DETAILED ACTION
This Office action details a first action on the merits for the above referenced application No. Claims 1-59 are pending in this application.
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 is a 35 USC 371 National Stage filing of international application No. PCT/IB2022/055680 filed on 19 Jun. 2022, and claims benefit under 35 USC 119(e) to US provisional application No. 63/212,671 filed on 20 Jun. 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12 Mar. 2024 has been considered by the examiner.
Claim Rejections - 35 USC § 112
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 1-25 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. Instant claim 1 is indefinite and confusing since the claims is at first directed to a substant which regulates immune checkpoints (material) and then goes on to recite the intended use of “for use as a medicament for treatment of a tumor of a patient wherein the administration pattern of the medicament comprises administering a therapeutically effective amount of the substance to the tumor in one or more session and implanting seeds carrying radium-224 in the tumor for intra-tumoral alpha-emitter radiotherapy less than two weeks from administering the substance”. It is not clear if the substance being claimed is a substance capable of regulating the immune checkpoints such as pembrolizumab and capable of the recited intended use or if the recited intended use modifies the substance so that it is a combination of a substance and seeds carrying radium-224. For example, claim 10 requires that the substance comprising pembrolizumab. Under the former interpretation, it is not clear if claim 10 is merely claiming for example pembrolizumab, a known prior art immune checkpoint inhibitor. Claims 2-25 depended to claim 1 and fall therewith. For the purpose of compact prosecution, the Examiner is interpreting the substance as claimed in claim 1 to be any substance suitable for regulating immune checkpoints and suitable for the recited intended uses.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-6, 8, 10-15, 17, 19, and 25 is/are rejected under 35 U.S.C. 102(a)(1),(2) as being anticipated by Takeda et al. (US 2023/0141284 A1; published 11 May 2023; see attached 892).
Regarding claims 1-6, 8, 10-15, 17, 19, and 25, Takeda et al. disclose pembrolizumab, atezolizumab, ipilimumab, relatimab, LY3321367, tiragolumab, enoblituzumab, and molalizumab ([0211]). 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. In claim 1, the following recitation amounts to an intended use “for use as a medicament for treatment of tumor of a patient wherein the administration pattern of the medicament comprises administering a therapeutically effective amount of the substance to the tumor, in one or more sessions, and implanting seeds carrying radium-224 in the tumor for intratumoral alpha emitter radiotherapy less than two weeks from administering the substance”. The substance that refers back to a substance recited in the preamble is separate from the seeds carrying radium-224. Claim 10 further defines the substance to comprise pembrolizumab which is an immune checkpoint inhibitor which regulates immune checkpoint and therefore suitable for the recited intended uses. Accordingly, pembrolizumab qualifies as a substance which regulates immune checkpoints and is suitable for use as a medicament for treatment of a tumor of a patient wherein the administration pattern of the medicament comprises administering a therapeutically effective amount of the pembrolizumab to the tumor in one or more sessions and implanting seeds carrying radium-224 in the tumor for intra-tumoral alpha emitter radiotherapy less than two weeks from administering the substance.
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.
Claim(s) 1-9, 25-35, 44-45 and 52-59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Domankevich et al. (WO 2020/089819 A1; published 7 May 2020; see attached 892), in view of Cao et al. (Research Square; published Feb. 2021; see attached 892).
