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 .
Claim Rejections - 35 USC § 112
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.
Claim 14 is 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.
Claim 14 recites “the aqueous solution is a eutectic mixture”. The parent claim recites “an aqueous solution comprising drug loaded micelles”. A micelle is a separate entity that is in not dissolved in the surrounding aqueous medium. However there is also recognized terminology that refers to a colloid as colloidal solution. In addition, the specification discusses the mixture PEG solvent, water, and block copolymer as a eutectic mixture in some embodiments (see paragraph 81). Thus it is unclear if the entire mixture of micelles and the surrounding aqueous solution is a eutectic mixture or if just the surrounding aqueous solution is a eutectic mixture in claim 14. For the sake of application of prior art and compact prosecution, the latter interpretation will be employed. Clarification is still required.
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.
Claims 1-12, 15-22, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Seo et al. (previously cited) in view of Shih et al. (US PGPub No. 2004/0001872) and Sui et al.(previously cited).
Seo et al. disclose micelles made via liquid-liquid phase separation (see abstract). The micelles are composed of diblock copolymers and encapsulate a hydrophobic drug with a water solubility of less than 10 mg/ml (see paragraphs 11, 22, and 26; instant claim 1). The process employs liquid poly(ethylene glycol) (PEG) and water to facilitate the desired organization of polymer and drug molecules. The liquid PEG has a preferable molecular weight of 100 to 10,000 Da and a most preferable size range of 200 to 1000 Da (see paragraph 24; instant claim 17). Seo et al. disclose an example where the polymer is a diblock copolymer of PEG and polylactide (PLA) at a block molecular weight of 2000 Da and 1800 Da, respectively (see example 7; instant claims 20-22).The polymer at 30 wt% and paclitaxel at 3.3 wt% are dissolved in liquid PEG with a 600 Da molecular weight into a clear solution via heating to a first temperature of 60-90⁰C for 20 minutes (see example 7; instant claims 2, 4, 9, 18-19, and 24). The solution is slowly cooled for an hour to a second temperature of about 25⁰C and diluted with water filtered and freeze dried (see example 7; instant claims 1 and 6, and 12). Seo et al. teach the addition of water to facilitate phase separation (see paragraph 24; instant claim 16). While silent in regard to solution saturation for the paclitaxel and PEG-PLA in liquid PEG, paragraph 84 of the instant specification details that “[a]t elevated temperatures, mixing PEG4kDa-b-PLA2.2kDa with PEG of different molecular weights at 5.0 wt.% yields a transparent solution. Cooling this mixture to room temperature causes turbidity over time and results in a waxy solid. We assumed that this phenomenon is a result of crystallization of the PEG block of the copolymer at reduced temperatures.” The PEG solution of Seo et al. is clear, thus based upon the same presumption as the applicant’s, it is undersaturated at the first temperature and, since it does not solidify upon cooling, it also is not supersaturated at the second temperature (see instant claims 1, 8, and 10). A process of production where the liquid PEG is not removed or has a higher final cooling temperature are not explicitly detailed.
Shih et al. teach a composition similar to that of Seo et al. where a PEG solvent is employed to dissolve a PEG-polyester block copolymer and poorly water soluble drug that are then dispersed in water to generate a colloidal/micellar drug depot (see paragraphs 16-17, 29, and 56). The preparation process permits direct administration of the liquid composition to a subject because the vehicle is biocompatible due to low toxicity and can be quickly dispersed upon reconstitution (see paragraphs 17 and 56-57). Like Seo et al., they also exemplify paclitaxel as the drug provided by the delivery vehicle; however, they do not remove the PEG solvent (see example 10). They note the benefit of composition components, like PEG as a solvent because it does not require removal, unlike toxic or foreign body reaction inducing solvents that are commonly employed to make drug releasing nanospheres, microspheres and depots (see paragraphs 3-12 and 56). They detail the PEG solvent to have a weight average molecular weight within the range of 150 to 1100 Da (see paragraph 44; instant claim 17).
