DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Applicants' arguments, filed November 21, 2025, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Election/Restrictions
New claim 43, drawn to a product, has been withdrawn from consideration as being drawn to a non-elected invention. Restriction between the method of delivering an active agent to a target cell (Group I) and product claims (Group II) was set forth in the Restriction Requirement mailed July 20, 2023. Group I comprising the method of delivering an active agent to a target cell was elected in the response filed September 18, 2023.
Response to Amendment
The declaration under 37 CFR 1.132 filed November 21, 2025 is insufficient to overcome the rejection of claims 1 – 12, 14 – 17, 19, 20, 22 – 27 and 38 – 42 based upon Ferrari et al. and additional secondary references as set forth in the last Office action because: the declarations mainly contains opinions and conclusions without supporting data as to how the conclusions were drawn and does not establish evidence of unexpected results reasonable commensurate in scope with the claims that outweighs the prima facie case of obviousness. As claim 43 is withdrawn from consideration (see above), the statements relating to claim 43 will not be addressed.
The declaration states that in the expert opinion of the Declarant, the method of claims 1 and 38 demonstrates unexpectedly superior results as not simply the speed, but the combination of where and when cleavage of the hydrazone bond occurs inside the cell is key to successful drug delivery in this context. If the hydrazone bond is cleaved too quickly, the drug will release in the blood before reaching the target cells or the drug will release into the cell before delivery to the nucleus when in the more acidic environment within a cancer cell. Drug release too close to the cell wall [animal cells have a cell membrane and not a cell wall so this statement it not clearly understood but assumed to be referring to the cell membrance] with result in the cell-surface efflux pumps removing all or most of the active agent before it reaches the nucleus. The therapeutic function of the drug will not be performed if the hydrazone bond is cleaved too slowly. Doxorubicin (Dox) conjugated to poly-L-glutamic acid (pDox) via a hydrazone bond released at a better intermediate rate to deliver the drug in proximity to the nucleus with pDox released from microparticles into the targeted tissue were taken up by cells wherein the quite acidic environment of the late-stage endosomes and lysosomes accelerates hydrazone bond cleavage to release Dox in the vicinity of the nucleus. Dox release deep in the cell makes the Dox less prone to expulsion from the cell via multi-drug resistant pumps. A complete citation to Rong et al. is provided on p 4 of the declaration but no copy of the reference was provided for consideration by the Examiner. It is the opinion of the Declarant that the degree to which the active agents tethered to biodegradable polymers via a hydrazone bond efficiently targets and delivers active agent to selectively kill cancer cells could not have been predicted at the time this application was filed. The magnitude of the unexpected efficacy and safely advantages observed arises from the two coordinated steps that were not predictable from the cited art: (i) acid-triggered cleavage of the hydrazone linker only in acidic endosomal/lysosomal compartments (not at physiological pH), and (ii) vesicular trafficking to perinuclear regions before cleavage, which positions released doxorubicin at the nucleus and beyond the reach of membrane drug-efflux pumps. The beneficial results discovered for pDox are expected to be consistent across the recited active agents and polymers used because the active agents are tethered to the polymer via the same hydrazone bond and the degradation of mechanisms [sic] are much slower than the hydrolysis of the hydrazone bond. Active agent uptake [presumably by the target cell] are expected to be consistent regardless of the choice of active agent and polymer selected.
