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 .
In view of the amendment, previous 112(b) rejection on claim 14 is hereby withdrawn.
In view of the amendment, previous 102(a)(1) or 102(a)(2) rejection over Zale et al’960 is hereby withdrawn.
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.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 2, 5, 6, 8, 9, 12-14 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Zale et al (US 2019/0029960 A1) in view of Qian et al (“Polycaprolactone-Based Mimetic Antimicrobial Peptide Copolymers Vesicles as an Effective Drug-Carrier for Cancer Therapy”, Polymers (Basel), Vol.11(11) (Oct. 31, 2019): 1783, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/31683611/ ) (with Wikipedia article on “Polylysine” obtained from the website: https://en.wikipedia.org/wiki/Polylysine , which is being cited here merely to support the Examiner’s assertion that polylysine is a polymer containing a positively charged hydrophilic amino group).
Zale teaches (see abstract) a therapeutic nanoparticle that includes a biocompatible polymer, a polymer-EGFR ligand conjugate, wherein the EGFR ligand is covalently bound through a chemical linker to the polymer, and a therapeutic agent.
Zale gives (see [0139]) an exemplary embodiment where nanoparticles comprising PLA-PEG (polylactic acid-polyethylene glycol), PLA-PEG-azide and PLA-Cy5 (fluorescent label – see [0138]) are first generated through a nano-emulsion process (Zale’s PLA-PEG and PLA-PEG-azide teach instant first polymer (1)). Then, epidermal growth factor (“EGF” of instant claim 2, which is instant ligand of claim 1 selected to activate an EGFR receptor), a naturally occurring EGFR ligand, is covalently tethered to DBCO (dibenzocyclooctyne – instant linker of claim 1 which associates the polymeric nanoparticle and the ligand) to allow for conjugation of DBCO (instant linker) to the azide moieties (instant anchor species of claim 5 that associates with the linker) on the nanoparticles using click chemistry (see [0142], [0144], Figs.3, 4 and 5, [0136] and claim 7).
Zale does not teach instant second polymer (2) comprising at least one positively charged group. Zale, however, teaches ([0048]-[0049]) that its therapeutic nanoparticle can include one or more additional, unfunctionalized polymers that can be natural or synthetic, homopolymers or copolymers. Among examples for such additional polymers, Zale include ([0056]) poly(caprolactone) (“PCL”), PEGylated poly(caprolactone) (“PEG-PCL”), polylysine (“PLL”) and PEGylated polylysine (“PEG-PLL”). Zale further teaches ([0093] and claim 14) that its therapeutic nanoparticle can be used to treat cancer and contains a therapeutic agent. Qian teaches (see the 1st paragraph under “3.2 Self-Assembly of PCL16-b-Kn Copolymers” and Conclusions) PCL16-b-Kn copolymers (where K stands for polylysine (“PLL”)), which exhibit broad antibacterial activity and can self-assemble into vesicles, with the hydrophilic PLL forming the corona of the vesicles and the hydrophobic PCL forming the membrane of the vesicles. Qian teaches that these vesicles can encapsulate and release drugs and can achieve controlled intracellular drug release and effective killing capabilities of cancer cells with low cytotoxicity to normal cells. Since Zale teaches that its therapeutic nanoparticles can be used in treating cancer and contains a therapeutic agent, and since Zale also teaches that the additional polymers that can be included in its nanoparticle can be homopolymers or copolymers and can be chosen from PCL and PLL, it would be obvious to one skilled in the art to use Qian’s PCL16-b-Kn Copolymers (where K stands for PLL) as the additional polymer in Zale’s therapeutic nanoparticle so as to encapsulate Zale’s therapeutic agent with a reasonable expectation of achieving controlled intracellular drug release and effective killing capabilities of cancer cells with low cytotoxicity to normal cells. As evidenced by the Wikipedia article on Polylysine (see the paragraph under “Chemical structure”), polylysine (PLL) is a polymer containing a positively charged hydrophilic amino group. Thus, Qian’s PCL16-b-Kn Copolymers (where K stands for PLL) teaches instant second polymer (2) comprising at least one positively charged group.