Domankevich et al. teach intratumoral alpha-emitter radiation and activation of cytoplasmic sensors for intracellular pathogen (see title). Domankevich et al. teach a method of treating a patient with a tumor and kits for such treatment. The method includes administering to the patient a substance which activates cytoplasmic sensors for intracellular pathogen in the tumor and treating the tumor with intra-tumoral alpha-emitter radiotherapy within two weeks of administering the substance which activates cytoplasmic sensors for intracellular pathogens (see abstract). Another class of tumor therapy referred to as immunotherapy involves the enhancement of a patient’s immune response against tumor cells (pg. 1). Domankevich et al. teach alpha-emitter radiation optionally including brachytherapy by insertion of seeds carrying alpha emitting atoms such as radium-224 and radium-223 into the tumor. In some embodiments, the daughter radionuclide atoms are slowly released from the seed at a rate of less than 25%, less than 10%, less than 5% or even less than 3% of the radionuclide atoms coupled to the seed per 24 h. The alpha emitter radiation comprises DaRT. The seeds are inserted into the patient with a bioabsorbable coating which prevents alpha-radiation and/or the daughter radionuclides from leaving the seeds (pg. 12). The alpha emitter radiotherapy is applied to the patient for at least 24 h, at least 5 d or even at least 10 d. The alpha emitter radiotherapy is provided to the patient within a given time before or after the ACSIP treatment (pg. 14). Supportive treatment comprises one or more treatments which downregulate checkpoint expression (PD-L1 expression) caused by radiotherapy. Supportive treatment of administering pomalidomide has the effective of countering tissue repair, downregulating inflammation and downregulating PD-L1 expression. Berzosertib (small molecule inhibitor) is another example of a drug which can be used to prevent DNA repair and to down regulate PD-L1 expression. Immunotherapy treatment includes administering a checkpoint blockade such as one or more anti PD-1, anti PD-L1, anti CTLA4, anti TIGIT, anti-LAG3, anti-TIM 3, anti CD134 and/or anti-CD137. (Molecules that internalize immune checkpoints are the same immune checkpoint proteins that the ICIs target.) Checkpoint blockade together with a TLR3 agonist (costimulatory molecule) which simulates the ACSIP from outside the tumor. Additional treatment comprises antiangiogenic factors. The additional treatment comprises iMiDs for example pomalidomide, thalidomide, lenalidomide, and apremilast (pgs.4 and 15). The timing of providing the additional treatment is optionally selected according to the specific type of the additional treatment. Checkpoint inhibitors when provided are administered during or after the alpha emitter radiotherapy, possibly even 3 d or even a week after beginning the alpha-emitter therapy and/or after completion of the alpha emitter radiotherapy (pg. 16). Domankevich et al. teach a kit comprising a sterile package 202 including one or more alpha emitter radiotherapy seeds for insertion into a tumor and one or more doses of an agent for ACSIP induction. The kit further includes on or more drugs required for supportive immune-modulatory treatments (pgs. 4 and 17). An experiment was performed on mice bearing 4T1 tumors (25 mm3) with DaRT seeds of 6.5 mm and 65 kBq (pg. 19).
Domankevich et al. do not exemplify the claimed substance, kit, device and method of treating a patient with a tumor that allows for treating a tumor with intra-tumoral alpha emitter radiotherapy by implanting seed carrying radium-224 and administering to a patient with a tumor a substance with regulated immune checkpoints within two weeks of beginning the treating of tumor with intra-tumor alpha emitter radiotherapy optionally wherein administering the substance comprises administering pomalidomide, berzosertib, an immune checkpoint inhibitor, bi-specific antibody, a substance that internalizes immune checkpoints, a LAG3 checkpoint inhibitor, a PD-1 checkpoint inhibitor, a PDL-1 checkpoint inhibitor, a small molecule inhibitor a co-stimulatory molecule, anti-angiolytic agent, and optionally wherein administering the substance comprises administering the substance at least 72 h, less than 2 wk, less than 144 h, or 12 d after beginning the treatment of the tumor with intra-tumoral alpha-emitter radiotherapy.
Cao et al. teach the synergistic anti-tumor effect of iodine-125 low dose brachytherapy and anti-PD1 therapy on lung cancer in mice (see title). Studies have shown that RT and anti-PD-1/PD-L1 therapy can have a synergistic effect and combination therapy can reverse the immunosuppressive state (pg. 3). Compared with 125I RPI and a-PD-1 combination therapy resulted in significantly longer survival (pg. 5). Those treated with combination therapy had significantly increase numbers of CD8+ TILs. These results showed that combined therapy could activated anti-tumor immunity and increase the number and activity of T cells in the TME. The immune activation effect of 125 IRPI is achieved through PD-1 blockade (pg. 6). Combination therapy could reshape T cell immunity and make the tumor immune microenvironment into one of immune activation (pg. 6). Cao et al. teach a schedule wherein a-PD-1 mAb followed after 3 d by 125I (schedule c) (pg. 6). Initiating 125I RPI earlier to delay tumor progression represents a more effective combination schedule (pg. 7). On day 12, PD-L1 was further upregulated; PD-1 expression was also upregulated. After 125I RPI combined with anti-PD-1 therapy, the immunosuppressive state was reversed, the infiltration of CD8+ in the TME increased nearly two fold and the proportion of Tregs reduced 3-fold which significantly inhibited growth of the primary and secondary tumors (pg. 7). 