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 .
Receipt is acknowledged of Applicant’s Amendment filed on 06/25/2026.
Claims 1, 6, 9-10, 14, 16, 19 have been amended.
Claims 31-34 have been added.
Claims 2-5, 13, 15, 30 have been canceled.
Claims 1, 6, 9-12, 14, 16-20, 22, 31-34 are pending in the instant application.
Claims 10, 12, 17-20 are withdrawn from consideration.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112, 2nd paragraph
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.
Claims 1, 14, 16, 9, 31, 33 are 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 1 contains the term "p-SCN-Bn-DOTA", which is not defined by the claims. Claims must stand alone to define the invention, and should not rely on the description or the drawings to give them meaning (see Ex Parte Fressola, 27 USPQ 2d 1608). Thus, claim 1, at the very least, should define "p-SCN-Bn-DOTA" by its formal name; once "p-SCN-Bn-DOTA" is defined, the term "p-SCN-Bn-DOTA" may be subsequently recited.
Claims 14, 16 and 33 contains the terms "PD-1, PDL1, CTLA-4" and “CD47”, which is not defined by the claims. Claims must stand alone to define the invention, and should not rely on the description or the drawings to give them meaning (see Ex Parte Fressola, 27 USPQ 2d 1608). Thus, claim 14, 16 and 33, at the very least, should define "PD-1, PDL1, CTLA-4" and “CD47” by its formal name; once "PD-1, PDL1, CTLA-4" and “CD47” are defined, the terms "PD-1, PDL1, CTLA-4" and “CD47” may be subsequently recited.
Regarding claims 9 and 31, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Note, withdrawn claim 10 also has the “such as” issue.
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.
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, 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over GERBER et al (Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts. Am J Nucl Med Mol Imaging 2015;5(5):493-503) in view of ALLEN (A comparative evaluation of Ac225 vs Bi213 as therapeutic radioisotopes for targeted alpha therapy for cancer. Australas Phys Eng Sci Med (2017) 40:369–376) and SIMON et al (US 9,603,954).
Regarding claims 1 and 22, GERBER teaches a method of targeting and diagnosing non-small cell lung cancer (“NSCLC”; see abstract) comprised of: administering to human patients (see pg. 500, 2nd col) a conjugated composition comprised of: radiolabeled 111In (see abstract); conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (see abstract; and pg. 500, 2nd col); and bavituximab (see title and abstract), which is a phosphatidylserine-targeting monoclonal antibody (see title and abstract).
GERBER further teaches potential role for immunotherapies such as checkpoint inhibitors and possibilities include conjugation of Bavituximab to a therapeutic radioisotope to capitalize on the antibody’s apparent tumor specificity (see pg. 501, bottom of col. 1-2). Thus, it would have been obvious to add checkpoint inhibitors and therapeutic radioisotopes for treating the tumor.
GERBER does not teach the specific therapeutic radioisotope, such as 225Ac; or the specific bifunctional chelator, such as p-SCN-Bn-DOTA.
ALLEN teaches that the prior art had known of therapeutic radioisotope, such as 225Ac, for treating cancer (see title and abstract).
SIMON teaches the prior art had known of using p-SCN-Bn-DOTA (see abstract; and col. 2, line 49-50) to conjugate a radionuclide, such as 225Ac (see abstract; and col. 8, line 55+), to a monoclonal antibody (see abstract; and col. 9-10).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a therapeutic radioisotope, such as 225Ac. The person of ordinary skill in the art would have been motivated to make those modifications, because it would treat the tumor and reasonably would have expected success because GERBER teaches using therapeutic radioisotope to capitalize on the antibody’s apparent tumor specificity.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using p-SCN-Bn-DOTA to conjugate. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because p-SCN-Bn-DOTA is a functional equivalent of DOTA compounds used for conjugation.
Regarding claim 6, the prior art would be capable of increase cell surface exposed phosphatidylserine on cancer cells, because the prior art administered the composition with the same ingredients as claimed by Applicant, unless proven otherwise.
Note, Applicant’s specification has no experiment showing the recited specific composition treating non-small cell lung cancer. Rather, Applicant’s specification appears to be a laundry list of known cancer treating agents and a laundry list of cancers.
Claim(s) 1, 6, 9, 11, 14, 16, 22, 31-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over GERBER et al (Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts. Am J Nucl Med Mol Imaging 2015;5(5):493-503) in view of ALLEN (A comparative evaluation of Ac225 vs Bi213 as therapeutic radioisotopes for targeted alpha therapy for cancer. Australas Phys Eng Sci Med (2017) 40:369–376) and SIMON et al (US 9,603,954) and BURAK et al (US 2021/0390789).
