lipid-based nanocarrier disclosed by Lam by replacing PEG(3400) with a PEG moiety having a molecular weight in the range of 250 Da to 7000 Da, including PEG(2000), results in the lipid based nanocarrier of claim 2, 5, and 6.
It would be obvious to one of ordinary skill in the art to modify the lipid-based nanocarrier disclosed by Lam by adding 225Ac-DOTA thereto and have a reasonable expectation of success. Lam discloses a lipid-based nanocarrier, DSPE-PEG(3400)-lysinamide. Lam discloses a chelating moiety can be attached, linked or coupled to the lipid-based nanocarrier, wherein the chelating moiety is DOTA or a metal chelate ligand. Petersen discloses 225Ac is a metal which may chelate a ligand DOTA. In which case, a metal chelate ligand is formed. So, Lam discloses a lipid-based nanocarrier that may have a metal chelate ligand attached, linked or coupled thereto and Petersen discloses 225Ac-DOTA is a metal chelate ligand. Thus, the combined teachings of Lam and Petersen suggest the lipid-based nanocarrier may be attached, linked, or coupled to 225Ac-DOTA. Therefore, it is reasonable to expect the lipid-based nanocarrier disclosed by Lam may be modified by adding 225Ac-DOTA thereto. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Lam discloses the lipid-based nanocarrier is intended for therapeutic applications, including introducing the carrier into cells. [Lam, 0006] Petersen discloses 225Ac is an ideal radioisotope for therapeutic applications because it emits low energy. Additionally, when 225Ac is in the form of a radiopharmaceutical that reaches a target site, the energy emitted is only deposited at the target site so nearby normal tissues are not irradiated. [Petersen, 0007] Therefore, one would have been motivated by the expectation that the aforementioned modification would enable the lipid-based nanocarrier disclosed by Lam to deposit the energy emitted from 225Ac-DOTA only at a target site rather than normal tissues.
It would be obvious to one of ordinary skill in the art to combine the teachings of Lam and Miller and conclude that the internalization of the lipid-based nanocarrier disclosed by Lam by the target cell is minimized due the presence of DSPE-PEG, and have a reasonable expectation of success. Lam discloses a lipid-based nanocarrier comprising DSPE-PEG, which is a negatively charged PEG liposome. Miller discloses sterically stabilized liposomes reduce interactions and uptake by the reticuloendothelial system (RES). Additionally, Miller discloses negatively charged PEG lipids reduce the interaction of liposomes with systemic cells because they present an electrostatic and steric barrier. As a result, negatively charged PEG lipids are hardly endocytosed by cells, like HeLa cells. So, Lam discloses a lipid-based nanocarrier comprising a negatively charged PEG lipid and Miller discloses negatively charged PEG lipids are hardly endocytosed (or internalized) by and have reduced (or minimal) interactions with non-systemic cancerous cells and systemic cells; both of which encompass “target cells.” Thus, the combined teachings of Lam and Miller suggest that DSPE-PEG is hardly internalized by and have minimal interactions with target cells. Therefore, it is reasonable to combine the teachings of Lam and Miller and conclude that the internalization of the lipid-based nanocarrier disclosed by Lam by the target cell is minimized due the presence of DSPE-PEG. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Lam discloses a lipid-based nanocarrier comprising DSPE-PEG, which is a negatively charged PEG liposome. Miller discloses PEG lipids are negatively charged and therefore present an electrostatic and steric barrier to interactions with cells. As a result, Miller declares it is appropriate to investigate the steric and electrostatic effects on PEG lipid/cell interactions, by comparing the endocytosis of cationic, neutral, and anionic PEG lipids. [Miller, Page 12876, Col. 2, Paragraph 1] Therefore, one would have been motivated by the expectation that the observations made by Miller during the investigation, would be applicable to the lipid-based nanocarrier disclosed by Lam, which comprises a negatively charged PEG lipid, DSPE-PEG.
It would be obvious to one of ordinary skill in the art to modify the lipid-based nanocarrier disclosed by Lam by replacing PEG(3400) with a PEG moiety having a molecular weight in the range of 250 Da to 7000 Da, including PEG(2000), and have a reasonable expectation of success. Lam discloses a lipid-based nanocarrier, DSPE-PEG(3400)-lysinamide. Lam further discloses the PEG moiety in the nanocarrier may have a molecular weight of about 250 to about 7000 Da. So, the PEG moiety may be selected from PEG(250) – PEG (7000), which includes PEG(2000). Thus, Lam suggests that the PEG(3400) moiety of the nanocarrier may be replaced with PEG(2000). Therefore, it is reasonable to expect the lipid-based nanocarrier disclosed by Lam may be modified by replacing PEG(3400) with PEG(2000). One would have been motivated to do so because the selection of a known material based on its suitability for its intended use is prima facie obvious. In the instant case, Lam discloses the PEG moiety in the nanocarrier may have a molecular weight of about 250 to about 7000 Da. Therefore, the selection of a known material, PEG(2000), based on its suitability as a PEG moiety having a molecular weight of 2000 Da, for its intended use in the lipid-based nanocarrier is prima facie obvious.