Sui et al. teach spherical structures formed from diblock copolymers of PEG and PCL envisioned for drug delivery (see abstract). They detail the formation of micelles from a diblock copolymer composed of a PEG and a PCL block with molecular weights that are the same, respectively, as the PEG and PLA blocks of Seo et al. (see page 692 second column last partial paragraph). In a method aligned with that of Seo et al., Sui et al. dissolve their polymer in a liquid PEG solvent with heating to 60⁰C and stirring for 20 minutes (see page 694 first column last partial paragraph-second column first partial paragraph). The solution is then cooled and water added with mixing after the addition, suggesting homogeneity (see page 694 second column first partial paragraph; instant claim 5). A water addition followed by thirty minutes of stirring, and two further additions of water followed by stirring are detailed (see page 694 second column first partial paragraph). After formation of an emulsion, it is filtered, but not dialyzed (see page 694 second column first partial paragraph; instant claims 13 and 16). Sui et al. further note that the cooling is performed down to temperatures near 37⁰C in order to be near physiological temperature, but caution against cooling much below 30⁰C due to the precipitation encountered with polymers of the same diblock monomers at larger molecular weights (see page 693 first column last partial paragraph). They further teach that the temperatures below 30⁰C suppressed assembly of the molecules in due to lower chain mobility (see page 693 second column first partial paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make a drug depot based on the teachings of Seo et al. in light of Shih et al. having a liquid PEG with a molecular weight in the range taught by Seo et al. because they both suggest nearly the same range and because Shih et al. teach that such PEG liquids are biocompatible and low toxicity. Here the range of liquid PEG molecular weights overlap with those instantly claimed which renders the instantly claimed range obvious. “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed.Cir. 1990)” (see MPEP 2144.05). It additionally would have been obvious to apply the process details of Sui et al. in the method of Seo et al. because both make micellar structures from very similar polymers via very similar techniques as drug carriers. More specifically, it would have been obvious to apply the cooling temperature of Sui et al. at 30 to 37⁰C to avoid potential precipitation of the polymer, but still be near physiological temperature. This modification would have been obvious as the application of the same technique to a similar process in order to yield the same improvement. This range overlaps with the instantly claimed range thereby rendering it obvious (see MPEP 2144.05). It also would have been obvious to induce the micelle formation with water addition, and cooling, as Seo et al. also teach, without the removal of the PEG solvent because Shih et al. and Sui et al. indicate that removal is not necessary for micelle formation or when the solvent is biocompatible. Further, the order of addition of PEG-PLA and paclitaxel to PEG liquid has a small, finite set of options that predictably yield the non-saturated solution at a first elevated temperature which are 1) both at once, 2) PEG-PLA followed by paclitaxel, 3) paclitaxel followed by PEG-PLA, or 4) alternating PEG-PLA and paclitaxel. It is obvious to choose from a finite number of identified, predictable solutions, with a reasonable expectation of success , thus the claimed order of addition is obvious. Additionally, MPEP 2144.04IVC highlights In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), noting that the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. In addition, MPEP 2144.04(V)(E) details that a continuous operation is obvious in light of a batch process, thus the limitations of instant claim 7 are also obvious in light of the process of Seo et al. The addition of water followed by stirring to homogeneity would follow or have been obvious as would the additions of water occurring over a time of period less than an hour. The latter would have been obvious because Seo et al. do not highlight the need to extend the duration of water addition, Sui et al. suggest times around 30 minutes, and there is no evidence of criticality of this parameter in the method. Freeze drying of the micellar composition also would follow as suggested by Seo et al. Finally, it also would have been obvious to select the highlighted PEG-PCL of Sui et al. as the polymer to make the paclitaxel micelles via the Sui et al. modified methods because the PCL is an envisioned option for the hydrophobic block of Seo et al. Therefore claims 1-12, 15-22, and 24 are obvious over Seo et al. in view of Shih et al. and Sui et al.
Claims 1-12 and 15-24 are rejected under 35 U.S.C. 103 as being unpatentable over Seo et al. in view of Shih et al. and Sui et al. as applied to claims 1-12, 15-22, and 24 above, and further in view of Zhan et al. (previously cited).
Seo et al. in view of Shih et al and Sui et al. render obvious the limitations of instant claims 1-12, 15-22, and 24. The paclitaxel loaded PEG-PLA micelles are not explicitly taught to have a targeting moiety bound to the end of the PEG chain.