125I RPI and anti-PD-1 therapy have a longer synergistic time window (pg. 8).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the substance, kit, alpha-emitting device, and method of treating a patient with a tumor of Domankevich et al. (substance, kit, alpha-emitting device, and method of treating a patient with a tumor allowing the implanting of brachytherapy seeds carrying radium-224 in the tumor and for the supportive administration to the patient a substance which regulates immune checkpoints preferably during or after alpha therapy possibly even 3 d or a week after beginning alpha-therapy) so that the substance, kit, alpha-emitting device, and method allow for administering to the patient a substance which regulates immune checkpoints within two weeks, less than 5 d, less than 12 h, less than 72 h, or less than 144 h of beginning the treating of the tumor with intra-tumoral alpha-radiotherapy and optionally wherein the substance comprises a bi-specific antibody such as anti-PDL1+anti CLRA4, an anti-angiogenic agent, a molecule that internalizes immune checkpoints, small molecule inhibitor, LAG3 checkpoint inhibitor, PD-1 checkpoint inhibitor, PDL1 checkpoint inhibitor, pomalidomide, bersosertib and/or a costimulatory molecule as taught by Domankevich et al. because it would have been expected to advantageously enable synergistic combination therapy by for example increasing CD8+ in the TME and/or significant prolonging of survival. It would have been further obvious to a person of ordinary skill in the art before the effective filing date to further modify Domankevich et al. so that the seed carrying the radium-224 coupled to the support is such that not more than 20% of the radium-224 atoms leave the support into the tumor in 24 h without decay when the seed is implanted in the tumor but upon decay at least 5% of the daughter radionuclide of the radium-224 atoms leave the support upon decay as taught by Domankevich et al. because the support would have been expected to advantageously enable optimal and effective DaRT. The length of the support is a result effective variable that a person of ordinary skill in the would have optimized at the time of invention. MPEP 2144.05.II. A person of ordinary skill in the art would have arrived at a length of at least 1 mm depending of the size of tumor in order to provide effective brachytherapy.
Claim(s) 1-59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Domankevich et al. (WO 2020/089819 A1; published 7 May 2020; see attached 892), in view of Cao et al. (Research Square; published Feb. 2021; see attached 892), in further view of Takeda et al. (US 2023/0141284 A1; published 11 May 2023; see attached 892), Marin-Avecedo et al. (J. Hematol. Oncol.; published 19 Mar. 2021; see attached 892) and Cruz-Bermudez et al. (Biomedicines; published 31 Mar. 2021; see attached 892).
Domankevich et al. teach as discussed above.
Domankevich et al. do not further teach a substance that is pembrolizumab, atezolizumab, ipilimumab, relatimab, LY3321367, tiragolumab, epacadostat, enoblituzumab, molalizumab, pexidartnib, enapotamab, vopraelimab, avadomide (TSR-022), medi0562 (tavolimab), elotuzumab, soragenib, vemurafenib, vorinostat, celecoxib, pepinemab, tebotelimab, or oric-533.
Cao et al. teach as discussed above.
Takeda et al. teach a cancer therapeutic method (see title). Takeda et al. teach examples of immune therapeutic drugs include pembrolizumab, atezolizumab, ipilimumab, relatimab, LY3321367, tiragolumab, epacadostat, enoblituzumab, molalizumab, pexidartinib, enapotamab, vopratelimab, avadomide (TSR-022), medi0562 (tavolimab), elotuzumab ([0211]). Takeda et al. teach sorafenib, vemurafenib, vorinostat ([0210]) and celecoxib (0228]).
Marin-Acevedo et al. teach next generation immune checkpoint inhibitors (see title). Marin et al. teach pepinemab and tebotelimab (table 1).
Cruz-Bermudez et al. teach the role of metabolism in tumor immune invasion (see title). Cruz-Bermudez et al. teach oric-533 as a CD73 inhibitor (table 2, pg. 13)
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Domankevich et al. so the immune checkpoint inhibitor and/or supportive treatment is at least one of oric-533, embrolizumab, atezolizumab, ipilimumab, relatlimab, LY3321367, tiragolumab, epacadostat, enoblituzumab, molalizumab, pexidartnib, enapotamab, vopratelimab, avadomide (TSR-022), medi0562 (tavolimab), elotuzumab, pepinamab, tebotelimab, sorafenib, vemurafenib, vorinostat and celecoxib as taught by Domankevich et al., Takeda et al., Marin-Acevedo et al., and Cruz-Bermudez et al. because those compounds would have been expected to provide a therapeutically effective immune checkpoint inhibitor or cancer treatment and/or help counter the undesirable side effects of the radiotherapy and provide a longer duration of survival.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached on (571)272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
Prosecution Insights