Claims 2-8 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Lam, Petersen, and Miller, as applied to claim 2, 5-7 and 15 above, and further in view of Annenkov (Synthesis of biomimetic polyamines, 2009, ARKIVOC, (xiii) 116-130).
With respect to claim 2, Lam, Petersen, and Miller disclose the teachings above.
With respect to claim 3, 4, and 8, Lam discloses in the lipid-based nanocarrier, DSPE-PEG-lysinamide, the lysinamide functions as a polycationic moiety. However, Lam discloses other suitable polycationic moieties include basic amino acids and their derivatives, spermine, spermidine, cationic dendrimers, polyamines, polyamine sugars, and amino polysaccharides. Moreover, Lam discloses the selection of which polycationic moiety to employ may be determined by the type of liposome application which is desired. [Lam, 0099]
Lam, Petersen, and Miller do not disclose the R1 moiety has an intrinsic pKa having a range from about 6.0 to 6.9 or is dimethyl ammonium propane.
However, with respect to claim 3, 4, and 8, Annenkov discloses a series of short-chain polyamines such as spermine and spermidine. Annenkov also discloses dimethyl ammonium propane is a polyamine. [Annenkov, Page 120, Compound 5]
Dimethylammonium propane is a moiety having a titratable cationic charge that becomes positively charged at pH=6, which is the physiological pH of a tumor interstitium. Additionally, dimethylammonium propane has a pKa of 6.7.
Modifying the lipid-based nanocarrier disclosed by Lam, Petersen, and Miller by replacing lysinamide with dimethylammonium propane, results in the lipid-based nanocarrier of claim 3, 4, and 8.
It would be obvious to one of ordinary skill in the art to modify the lipid-based nanocarrier disclosed by Lam, Petersen, and Miller by replacing lysinamide with dimethylammonium propane and have a reasonable expectation of success because Lam, Petersen, and Miller disclose a lipid-based nanocarrier, DSPE-PEG-lysinamide, wherein lysinamide functions as a polycationic moiety. However, Lam further discloses other suitable polycationic moieties include basic amino acids and their derivatives, spermine, spermidine, and polyamines. Annenkov discloses spermine, spermidine, and dimethylammonium propane are all short-chain polyamines. So, Lam, Petersen, and Miller disclose a lipid-based nanocarrier, DSPE-PEG-lysinamide, wherein the polycationic moiety, lysinamide, may be replaced with a polyamine, and Miller discloses spermine, spermidine, and dimethylammonium propane are all polyamines. Thus, the combined teachings of Lam, Petersen, Miller, and Annenkov suggest dimethylammonium propane may function as the polyamine in the lipid-based nanocarrier. Therefore, it is reasonable to expect the lipid-based nanocarrier disclosed by Lam, Petersen, and Miller may be modified by replacing lysinamide with dimethylammonium propane. One would have been motivated to do so because the selection of a known material based on its suitability for its intended use is prima facie obvious. In the instant case, Lam discloses a lipid-based nanocarrier, DSPE-PEG-lysinamide, wherein lysinamide functions as a polycationic moiety. However, Lam further discloses polyamines are suitable polycationic moieties in the nanocarrier. Therefore, the selection of a known material, dimethylammonium propane, based on its suitability as a polyamine for its intended use as a polycationic moiety in the lipid-based nanocarrier disclosed by Lam is prima facie obvious.
Response to Arguments
Applicant’s arguments on page 5-8 of the Remarks filed 7/28/2025, with respect to the rejections of claim(s) 1-15 and 22-25 under 35 U.S.C 103 have been fully considered and are persuasive. Applicant’s arguments essentially state the previous references of record do not teach the claims as amended. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of references cited above.
Applicant’s arguments on page 9 of the Remarks with respect to the teachings of Sgouros, Dhar, Auguste, and Petersen have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Furthermore, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, the Examiner has taken into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, in order to form the basis for the obviousness rejections set forth. No statement in the Office Action includes knowledge gleaned only from the Applicant's disclosure. Applicant is reminded that inherency is distinct from hindsight reasoning. A reference need not explicitly teach an inherent property because the presence thereof is necessarily present when the claimed elements are disclosed therein. To that end, the absence of such an explicit teaching does not mean the Office has relied on the Applicant’s disclosure.
To the extent that the Applicant believes a property is not inherent or was not known in the art prior to the effective filing date of the instant disclosure, Applicant is encouraged to identify what knowledge and/or property they believe the Examiner has gleaned only from the instant disclosure. At which point the Examiner may cite additional art, if necessary, to demonstrate that the knowledge and/or property was within the level of ordinary skill at the time the claimed invention was made.
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 KAILA A CRAIG whose telephone number is (703)756-4540. The examiner can normally be reached Monday-Friday 0800-1600.
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618