Zhan et al. teach the utility of paclitaxel loaded PEG-PLA micelles to treat glioblastoma and their improved efficacy for this cancer via the conjugation of cyclic RGD to the PEG terminus (see abstract, page 137 first column first full paragraph and last partial paragraph-second column first full paragraph, page 138 second column first paragraph, scheme 1, and figures 7-8).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ a PEG-PLA with cyclic RGD at the PEG terminus in the modified method of Seo et al. in light of Zhan et al. This modification would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. Therefore claims 1-12 and 15-24 are obvious over Seo et al. in view of Shih et al., Sui et al., and Zhan et al.
Claims 1-12, 15-22, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Seo et al. in view of Shih et al and Sui et al. as applied to claims 1-12, 15-22, and 24 above, and further in view of Tam et al. (previously cited).
Seo et al. in view of Shih et al and Sui et al. render obvious the limitations of instant claims 1-12, 15-22, and 24. While paclitaxel is the hydrophobic drug loaded in PEG-PLA micelles, an oligo(lactic acid) conjugated version is not explicitly taught.
Tam et al. teach the utility of paclitaxel as an anticancer agent and its delivery via loaded PEG-PLA diblock copolymer micelles (see page 8674). However, an oligo(lactic acid)-paclitaxel conjugate loaded into PEG-PLA diblock copolymer micelles was found to be less toxic to the treated subject (see page 8676 second column last partial paragraph-page 8687 first column first partial paragraph, figures 1 and 6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select the oligo(lactic acid)-paclitaxel as the hydrophobic drug employed in the modified micelles of Seo et al. because it provides a superior performance over paclitaxel that they exemplify. This modification would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. Therefore claims 1-12, 15-22, and 24-25 are obvious over Seo et al. in view of Shih et al, Sui et al., and Tam et al.
Claims 1-12, 14-22, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Seo et al. in view of Shih et al. and Sui et al. as applied to claims 1-12, 15-22, and 24 above, and as further evidenced by Huang et al. (Journal of Polymer Science B: Polymer Physics 2001 39: 496–506).
Seo et al. in view of Shih et al and Sui et al. render obvious the limitations of instant claims 11-12, 15-22, and 24, where the PEG solvent weight average molecular weight can range from 150 to 1100 Da based on Shih et al. Seo et al. provide an approximately 1:1 mass ratio of liquid PEG to water in their dilution of the block copolymer drug and PEG solvent solution (see example 7). The occurrence of a eutectic mixture between the water and PEG liquid which compose the external aqueous solution is not detailed. Huang et al. teach that a eutectic solution occurs between water and PEG once it has a molecular weight of 1000 Da and at various concentrations (see abstract and page 498 and figure 1 and 3). They show that the eutectic point temperature for the solutions are higher than -50°C (see figure 3). Since the overlap between the prior art range and the claimed range for the PEG solvent includes sizes of 1000 Da and beyond and renders the claimed rang obvious, the occurrence of a eutectic mixture also is obvious. Therefore claims 1-12, 14-22, and 24 are obvious over Seo et al. in view of Shih et al and Sui et al. as evidenced by Huang et al.
Response to Arguments
Applicant's arguments filed October 13, 2025 have been fully considered. In light of the amendment to the claims, the objection, rejection under 35 USC 112, rejections under 35 USC 102, and the rejection over Seo et al. as the sole reference under 35 USC 103 are hereby withdrawn. The remaining rejections under 35 USC 103 are modified and based upon the Seo et al. in view of Siu et el. The applicant’s arguments against this rejection are not persuasive.
The applicant argues that because Sui et al. teach methods of producing micelles by preparing a solution from liquid PEG and a PEG block, where the PEG liquid is removed, then their teachings do not support such a method when the PEG is not removed. To the contrary, Sui et al. also teach a method of making a micelle preparation from a solution of PEG solvent and PEG block copolymer where the PEG solvent is not removed, as was noted in the rejection. Shih et al. has been cited as a new reference to further reiterate the recognized utility of this technique for preparing micelle drug vehicles and the motivation to employ a PEG solvent specifically because it does not need to be removed due to its biocompatibility profile.
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 CARALYNNE E HELM whose telephone number is (571)270-3506. The examiner can normally be reached Mon-Fri 9-5.
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/CARALYNNE E HELM/Examiner, Art Unit 1615
/MELISSA S MERCIER/Primary Examiner, Art Unit 1615