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 .
Summary
Receipt of Applicant’s Remarks and Amendments filed on 01/16/2026 is acknowledged. Claims 1-16 are pending.
Claims 2-5, 9-10 and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. The election is made FINAL.
Claims 1, 11, 13-15 are amended.
Claims 1, 6-8, and 11-15 are pending and under examination in this application.
Claim Objections
In view of corrections made on claims 2-5, 9-10 and 16, the objections are withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 6-8 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Shengrong et al. (CN 104689330 A) hereinafter the reference is referred as Shengrong in in view of Huang et al. (WO 20180534 A1) hereinafter the reference is referred as Huang.
Shengrong teaches antitumor drug PEGylation and applications of the antitumor drug PEGylation in reversal of tumor multidrug resistance, wherein the PEGylated antitumor drug is prepared by conjugating activated PEG onto an antitumor drug, and can be used for preparing the drug for reversal of tumor multidrug resistance, and according to the present invention, the antitumor drugs (particularly water insoluble drugs) containing amino, carboxyl, hydroxyl and other modifiable groups are PEGylated so as to increase the water solubility, such that excellent characteristics of micelle self-assembly forming, production of invisible nanoparticles or active targeting tumor nanoparticles, drug release behavior regulation, system toxicity reducing, biological half-life improving, EPR effect production, tumor passive/active targeting production, tumor multidrug resistance reversal and the like are provided (abstract) and Figure 1 below is a 1 H NMR spectrum of PEG-RAPA:
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653
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Regarding claims 1 and 14, Shengrong teaches PEGylated antitumor drug prepared by coupling activated (page 2, ¶ 3), wherein the Anti-tumor drugs (i.e., rapamycin) can self-assemble to form invisible nanoparticles after PEGylation, resulting in EPR effect, passive targeting of tumors and long-blood circulation (page 2, ¶ 15).
Regarding claims 6 and 8, Shengrong teaches the PEGylated antineoplastic agent can self-assemble to form micelles, make invisible nanoparticles or make active targeted tumor nanoparticles, and the prepared micelles, stealth nanoparticles or actively targeting tumor nanoparticles can produce an EPR effect. Moreover, the prepared micelles and stealth nanoparticles have passive targeting and long-blood circulation in vivo (page 2, ¶ 11). Therefore, the limitation of a nano-drug comprising PEGylated rapamycin is taught.
Regarding claims 14 and 15, Shengrong teaches the PEGylated antitumor drug can be linked to a target, wherein the target comprises folic acid, biotin, RGD, an
antibody or a nucleic acid aptamer (claim 4) and wherein the cytotoxic antitumor drug is a drug acting on a DNA chemical structure, a drug affecting nucleic acid biosynthesis, a drug acting on nucleic acid transcription, and a topoisomerase inhibition Drug or drug that interferes with tubulin synthesis (claim 7).
Huang teaches protein-based drug delivery systems to treat disease for chemotherapeutic agents (page 1, lines 19-21). Moreover, Huang discloses in one embodiment, the surface altering agents such as PEG are chemically bound or physically adsorbed to the proteins forming the nanocages or the proteins are recombinantly produced with surface modifying proteins or peptides. In another embodiment, the proteins are chemically linked, physically adsorbed to the assembled protein nanocages (page 15, lines 16-20). Notably, Huang discloses preferred classes of small molecules to include in the protein nanocages include cancer therapeutics such as chemotherapeutic agents, cytokines, chemokines, and radiation therapy, and the majority of chemotherapeutic drugs can be divided in to: alkylating agents, 30 antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antitumor agents. All of these drugs affect cell division or DNA synthesis and function in some way (page 22, lines 26-32), and the protein nanocage agent can be included with rapamycin (page 68, claim 14).
Regarding claim 7, Huang teaches the percent agent loading is from about 1 % to about 80%, from 15 about 1 % to about 50%, preferably from about 1 % to about 40% by weight, more preferably from about 1 % to about 20% by weight, most preferably from about 1 % to about 10% by weight (Page 20, lines 10-14).
