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 .
Priority
This Application claims priority benefit of U.S. Provisional Application No. 63/361,403, filed December 16, 2021.
Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 9, 2026 has been entered.
Claim Status
Claims 1, 4, 10, 13, 15, and 17-20 are currently pending and subject to examination.
Claim Rejections - 35 USC § 103- Previously Presented
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.
The rejection of claims 1, 4, 10, 13, 15, and 17-20 under 35 U.S.C. 103 as being unpatentable over Dymova et al. (Cancer Communications, Volume 40, Issue 9, p. 406–421, Sep. 2020) in view of by Torgov et al. (US20200283456A1, Published September 10, 2020) is maintained.
Response to Arguments
The Applicant argues that none of the references teach the specific BPA-BPA compound and therefore the references do not teach all the limitations in the claims (Remarks, p. 5-6). These arguments were fully considered but are not persuasive. In arguing that the compound is patentable because the exact compound is not known in the prior art, the Applicant is arguing that the compound must be anticipated in order to be unpatentable. However, compounds can also be rejected on the grounds of obviousness:
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
MPEP § 2144.09.
The claimed compounds has a very close structure to the prior art compounds BPA-Tyr and Tyr-BPA taught by Dymova. The difference is that the claimed compound is BPA-Tyr-BPA. One of ordinary skill in the art would have a reasonable expectation of success to make the compound BPA-Tyr-BPA under the expectation that it would have similar properties to BPA-Tyr and Tyr-BPA. This is strengthened by the fact that amino acids with two BPA moieties are known in the art as demonstrated by Torgov. The relevant compounds are shown below.
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claimed compound;
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(Dymova, Fig. 2, page 410) (Prior Final Action, page 4);
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(Torgov, Specification, paragraph 0140) (Prior Final action, page 4).
Furthermore, the MPEP explicitly states that “mere duplication of parts has no patentable significance unless a new and unexpected result is produced” (MPEP § 2144.4).
The applicant argues that there is not a finite number of predictable solutions in the context of the claimed invention. (Remarks, p. 7). These arguments were fully considered but are not persuasive. As previously mentioned, a prima facie case of obviousness for chemical compounds is found when chemical compounds have very close structural similarities and similar utilities. One of ordinary skill in the art would have a reasonable expectation of success to make the compound BPA-Tyr-BPA under the expectation that it would have similar properties to BPA-Tyr and Tyr-BPA. The Applicant has done nothing more than duplicate a part on Tyr-BPA or BPA-Tyr to make a new compound with the same utility as the prior art compounds. This is a known option as demonstrated by Torgov above.
The Applicant argues that they have shown synergism and superior properties to the prior art compounds (Remarks, p. 8-9). These arguments were fully considered but are not persuasive. The Applicant’s disclosure does not show that di-boronated peptides perform significantly better than mono-boronated peptides. Both the His-BPA mice (mono-boronated) and BPA-BPA mice (di-boronated) were cured:
“His-BPA, and BPA-BPA, dosed at 900 mg/kg with irradiation, had significant tumor regression that was sustained out to 36 days of growth monitoring. Visual inspection and histological examination of the tumor area of a His-BPA treated mouse showed lack of tumor tissue and only scar tissue at the original tumor site, suggestive of actual tumor cures following BNCT treatment.”
Specification, page 52.
Contrary to the Applicants assertion that Fig. 34 shows superior tumor regression on Day 40 versus His-BPA, it is clear that Figure 40 does not show a significant difference between His-BPA and BPA-BPA. The Applicant shows that the His-BPA treated mouse is cured:
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Fig. 34B.
The Applicant argues that BPA-BPA has improved efficiency with 6 minutes of radiation (Remarks, p. 9). Figure 33, however, does not show a significant difference in tumor volume between BPA-BPA and His-BPA with 6 minutes of radiation. The difference in boron accumulation would be expected given that the molecule has two of these elements as compared to two, but the increased accumulation does not show any synergism or even additive effects as discussed above.