As discussed above, the references teach Applicant’s invention.
The references do not teach further using immune checkpoint therapy, such as PD-1.
BURAK teaches the prior art had known of treating cancer, such as non-small cell lung (see [0022]) comprised of: administering in a lower effective dose (see [0007]; and [0089]) radionuclide, such as 225Ac (see abstract; and [0167]) with checkpoint inhibitors (see abstract), such as programmed death ligand 1 (“PD-L1”; see [0178]). Additional disclosures include: single dose (see [0199]); experiment on murine colon carcinoma model (see [0219]); 400 nCi dose of 225Ac was given to mice (see [0221]); checkpoint inhibition combination therapy with radionuclide improves an immune response to tumor (see [0005]-[0007]).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using immune checkpoint therapy, such as PD-1.
The person of ordinary skill in the art would have been motivated to make those modifications, the combination therapy would improve response in treating tumors and reasonably would have expected success because the references dealt in the same field of endeavor, such as treating cancer.
The references do not specifically teach administering the antibody protein and radiation dosages in the amounts as claimed by Applicant. The amount of therapeutic radiation dosages and targeting antibody proteins in a method to treat cancer using therapeutic radioisotope active agents and targeting antibody proteins is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal radiation dosages and targeting antibodies in order to best achieve the desired results, such as effective targeting and treatment of the cancer with minimal adverse effects when treating human patients. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of radiation dosage and targeting antibody amounts would have been obvious at the time of Applicant's invention.
Response to Arguments
Applicant argues that "PD-I", "PD-LI", and "CTLA-4" (Claim 14) specifically, these are standardized protein nomenclature designations. PD-I (Programmed Death-I), PD-LI (Programmed Death-Ligand 1), are immune checkpoint proteins. CTLA-4 (Cytotoxic TLymphocyte-Associated protein 4) is an immune checkpoint receptor. These designations are approved by the HUGO Gene Nomenclature Committee (HGNC), the international authority for human gene naming. They represent core knowledge for anyone skilled in immuno-oncology as of the August 2021 priority date. Requiring "formal chemical names" for these well-established proteins is akin to requiring the full chemical names for "DNA" or "ATP." As to "p-SCN-Bn-DOTA" (previously recited in Claim 30, now in claim 1), this is a well-recognized abbreviation in radiopharmaceutical chemistry for S-2-(4-Isothiocyanatobenzyl )-1, 4, 7, I 0-tetraazacyclododecane tetraacetic acid, a commercially available bifunctional chelating agent which is completely described by and equated with the full chemical name and source at para’ 24 (on page 32) of the originally filed specification. This chelator is recognized by this name in the art for conjugating certain radiometals to antibodies and is sold commercially under this designation.
The Examiner finds this argument unpersuasive, because as discussed in the rejection, Claims must stand alone to define the invention, and should not rely on the description or the drawings to give them meaning (see Ex Parte Fressola, 27 USPQ 2d 1608). Thus, claim 21, at the very least, should define "p-SCN-Bn-DOTA" by its formal name; once "p-SCN-Bn-DOTA" is defined, the term "p-SCN-Bn-DOTA" may be subsequently recited. Claims 14, 16 and 33 contains the terms "PD-1, PDL1, CTLA-4" and “CD47”, which is not defined by the claims. Claims must stand alone to define the invention, and should not rely on the description or the drawings to give them meaning (see Ex Parte Fressola, 27 USPQ 2d 1608). Thus, claim 14, 16, 33, at the very least, should define "PD-1, PDL1, CTLA-4" and “CD47” by its formal name; once "PD-1, PDL1, CTLA-4" and “CD47” are defined, the terms "PD-1, PDL1, CTLA-4" and “CD47” may be subsequently recited.
Applicant argues that Gerber radiolabels bavituximab with min for diagnostic imaging purposes, not therapeutic treatment. The presently claimed invention specifically uses the therapeutic radionuclide 225 Ac, an alpha particle emitter, at therapeutic doses for treating cancer. The differences between diagnostic imaging and therapeutic treatment are substantial. The leap from diagnostic imaging (Gerber) to therapeutic treatment (presently claimed invention) is not an obvious modification. It requires: (1) selecting different radionuclides with different physical properties and types of radiation emitted thereby; (2) determining appropriate therapeutic dose ranges, especially with respect to radiation dose (not taught by Gerber's imaging doses); (3) addressing different safety and efficacy considerations; and (4) achieving different clinical endpoints.