Regarding claims 11, 12 and 13, Huang teaches in the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof, and the powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles, and methods for making porous particles are well known in the art. Moreover, Huang teaches sucrose (page 38, line 17) corresponding to the freeze-drying protective agent and pharmaceutically acceptable carrier (page 10, lines 23-32), for example carriers as polyethyleneimine (page 22, line 21), and suitable liquid carriers include, but are not limited to, distilled water, de-ionized water, pure or ultrapure water, saline, and other physiologically acceptable aqueous solutions containing salts and/or buffers, such as
phosphate buffered saline (PBS), Ringer's solution, and isotonic sodium chloride, or any other aqueous solution acceptable for administration to an animal or human (page 34, lines 24-29), and dry powder formulations are typically prepared by blending one or
more protein nanocages or the self-assembling proteins or peptides with one or more pharmaceutically acceptable carriers. Optionally, additional active agents may be incorporated into the mixture, and the mixture is then formed into particles suitable for pulmonary administration using techniques known in the art, such as lyophilization, spray drying, agglomeration, spray coating, coacervation, low temperature casting, milling (e.g., air-attrition milling Get milling), ball milling), high pressure homogenization, and/or supercritical fluid crystallization (page 36, lines 12-20), and the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof (page 37, lines 26-29).
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 synthesize the PEG-RAPA nano-drug as taught by Shengrong and incorporate the freeze-dried preparation method with a pharmaceutically acceptable carrier known in the art as taught by Huang. One would have been motivated to use a freeze-dried preparation method because this technique yields a powder of the active ingredient plus any additional desired ingredient in the composition in order to increase dissolution of the particles and the benefits of the freeze-dried preparation are well known in the art. The product structure of Shengrong that was determined by the NMR spectrum differs from the claimed structure of formula (1), however, it can be determined that the product structure is the same according to the types of raw materials and the reaction mechanism disclosed in Shengrong, and the claimed distinguishing feature on the degree of polymerization of PEG would have been obvious to a person having skilled in the art to perform. Moreover, Shengrong
discloses that "the number average molecular weight of PEG is 0.1 K-1000 K" (claim 2), and a person skilled in the art would have been motivated to select PEG having a suitable degree of polymerization by means of conventional experiments. Therefore, the technical solution of the claimed PEGylated rapamycin compound represented in formula (1), wherein n is 10-150, would have been obvious to a person skilled in the art to solve. The combined teachings of Shengrong in view of Huang discloses PEGylated rapamycin composition and methods for preparation thereof.
One of ordinary skill in the art would have found it obvious to apply the different methods of preparation and use the technique of freeze-drying method to improve the dissolution of the particles upon delivery and use as taught by Huang. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Response to Arguments
Applicant's arguments filed 01/16/2026 have been fully considered but they are not persuasive. Applicant argues:
Argument 1: Shengrong Does Not Disclose the Specific Structure of Formula (I)
The argument is unpersuasive. Shengrong discloses the same PEG-RAPA conjugate via activated PEG coupling to rapamycin’s hydroxyl group, forming an ester link (abstract; page 2, ¶3; Figure 1 structure). Applicant’s cited NMR peaks (4.09 ppm (a); 3.31 ppm (c)) match Shengrong’s spectrum (Figure 1, page 5), confirming identical bonding (PEG to rapamycin backbone). Any visual difference in depiction is immaterial; identity is established by raw materials (activated PEG, rapamycin) and mechanism (esterification, common for OH-PEGylation). Self-assembly into nanoparticles does not preclude the high-purity conjugate—it’s the same molecule.
Argument 2: n=10-150 Is Not Routine
The argument is unpersuasive. Shengrong’s PEG MW (0.1K-1000K) overlaps/encompasses n=10-150 (claim 2). Selection is optimizable for solubility/micelle stability (page 2, ¶11), a result-effective variable (MPEP 2144.05(II)).
Argument 3: Huang Doesn’t Cure Deficiencies; Focus on EPR vs. Immune Tolerance
Huang is not relied on for the compound but for obvious formulations and combinations (freeze-drying, carriers, protein co-delivery). Shengrong’s deficiencies (if any) are minimal, as it teaches the compound. The claimed use (ADA inhibition) is intended use, not structurally limiting for Claim 1 (compound per se). For Claims 14-15, combining PEG-RAPA with biological drugs (e.g., proteins like urate oxidase) is obvious per Huang’s rapamycin-protein nanocages (page 68, claim 14), motivated by enhanced delivery/immunomodulation.
Argument 4: Unexpected Results (Superior ADA Inhibition vs. Rapa PLGA Nanoparticles)
The argument is unpersuasive. There is no direct comparison to closest prior art (Shengrong’s PEG-RAPA), and data must be commensurate in scope (n=10-150; all biological drugs, and truly unexpected results, and superiority over Shengrong’s PEG-RAPA likely provides similar benefits (solubility/targeting).
The amendments do not overcome the rejection; claims remain obvious.
Conclusion
No claims are allowed.
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.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615