The Applicant argues that the claimed invention is not a predictable use of prior art elements because not all compounds synthesized by the Applicant worked or showed good functional data (Remarks, p. 10). These arguments were fully considered but are not persuasive. The prior art establishes that BNCT with BPA is used in the clinic with high efficacy (Dymova, p. 407) and that Tyr-BPA and BPA-Tyr are third generation boron compounds which “show greater specificity for tumor cells, tumor cell nuclei, and tumor cell DNA, so the required concentration of boron compounds for effective BNCT can be reduced.” (id., p. 411). The relevant prior art elements are BPA-Tyr, Tyr-BPA and BPA-BPA, and the Applicant has not demonstrated unpredictable use of these elements.
The affidavit under 37 CFR 1.132 filed Dec. 12, 2025 is insufficient to overcome the rejection of the pending claims based upon 35 U.S.C. 103 as set forth in the last Office action because:
(1) The Applicant does not compare the claimed invention to the closest prior art. The Applicant compares the borylated dipeptide to L-Ala-BPA. In order for an affidavit to rebut a prima facie case of obviousness, the affadavit must compare the claimed subject matter with the closest prior art (MPEP 716.02(e)). L-ala-BPA is not the closest prior art and was not cited in the prior office action. The closest prior art is BPA-Tyr, Tyr-BPA, (Dymova) and/or BAA no. 1 (Torgov). The Applicant shows that a similar boronated aromatic amino acid, His-BPA, performs comparably to the claimed invention (Figs. 33-34). A comparison with the closest prior art is required.
(2) The affidavit also alleges that Dymova teaches that boronated peptides are transported via PEPT1/PEPT2 receptors and not LAT1 and that Dymova reports elevated PEPT1/2 mRNA levels in certain cancer cell lines (affidavit, p. 4). This is simply not true. Dymova does not discuss PEPT1/2 and specifically mentions transport by LAT1:
BPA enters tumor cells by selective uptake mediated by the system L-amino acid transporters (LAT1). The expression of LAT1 is highly up-regulated in various cancers, where it is presumed to contribute to tumor growth by increasing the amino acid supply. The functions of the different transporters (ATB0,+, LAT1, and LAT2) in BPA uptake has been evaluated by high-performance liquid chromatography [19]. Furthermore, (18)F-BPA is also a substrate of LAT1 and shows comparable transport ability with BPA into the tumors, and tissue boron concentration of BPA can be quantitatively estimated using L-[(18)F]BPA/PET [20-23].
Dymova, p. 409.
Torgov also discusses LAT1 mediated transport (e.g. paragraph [0169]).
Reiterated Rejection
Claims 1, 4, 10, 13, 15, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Dymova et al. (Cancer Communications, Volume 40, Issue 9, p. 406–421, Sep. 2020) in view of by Torgov et al. (US20200283456A1, Published September 10, 2020).
Claim 1 is directed towards a composition comprising the compound:
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.
Dymova teaches two similar borylated amino acids (BAAs) for Boron Neutron Capture Therapy (BNCT):
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(Dymova, Fig. 2, page 410).
While these compounds contain a single B(OH)2 instead of two as in the claimed compound, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to duplicate the boron moiety on both ends of the molecule because Torgov teaches compositions for BNCT comprising BAAs with B(OH)2 on both ends of the molecule as in the claimed compound:
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(Torgov, Specification, paragraph 0140);
The invention described herein relates to the field of boron neutron capture therapy (BNCT). Specifically, the invention relates to borylated amino acid (“BAA”) or (“BAAs”) compositions which can be used as a vehicle for neutron capture therapy in humans. The invention further relates to the treatment of cancers and other immunological disorders and diseases.
Torgov, Specification, paragraph 0003.
The MPEP also states that compounds which differ by the successive addition of the same chemical group are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties (MPEP § 2144.09.II).
Furthermore, the Applicant’s disclosure does not show that di-boronated peptides perform significantly better than mono-boronated peptides. Both the His-BPA mice (mono-boronated) and BPA-BPA mice (di-boronated) were cured:
“His-BPA, and BPA-BPA, dosed at 900 mg/kg with irradiation, had significant tumor regression that was sustained out to 36 days of growth monitoring. Visual inspection and histological examination of the tumor area of a His-BPA treated mouse showed lack of tumor tissue and only scar tissue at the original tumor site, suggestive of actual tumor cures following BNCT treatment. Figure 33(B).”