These statements are unpersuasive. While an opinion as to a legal conclusion is not entitled to any weight, the underlying basis for the opinion may be persuasive. In re Chilowsky, 306 F.2d 908, 134 USPQ 515 (CCPA 1962) (MPEP 716.01(c)). The declarations present conclusions and opinions but no data as the actual behavior of the claimed conjugates. There is a brief mention of microparticles but the discussion focuses almost exclusively on the polymer-hydrazone bond-active agent conjugate. While this element is an important part of the claimed method, the claims also require a porous oxide material or porous etched material with a plurality of reservoirs, that can also be targeted (e.g., claim 10), having the polymer-hydrazone bond-active agent conjugate dispersibly contained within those reservoirs that is then released at the target cell. One of ordinary skill in the art would reasonably expect loading into such a structure to alter the behavior of the conjugate in the bloodstream as the polymer-hydrazone bond-conjugated alone is not administered directly into the blood stream. No specific data for any of the conclusions is provided along with what would be expected given the known pH dependent cleavage rate of hydrazone bonds and pH of intracellular structures. The sensitivity of hydrazone bond cleavage at different pH values is an inherent property (see Figure 6 of Qi et al., Frontiers in Pharmacology, 2018 and Dockery and section 3.1.1 of Dockery et al., Adv Cancer Res, 2018). The preamble of claim 1 and 38 is “[a] method of delivering an active agent to a target cell in a subject in need thereof” (emphasis added) so a therapeutic effect is not required and the only active step in each claim is administration to such a subject of the composition of porous particles whose reservoirs contain the polymer-hydrazone bond-active agent conjugate. The claims do not require release of the therapeutic agent “in the vicinity of the nucleus”. The claims recite a Markush group for the active agent and while most items listed are used almost exclusively for the treatment of cancer but vinca alkaloids in particular have other uses of treating diabetes, high blood pressure or as a disinfectant (Moudi et al, Int J Preventive Med, 2013, p 1232, col 1, ¶ 1). As the declaration fails to establish a clear nexus with the claimed method, does not reference any evidence of record or present additional evidence in support of the conclusions offered to demonstrate the stated behavior of the polymer-hydrazone bond-active agent conjugate is in fact unexpected, the evidence of record in support of the alleged unexpected results does not outweigh the prima facie case of obviousness.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1 – 12, 14 – 17, 19, 20, 22 – 27, 40 and 42 were rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ferrari et al. (US 2008/0311182) in view of Oh et al. (WO 99/59548) and Xiong et al. (Biomaterials, 2010). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed July 1, 2025 and those set forth herein.
Applicants traverse this rejection on the grounds that the methods recited in claims 1 and 38 exhibit unexpectedly superior properties and references the concurrently filed declaration. Claim language about the hydrazone bond being the particular cleavable bond, entering the target cell via vesicular transport and active agent release after cleavable bond cleavage is highlighted. The majority of the remarks is taken from the declaration that was addressed in detail above.
As discussed herein, the prior art renders obvious the preparation of a polymer -hydrazone bond-active conjugate as required by the instant claims that is located within the reservoirs of a porous particle that are then administered to a subject as required by claim 1. Applicants bear the burden of explaining the evidence offered in supported of the alleged unexpected results (see MPEP 716.02 et seq.) including what the expected results would be. The declaration does not provide any evidence as to the results observed and does not address what the expected results would be. Hydrazone bonds are known to be pH sensitive and without establishing what the expected results would be, it cannot be determined if the results obtained for the claimed drug conjugate are in fact unexpected. A nexus between the claimed invention and the secondary evidence is also required for that evidence to be of probative value (see MPEP 716.01(b)) and that has not been clearly established. As the evidence of record in support of the alleged unexpected results does not outweigh the prima facie case of obviousness, the obviousness rejection is maintained.
Claims 1 – 12, 14, 15, 17, 19, 20, 22 – 27, 38, 39 and 41 were rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ferrari et al. (US 2008/0311182) in view of Li (Adv Drug Del Rev, 2002) and Xiong et al. (Biomaterials, 2010). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed July 1, 2025 and those set forth herein.
No specific arguments regarding this rejection were set forth for the Examiner to address herein.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Regarding the nonstatutory double patenting rejections below that all based on US 10,842,749, Applicants state that no permissible combination of the cited references discloses or renders obvious all of the recitations of amended claim 1 and claim 38 as argued previously.
As discussed in greater detail, these arguments are unpersuasive. The claims of US’749 recite poly-L-glutamic acid-hydrazone bond-doxorubicin conjugates used in a method with the same active step as the instant claims. Given the broadening amendment to claim 1 to no longer exclude doxorubicin-hydrazone bond-polyglutamic acid, there is now even more overlap between the claims of US’749 and those of the instant application.
Claims 1 – 12, 14 – 17, 19, 20, 22 – 27, 38, 39 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17 - 59 of U.S. Patent No. 10,842,749. This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed July 1, 2025 and those set forth herein.
As claim 1 had been broadened to no longer exclude the combination of doxorubicin and poly-glutamic acid, additional claims are now rendered obvious by the claims of US’749 and dependent claims such as claims 18 – 24 and 27 – 31 recite the same limitations as the dependent claims of the instant application.
Claims 1 – 12, 14, 15, 17, 19, 20, 22 – 27, 38, 39 and 41 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17 - 59 of U.S. Patent No. 10,842,749 in view of Li (Adv Drug Del Rev, 2002). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed July 1, 2025 and those set forth herein.
Claims 1 – 12, 14 – 17, 19, 20, 22 – 27, 40 and 42 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17 - 59 of U.S. Patent No. 10,842,749 in view of Ferrari et al. (US 2008/0311182) in view of Oh et al. (WO 99/59548) and Xiong et al. (Biomaterials, 2010). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed July 1, 2025 and those set forth herein.
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 Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618