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 .
Applicants' arguments, filed November 24, 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.
Claim Rejections - 35 USC § 112 – Failure to Further Limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 requires that the intended use of the composition is “for use in diagnosing and treating tumor tissue-covering biofilm”. Claim 18 as currently presented merely requires the compositions of claim 1, so the composition itself is not further limited by this claim. The intended use recitation in claim 18 of “[a] combined diagnostic and therapeutic agent for treating tumor tissue-covering biofilm” is worded slightly differently but encompasses the exact same subject as the intended use recitation of claim 1. Therefore claim 18 fails to further limit claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 1, 6, 10, 11, 13 and 18 – 20 were rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (Small methods, 2020) in view of Lehouritis et al. (Sci Reports, 2015). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed June 23, 2025 and those set forth herein.
Applicants traverse this rejection on the grounds that the present invention is neither disclosed nor implied by any of the cited references. Lehouritis is foundational research that highlights the critical clinical problem that the invention addresses but their research focused on planktonic (free-floating) bacteria and left the more complex, clinically prevalent challenge unsolved. The present invention is a novel, integrated system to solve the problem at a more advanced level given the characteristics of biofilms. A novel NIR (near-infrared)-activated AIE (aggregation-induced emission) photosensitizer MeTPP eradicates biofilms by generating high levels of reactive oxygen species (ROS) to physically and chemically disrupt the biofilm to kill embedded bacteria, including those that are drug-tolerant persister cells. The present invention also provides a proactive solution for its most recalcitrant form using photodynamic therapy to clear the biofilm barrier enabling subsequent chemotherapeutic agents to reach their tumor targets unimpeded. Multiple references are cited that were provided on a concurrently filed IDS filed with the 37 CFR 1.17(p) fee which discuss the differences between planktonic bacteria and biofilms. For brevity, the discussion of these references on p 10 – 15 of the Remarks filed November 24, 2025 will not be reiterated here. The present invention with a potent bactericidal photosensitizer enhanced internalization of commercial drugs such as antitumor therapeutics.
These arguments are unpersuasive. The instant claims are drawn to a composition, not a method of use, requiring a combination of a compound of formula (I) as in claim 1 and an anti-tumor therapeutic. Language such as “for use in diagnosing and treating tumor tissue-covering biofilm” in the preamble of claim 1 and “[a] combined diagnostic and therapeutic agent for treating tumor tissue-covering biofilm” in claim 18 are the intended use of the claimed composition that does not breathe life into the body of the claims. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Explicit appreciation by one of ordinary skill in the art before the effective filing date of the present invention that the compounds of Shi et al. would exhibit antibacterial activity against not just planktonic bacteria but also against biofilms is not required to render obvious the claimed combination of compound of formula (I) and an anti-tumor therapeutic. Lehouritis et al. does not need to teach that bacterial biofilms are responsible for the decreased efficacy of drugs such as doxorubicin or gemcitabine and/or that antibacterial agents that might be used to counteract such effects would be required to effectively kill bacteria in biofilms to render the claimed composition obvious. Based on the disclosures of Shi et al. and Lehouritis et al. and the knowledge of the person of ordinary skill in the art, a person of ordinary skill in the art would have been motivated to prepare a composition comprising both an anti-tumor therapeutic such as doxorubicin or gemcitabine with a compound known to generate singlet oxygen to image and selectively kill bacteria over mammalian cells which is the second required component of the claimed composition. Applicants have not presented any evidence that one of ordinary skill in the art would not have had a reasonable expectation of success of preparing the claimed composition rendered obvious by the combined teachings of Shi et al., Lehouritis et al. and the knowledge of an artisan of ordinary skill in the art comprising a known anti-tumor therapeutic whose efficacy was decreased by the presence of bacteria and an agent known to selectively kill bacterial over mammalian cells. There is no evidence of record as unexpected results from the claimed combination of ingredients.
Applicants state that the Examiner previously disagreed with an argument about the use of Shi’s TCP-2 to treat three-dimensional, tumor-tissue covering biofilms and has alleged that the arguments regarding that greater steric hindrance arising from the methyl group as compared to a hydrogen atom of Shi’s compound lacks factual support. Page 16 of the Remarks filed November 24, 2025 provides three supporting references that were provided on a concurrently filed IDS filed with the 37 CFR 1.17(p) fee. MeTPP represents a significant and non-obvious advancement over the TBP-2 molecules disclosed by Shi et al. The methyl group introduction onto the triphenylamine donor is done deliberately to exploit steric hindrance to fundamentally alter the photophysical behavior of the molecule. This design is rigorously supported by recent publications in high impact journals including ACS Nano and Advanced Materials. For brevity, the discussion on p 17 – 19 of the Remarks filed November 24, 2025 will not be reiterated here. The methyl modification is not a trivial alteration but a critical design element that produces a multi-faceted enhancement that overcomes the inherent limitations of previous structures such as TBP-2.