Thus, Zale in view of Qian renders obvious instant claims 1, 2, 5, 6, 8 and 12 (Zale’s PLA-PEG and PLA-PEG-azide teaches instant first polymer of claim 6 comprising PEG and PLA; Qian’s PCL16-b-Kn Copolymers (where K stands for PLL) teaches instant second polymer of claim 8 comprising PLL).
With respect to instant claim 9, Qian gives examples (see section 3.2 that starts on pg.4) of its PCL16-b-Kn diblock copolymers (where K is PLL and n ranges from 11 to 27). Such diblock copolymers teach instant PLL-PCL diblock copolymer of claim 9. As to instant Mw range of about 1500 – about 30,000, since there are 16 repeating caprolactone units and 11-27 repeating lysine units in Qian’s PCL16-b-Kn diblock copolymers (with K being PLL and n ranging from 11 to 27), this gives Mw range of 3,232 – 5,280 (as calculated by the Examiner). Such range falls within instant Mw range, thus teaching instant Mw range. Thus, Zale in view of Qian renders obvious instant claim 9.
With respect to instant claim 13, Zale teaches ([0046]) that its nanoparticles may have a hydrodynamic diameter of about 50 – about 140 nm. Such range overlaps with instant range about 10 – about 80 nm for the hydrodynamic diameter, thus rendering instant range prima facie obvious. In the case “where the [claimed] ranges overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness would exist which may be overcome by a showing of unexpected results, In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Thus, Zale in view of Qian renders obvious instant claim 13.
With respect to instant claim 14, since Zale in view of Qian teaches instant therapeutic composition of claim 1 comprising all of instant components, the hydrodynamic diameter for Zale’s therapeutic nanoparticles (as modified by the teaching of Qian) would naturally remain unchanged following the therapeutic nanoparticles’ exposure to water for 1 week as instantly recited (besides, Zale also aims for a long-term storage of its nanoparticle stocks in aqueous suspensions – see [0135]). Thus, Zale in view of Qian renders obvious instant claim 14.
With respect to instant claim 23, Zale teaches (claim 13) a pharmaceutically acceptable composition comprising a plurality of therapeutic nanoparticles (as discussed above) and a pharmaceutically acceptable excipient. Thus, Zale in view of Qian renders obvious instant claim 23.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Zale et al (US 2019/0029960 A1) in view of Qian et al (“Polycaprolactone-Based Mimetic Antimicrobial Peptide Copolymers Vesicles as an Effective Drug-Carrier for Cancer Therapy”, Polymers (Basel), Vol.11(11) (Oct. 31, 2019): 1783, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/31683611/ ) as applied to claim 2 above, and further in view of Qin et al (“EGFR Signaling: Friend or Foe for Cartilage?”, JBMR Plus. Vol.3(2) (Feb. 13, 2019) : e10177, obtained from the website: https://pmc.ncbi.nlm.nih.gov/articles/PMC6383702/ ).
As discussed above, in Zale, EGF is used as the EGFR ligand (instant ligand selected to activate an EGFR receptor). Although Zale does not teach instant TGFa as its EGFR ligand, as evidenced by Qin (see the 2nd paragraph under “Introduction” and the caption under Fig.1), EGF and TGFa are well known in the art as equivalent ligands that bind only to EGFR (and activate the receptor). Thus, it would be obvious to one skilled in the art to use TGFa as Zale’s EGFR ligand with a reasonable expectation of success. Thus, Zale in view of Qian, and further in view of Qin renders obvious instant claim 3.