Specification, page 52.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 4 is directed towards kits comprising the composition of claim 1. While Dymova does not teach kits, Torgov teaches kits comprising BAAs:
For use in the laboratory, prognostic, prophylactic, diagnostic and therapeutic applications described herein, kits are within the scope of the invention. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in the method, along with a label or insert comprising instructions for use, such as a use described herein. For example, the containers) can comprise a BAA or several BAAs of the disclosure. Kits can comprise a container comprising a drug unit. The kit can include all or part of the BAAs and/or diagnostic assays for detecting cancer and/or other immunological disorders.
Torgov, Specification, paragraph 0131.
Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to include the claimed compound in a kit. Thus, claim 4 was prima facie obvious at the time of filing.
Claim 13 recites:
A method of performing Neutron Capture Therapy in the treatment of human cancer comprising:
synthesizing a Dosage Unit Form of a borylated di-peptide amino acid (Bdi-AA) composition having the following chemical structure:
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injecting the Bdi-AA into a tumor, whereby the Bdi-AA accumulates into a cell; and
irradiating the Bdi-AA with neutrons.
For step a. the rejection of claim 1 is incorporated herein by reference. One of ordinary skill in the art would be motivated and have a reasonable expectation of success to synthesize the claimed compound because similar compounds are known in the art. Dymova teaches that BAAs are infused into the body and accumulate in the tumor and then the tumor is irradiated with neutrons:
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Dymova, page 409.
The specification shows that the injection into the tumor is performed similarly as the BAAs are injected into the tail vein of tumor bearing mice and the BAA accumulates in the tumor (Specification, page 50). Furthermore, Torgov teaches the steps:
In a further embodiment, the invention comprises methods of concentrating Boron in a cell comprising (i) synthesizing a borylated amino acid (“BAA”); (ii) administering the BAA to a patient, and (iii) irradiating the cell with neutrons.
Torgov, Specification, paragraph 0016.
Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to treat cancer with BCNT by injecting the tumor with the BAA and irradiate the BAA with neutrons. Thus, claim 13 was prima facie obvious at the time of filing.
Claim 15 recites: “The method of claim 13, wherein the Neutron Capture Therapy is Boron Neutron Capture Therapy.” As shown above, both Dymova and Torgov teach BNCT. Therefore, claim 15 was prima facie obvious at the time of filing.
Claim 17 recites: “The method of claim 15, wherein the irradiation comprises epithermal neutrons.” Dymova teaches that BNCT requires epithermal neutrons: “For BNCT implementation, it is necessary to have a beam of epithermal neutrons of high intensity (with energies from 0.5 eV to 10 keV).” (Dymova, p. 415). Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to use epithermal neutrons. Thus, claim 17 was prima facie obvious at the time of filing.
Claim 18 recites: “The method of claim 13, wherein the cancer is colon cancer”. Claim 19 is directed towards treating head and neck cancer with the method of claim 13. Claim 20 recites: “The method of claim 13, wherein the cancer is pancreatic cancer.” Dymova teaches BCNT treats many types of cancer including head and neck cancer:
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Dymova, page 413.
While Dymova does not teach colon cancer and pancreatic cancer, Torgov teaches the treatment of locally invasive malignant tumors with Neutron Capture therapy:
“The term “neutron capture therapy” means a noninvasive therapeutic modality for treating locally invasive malignant tumors such as primary brain tumors and recurrent head and neck cancer and other immunological disorders and disease by irradiating a neutron capture agent with neutrons.”
Torgov et al., paragraph 0066.
Colon cancer and pancreatic cancers are locally invasive malignant tumors. Therefore, one of ordinary skill in the art would have a reasonable expectation of success to treat colon cancer and pancreatic cancer with BCNT as in claim 13. Thus, claims 18-20 were prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(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 HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629