These arguments are unpersuasive. The properties of chemical compounds are determined by their structure and compounds of different structures would reasonably be expected to have different properties. The question is not whether different compounds have different properties but rather if the observed differences in properties between different compounds are unexpected. One of the cited references, Wang et al. (Adv Materials, 2018) is prior art and suggests improved singlet oxygen for the methyl containing triphenylamine group compared to a triphenylamine group with hydrogen atoms, although the compounds studied have a different heterocycle adjacent to the triphenylamine moiety than the claimed compounds. While neither Wan et al. or Ma et al., the other two cited references, qualify as prior art, the teachings of the effect of the addition of methyl groups to the triphenylamine moiety of fluorescent compounds and that such as change improves the properties align with the teachings of Wang et al. This suggests that the effect of methyl substitution would be reasonably predictable to one of ordinary skill in the art. The evidence of record does not establish that the differences between TBP-2, the compound of Shi et al. with hydrogen containing triphenylamines, and the compound of formula (I) of instant claim with methyl groups on the triphenylamine moiety, demonstrate unexpected or non-obvious properties. Therefore the rejection is maintained.
Claim(s) 1, 6, 10, 11, 13 and 18 – 20 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (Small methods, 2020) in view of Wang et al. (Adv Materials, 2018, cited on IDS filed November 24, 2025 with the timing fee set forth in 37 CFR 1.17(p)) and Lehouritis et al. (Sci Reports, 2015).
PASTE FROM above
Shi et al. discloses the synthesis of TBP-2 with the structure of
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as shown in scheme 1. The compounds are disclosed as AIE photosensitizers that generate with high efficiency singlet oxygen to image and selectively kill bacteria over mammalian cells with activity against both Gram positive (G(+)) and Gram negative (G(-)) bacteria (abstract).
Compounds with methyl groups on the triphenylamine moiety are not disclosed.
Wang et al. studies the properties of the compounds TTPy and MeTTPy that have the following structures as shown in Figure 1A
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that both contain a triphenyl amine group with either hydrogen atoms (TTPy) or methyl groups (MeTTPy), and then a vinyl heterocyclic group connected to a pyridine ring with a quaternary nitrogen in the ring (whole document, e.g., Figure 1A). These compounds are AIE lumogens with simple structures, excellent photostabilities, large Stokes shifts, bright emission, and good biocompatibilities (abstract). As shown in Figures 1B – 1E, the addition of methyl groups to the triphenylamine group produces a shift in the absorption and emission spectra. As shown in Figures 4, MeTTPy generated more reactive oxygen species (ROS; Figure 4A) and greater decomposition of ABDA (9,10-anthracenediyl-bis(methylene) dimalonic acid; Figure 4B). The materials are able to selectively stain cancer cells over normal cells with high specificity and MeTTPy has an extraordinarily high ROS generation efficiency with up to 90.7% ROS quantum yield (¶ bridging cols 1 and 2 on p 8).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to add methyl groups to the phenyl rings of the AIE-active photosensitizer TBP-2 of Shi et al. to improve the efficiency of ROS generation and the antibacterial activity. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Wang et al. discloses that the replacement of hydrogen atoms with methyl groups in the triphenylamine portion of AIE compounds produces a compound with higher ROS generation efficiency and greater ability to decompose ABDA. Given the similarity in structures of the AIE photosensitizers in Shi et al. and Wang et al., the person of ordinary skill in the art would reasonably expect similar improvements in the properties of TBP-2 when methyl groups are present. There is no evidence of record that the differences in properties between TBP-2 and the compound of formula (I) of instant claim 1 are unexpected and/or non-obvious.
The presence of an anti-tumor therapeutic such as gemcitabine or doxorubicin is not disclosed by either reference.
Lehouritis et al. investigated the potential for bacteria to influence the efficacy of small drug chemotherapeutics (whole document, e.g., ¶ 2 on p 1). Two bacterial strains were used to examine for changes in efficacy of cancer cell killing mediated by a range of chemotherapeutic agents (p 2, ¶ 1) and some results are shown in table 1. Using an in vitro screen with the bacteria Escherichia coli and Listeria welshimeri, gemcitabine and doxorubicin reduced the cytotoxity. The cytotoxicities of about 30% of the drugs tested decreased (p 7, ¶ 2). Because of the popularity of gemcitabine, an in vivo model was use that showed support for tumor bacterial growth in vivo and the presence of E. coli also decreased gemcitabine efficacy as shown in figure 4 (see also ¶ bridging p 8 and 9).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to prepare a composition comprising a methylated compound as taught by Shi et al. and Wang et al. as having antibacterial activity and a chemotherapeutic such as doxorubicin or gemcitabine. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Lehouritis et al. discloses that the efficacy of chemotherapeutics such as doxorubicin or gemcitabine is decreased by the presence of bacteria such as E. coli. Thus, one of ordinary skill in the art would prepare a composition containing both a chemotherapeutic agent such as gemcitabine and a compound as required in claim 1 that is capable of generating singlet oxygen to image and selectively kill bacteria over mammalian cells with activity against both Gram positive (G(+)) and Gram negative (G(-)) bacteria, reasonably expecting that such a composition could ameliorate some of the decreased efficacy of doxorubicin or gemcitabine by reducing the amount of bacteria due to the anti-bacterial properties of the compounds rendered obvious by Shi et al. and Wang et al.
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).
Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on November 24, 2025 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b). 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