Claim(s) 4 is rejected under 35 U.S.C. 103 as being unpatentable over Zale et al (US 2019/0029960 A1) in view of Qian et al (“Polycaprolactone-Based Mimetic Antimicrobial Peptide Copolymers Vesicles as an Effective Drug-Carrier for Cancer Therapy”, Polymers (Basel), Vol.11(11) (Oct. 31, 2019): 1783, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/31683611/ ) as applied to claim 1 above, and further in view of Engel et al (“A highly efficient peptide substrate for EGFR activates the kinase by inducing aggregation”, Biochem J. vol.453(3) (Aug. 1, 2013): pg.337-44, obtained from the website: https://pmc.ncbi.nlm.nih.gov/articles/PMC4048812/ ).
Zale does not teach instant ligand which differs from a naturally-occurring ligand by one or more amino acids. Zale, however, teaches ([0070]) that its EGFR ligand can be a modified EGFR peptide having a Mw of about 1,200 to 1,900. Engel teaches (see abstract) that Peptide C, a synthetic peptide substrate of EGFR, can increase EGFR kinase activity (i.e., activates an EGFR receptor). Engel further teaches (see pg.3, the paragraph under “Peptide substrates”) that the sequence of Peptide C is RAHEEIYHFFFAKKK, which Mw is 1,802 (as calculated by the Examiner) which falls within the Mw range of about 1,200 to 1,900 (as taught by Zale). Since Zale teaches that its EGFR ligand can be a modified EGFR peptide having a Mw of about 1,200 to 1,900, it would be obvious to one skilled in the art to use Engel’s synthetic Peptide C (instant ligand of claim 4 which differs from a natural-occurring ligand by one or more amino acids) as Zale’s EGFR ligand with a reasonable expectation of success in increasing EGFR kinase activity. Thus, Zale in view of Qian, and further in view of Engel renders obvious instant claim 4.
Claim(s) 7 is rejected under 35 U.S.C. 103 as being unpatentable over Zale et al (US 2019/0029960 A1) in view of Qian et al (“Polycaprolactone-Based Mimetic Antimicrobial Peptide Copolymers Vesicles as an Effective Drug-Carrier for Cancer Therapy”, Polymers (Basel), Vol.11(11) (Oct. 31, 2019): 1783, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/31683611/ ) as applied to claim 6 above, and further in view of Yu et al (US 10,172,796 B2).
With respect to instant claim 7, as already discussed above, Zale’s nanoparticles comprise PLA-PEG, PLA-PEG-azide and PLA-Cy5, and as also discussed above, Zale’s PLA-PEG and PLA-PEG-azide teach instant first polymer of claim 6 comprising PEG and PLA. Although Zale’s PLA-PEG and PLA-PEG-azide do not teach instant PEG-PCL diblock copolymer of claim 7, Zale teaches ([0056]) the equivalence of PEGylated PLA and PEGylated PCL. Thus, it would be obvious to one skilled in the art to replace Zale’s PLA-PEG with PCL-PEG (Instant PEG-PCL diblock copolymer of claim 7) with a reasonable expectation of success. As to instant Mw range of about 3,000 to about 30,000, Zale does not explicitly teach such limitation. However, as evidenced by Yu et al (claims 1-3), PEG-PCL diblock copolymers, which form polymer micelles (encapsulating a drug) used in a pharmaceutical formulation for treating cancer, are known to have molecular weight that ranges from 1,000 to 5,000. It would be obvious to one skilled in the art to use PCL-PEG diblock copolymer having Mw range from 1,000 to 5,000 (instead of PLA-PEG) to form Zale’s nanoparticles with a reasonable expectation of success. The Mw range of 1,000-5,000 overlaps with instant Mw range of about 3000 – about 30,000, thus rendering instant range prima facie obvious. In re Wertheim, supra. Thus, Zale in view of Qian, and further in view of Yu renders obvious instant claim 7.
Claim(s) 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Zale et al (US 2019/0029960 A1) in view of Qian et al (“Polycaprolactone-Based Mimetic Antimicrobial Peptide Copolymers Vesicles as an Effective Drug-Carrier for Cancer Therapy”, Polymers (Basel), Vol.11(11) (Oct. 31, 2019): 1783, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/31683611/ ) as applied to claim 1 above, and further in view of Wang et al (“Preferential tumor accumulation and desirable interstitial penetration of poly(lactic-co-glycolic acid) nanoparticles with dual coating of chitosan oligosaccharide and polyethylene glycol-poly(D,L-lactic acid)”, Acta Biomaterialia, vol.29 (2016), pg.248-260, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/26476340/ ) .