The Examiner finds this argument unpersuasive, because GERBER further teaches potential role for immunotherapies such as checkpoint inhibitors and possibilities include conjugation of Bavituximab to a therapeutic radioisotope to capitalize on the antibody’s apparent tumor specificity (see pg. 501, bottom of col. 1-2). Thus, it would have been obvious to add checkpoint inhibitors and therapeutic radioisotopes for treating the tumor. Additionally, Applicant’s specification has no experiment showing the recited specific composition treating non-small cell lung cancer. Rather, Applicant’s specification appears to be a laundry list of known cancer treating agents and laundry list of cancers.
Applicant argues that Applicant has carefully reviewed Burak (US 2021/0290789) in its entirety and can confirm that Burak does not mention phosphatidylserine, PS-targeting, or bavituximab whatsoever. Burak teaches general radioimmunoconjugates combined with checkpoint inhibitors. The radioimmunoconjugates in Burak can target any antigen. There is no limitation to, teaching of, or suggestion regarding phosphatidylserine targeting specifically, and thus no guidance. Thus, one of ordinary skill could not be motivated to specifically apply Burak's teachings about general radioimmunoconjugates with checkpoint inhibitors to phosphatidylserine-targeting antibodies. Burak provides no bridge between its general radioimmunoconjugate teaching and any specific application to PS-targeting agents.
The Examiner finds this argument unpersuasive, because the primary reference GERBER teaches phosphatidylserine, PS-targeting, and bavituximab> BURAK is a secondary reference to show that the prior art had known of of treating cancer, such as non-small cell lung (see [0022]) comprised of: administering in a lower effective dose (see [0007]; and [0089]) radionuclide, such as 225Ac (see abstract; and [0167]) with checkpoint inhibitors (see abstract), such as programmed death ligand 1 (“PD-L1”; see [0178]). Additional disclosures include: single dose (see [0199]); experiment on murine colon carcinoma model (see [0219]); 400 nCi dose of 225Ac was given to mice (see [0221]); checkpoint inhibition combination therapy with radionuclide improves an immune response to tumor (see [0005]-[0007]).
Applicant argues that Claims 9 and 11 reciting Specific Dosage Ranges: The claims recite specific dosage ranges that are not taught by Burak: Claim 9 recites radiation dose of 0.1 to 50 μCi/kg subject body weight, or 0.1 to 5 μCi/kg, or 5 to 20 μCi/kg. Claim 11 recites administered as a single dose. While Burak may teach single dose administration generally, Burak does not teach these specific dose ranges for PS-targeting radioimmunoconjugates, nor does Burak teach that these specific ranges would be optimal or even appropriate. The Examiner characterizes dose optimization as "routine," but dosimetry for alpha-emitters like 225 Ac (which has unique properties including short path length and high linear energy transfer) is non-trivial. The specific ranges claimed may represent a low-dose radioimmunotherapy paradigm that is not obvious from Burak's general teaching.
The Examiner finds this argument unpersuasive, because as discussed in the rejection, the amount of therapeutic radiation dosages and targeting antibody proteins in a method to treat cancer using therapeutic radioisotope active agents and targeting antibody proteins is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal radiation dosages and targeting antibodies in order to best achieve the desired results, such as effective targeting and treatment of the cancer with minimal adverse effects when treating human patients. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of radiation dosage and targeting antibody amounts would have been obvious at the time of Applicant's invention. Additionally, Applicant’s specification has no experiment showing the recited specific composition treating non-small cell lung cancer. Rather, Applicant’s specification appears to be a laundry list of known cancer treating agents and a laundry list of cancers.
Applicant argues that Simon (US Patent No. 9,603,954) teaches methods for conjugating 225 Ac to antibodies using p-SCN-Bn-DOTA. It is a process patent focused on conjugation chemistry, not a patent about therapeutic applications or antibody selection. Simon does not teach: (1) which antibodies to conjugate with 225Ac; (2) why to use PS-targeting antibodies; (3) therapeutic applications for cancer treatment; or ( 4) the specific combination of PS-targeting plus 225Ac plus checkpoint inhibitors. Simon describes a conjugation method that could be applied to any antibody. It provides no teaching, suggestion, or motivation regarding phosphatidylserine-targeting antibodies specifically.
The Examiner finds this argument unpersuasive, because as discussed in the rejection, it would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using p-SCN-Bn-DOTA to conjugate. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because p-SCN-Bn-DOTA is a functional equivalent of DOTA compounds used for conjugation.
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.
Telephonic Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAKE MINH VU whose telephone number is (571)272-8148. The examiner can normally be reached Mon-Fri 9:00am-5:30pm.
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/JAKE M VU/Primary Examiner, Art Unit 1618
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