Zale is silent about the surface charge of its therapeutic nanoparticles. After stating that rapid clearance from blood and poor penetration capacity in heterogeneous tumors represent a great challenge for polymeric nanoparticles as effective delivery systems for anticancer drugs, Wang states that through his study he discovered that polymeric nanoparticles with a slight positive charge (+ 3.54 mV) showed an improved accumulation and interstitial penetration capacity to/in tumor site, and thus led to an enhanced antitumor efficacy (see ABSTRACT and Statement of significance on pg.248). Since Zale is silent as to the surface charge of its therapeutic nanoparticles, it would have been obvious to one skilled in the art to prepare Zale’s therapeutic nanoparticles (as modified by the teaching of Qian) with a slight positive charge (about + 3.54 mV) (which falls within instant range of about -5 mV to about 30 mV) in order to improve accumulation and interstitial penetration capacity to/in tumor site and thus to achieve an enhanced antitumor efficacy for tis therapeutic nanoparticles, as taught by Wang. Thus, Zale in view of Qian, and further in view of Wang renders obvious instant claims 10 and 11.
Claim(s) 15, 17, 18 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Zale et al (US 2019/0029960 A1) in view of Qian et al (“Polycaprolactone-Based Mimetic Antimicrobial Peptide Copolymers Vesicles as an Effective Drug-Carrier for Cancer Therapy”, Polymers (Basel), Vol.11(11) (Oct. 31, 2019): 1783, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/31683611/ ) and Wang et al (“Preferential tumor accumulation and desirable interstitial penetration of poly(lactic-co-glycolic acid) nanoparticles with dual coating of chitosan oligosaccharide and polyethylene glycol-poly(D,L-lactic acid)”, Acta Biomaterialia, vol.29 (2016), pg.248-260, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/26476340/ ).
With respect to instant claim 15, 17, 18 and 28, for the reasons explained above, Zale in view of Qian and Wang teaches all the limitations of instant claim 15. Thus, Zale’s therapeutic nanoparticles (as modified by the teachings of Qian and Wang) would naturally be capable of being used for osteoarthritis treatment as instantly recited in claim 15. Thus, Zale in view of Qian and Wang renders obvious instant claims 15, 17, 18 and 28 (instant limitations of claims 17, 18 and 28 were already addressed above).
Claim(s) 16 is rejected under 35 U.S.C. 103 as being unpatentable over Zale et al (US 2019/0029960 A1) in view of Qian et al (“Polycaprolactone-Based Mimetic Antimicrobial Peptide Copolymers Vesicles as an Effective Drug-Carrier for Cancer Therapy”, Polymers (Basel), Vol.11(11) (Oct. 31, 2019): 1783, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/31683611/ ) and Wang et al (“Preferential tumor accumulation and desirable interstitial penetration of poly(lactic-co-glycolic acid) nanoparticles with dual coating of chitosan oligosaccharide and polyethylene glycol-poly(D,L-lactic acid)”, Acta Biomaterialia, vol.29 (2016), pg.248-260, obtained from the website: https://pubmed.ncbi.nlm.nih.gov/26476340/ ) as applied to claim 15 above, and further in view of Qin et al (“EGFR Signaling: Friend or Foe for Cartilage?”, JBMR Plus. Vol.3(2) (Feb. 13, 2019) : e10177, obtained from the website: https://pmc.ncbi.nlm.nih.gov/articles/PMC6383702/ ).
As discussed above, in Zale, EGF is used as the EGFR ligand (instant ligand selected to activate an EGFR receptor). Although Zale does not teach instant TGFa as its EGFR ligand, as evidenced by Qin (see the 2nd paragraph under “Introduction” and the caption under Fig.1), EGF and TGFa are well known in the art as equivalent ligands that bind only to EGFR (and activate the receptor). Thus, it would be obvious to one skilled in the art to use TGFa as Zale’s EGFR ligand with a reasonable expectation of success. Thus, Zale in view of Qian and Wang, and further in view of Qin renders obvious instant claim 16.
Response to Arguments
Applicant's arguments filed on April 21, 2026 have been fully considered but they are not persuasive. Applicant’s arguments are summarized as follows: (i) applicant first argue that since Zale does not teach instant second polymer, Qian was brought in to teach the presence of PCL-PLL, but that Qian only teaches that PCL-PLL copolymers could be used in vesicles that carry therapeutic materials, not that PCL-PLL copolymers are incorporated into the therapeutic materials. Applicant conclude that Qian thus does not teach applicant’s technology because one would have to make a fundamental change to the way which Qian operates, which goes against MPEP 2143.01(VI). The Examiner disagrees. Citing In re Ratti, 270 F.2d 810, 813, 123 USPQ 349, 352 (CCPA 1959), MPEP 2143.02(VI) states that If the proposed modification or combination of the prior art would change the principle of operation of the prior art invention being modified, then the teachings of the references are not sufficient to render the claims prima facie obvious. In instant case, it is the Zale reference being modified by the teaching of Qian (not the other way around), and the Examiner believes that the proposed modification would not change the operation principle of Zale (the prior art invention being modified): as already discussed above, Qian teaches PCL16-b-Kn copolymers (where K stands for polylysine (“PLL”)), which exhibit broad antibacterial activity and can self-assemble into vesicles. Qian teaches that these vesicles can encapsulate and release drugs and can achieve controlled intracellular drug release and effective killing capabilities of cancer cells with low cytotoxicity to normal cells. Based on Qian’s teaching, it would be obvious to one skilled in the art to use Qian’s PCL16-b-Kn Copolymers (where K stands for PLL) as the additional polymer in Zale’s therapeutic nanoparticle so as to encapsulate Zale’s therapeutic agent with a reasonable expectation of achieving controlled intracellular drug release and effective killing capabilities of cancer cells with low cytotoxicity to normal cells. Since Zale already teaches that its therapeutic nanoparticles can be used in treating cancer and contains a therapeutic agent, and since Zale also teaches that the additional polymers that can be included in its nanoparticle can be homopolymers or copolymers and can be chosen from PCL and PLL, modifying Zale with Qian’s teaching (to further include PCL16-b-Kn Copolymers (where K stands for PLL)) would not change the operating principle of Zale. Besides, applicant themselves are using their polymers as carriers of the therapeutic materials (for example, see [0068] of present specification where applicant state “[w]e have addressed the TGFa delivery challenges by conjugating TGFa onto nanometer-sized polymeric micellar nanoparticles. . . . Compared to other drug nanocarriers, the polymeric nanoparticles provide several clear advantages, . . .; see also [0055] of present specification where applicant state “[t]o overcome this challenge, we engineered a nanoparticle delivery system to prolong the retention of active TGFa in the knee joint . . .”). (ii) Applicant next argue that the amended claim 15 now requires that instant therapeutic composition is for osteoarthritis treatment and that the Examiner’s use of the Wang reference is misplaced because Wang only teaches that the slight positive charge of nanoparticles is useful only in the context of treating tumors not in the context of cartilage treatment and that the ligands claimed in instant claim 15 are not present in Wang. The Examiner disagrees. Since both Zale and Wang are about treating cancer tumors, combining Wang with Zale is not misplaced. Furthermore, for the reasons already explained above, Zale in view of Qian and Wang teaches all the limitations of instant claim 15, including instant ligand. Thus, Zale’s therapeutic nanoparticles as modified by the teachings of Qian and Wang would inherently be capable of being used for osteoarthritis treatment as instantly recited in claim 15 (instant claim 15 is not a method claim comprising an active step of treating osteoarthritis). "Where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation". Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
June 27, 2026
Prosecution Insights