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 .
Claims Status
Claims 1-10, 14-17, 19, 31-32, 37, 39-40, 43-44, 46, 52-53, 55, and 62 are pending and are examined on the merits.
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 40 and 53 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.
Each of Claims 40 and 53 recites the limitation "Compound No. 14". There is insufficient antecedent basis for this limitation in the claim. While Claim 1, from which Claims 40 and 53 depend, recites “a compound”, there is no recitation of the term “Compound No. 14”.
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.
Claims 1, 10, 19, 31, and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Baird et al. 2016 (Cancer research, 76(1), 50-61.; PTO-892), herein “Baird”, in view of Yoshikawa et al. 2018 (WO 2018/100558 A2; IDS dated 08/15/2024), herein “Yoshikawa”.
Baird teaches a method of treating cancer comprising administering a cyclic dinucleotide (CDN) STING agonist (RR-CDG) in combination with radiation therapy (Abstract; Fig. 1). Baird further teaches that while radiation therapy alone was ineffective, the combined therapy was synergistic resulting in tumor regression at lower doses of the STING agonist than required as a single agent (§ Results – dose-dependent synergy between RR-CDG and RT).
Regarding instant Claim 10, Baird teaches mice were irradiated with CT-guided beams using the XStrahl SARRP platform (i.e. external beam radiation) (§ RT of tumors).
Regarding instant Claim 19, Baird teaches the combined CDN/radiation treatment is effective at treating mice bearing 3LL tumors, a lung cancer (Pg. 53, ¶1).
Regarding instant Claim 31, Baird teaches that Panc02 tumors are spontaneously metastatic and that combined CDN/radiation treatment eliminated metastatic disease – in contrast to radiation alone (Pg. 54, Col. 2, ¶1).
Regarding instant Claim 55, Baird teaches that the radiation was dosed at 10 Gy (Pg. 53, ¶1). Regarding the limitation that said dose is a “fraction” dose, Baird notes that the radiation dose was administered in as single “suboptimal” dose (Pg. 52, last ¶). Because the instant specification defines the term “fraction dose” as “the dose of radiation administered in each individual fraction” (¶0125) and states that the radiation can be administered “in 1 fraction” (¶0079), the single suboptimal dose taught by Baird appears to meet this limitation. Moreover, Baird teaches that “Fractionation of radiation over 5–7 weeks of daily treatment is a superior technique to ensure selective cancer versus normal cell death” (Pg. 58, last ¶).
Baird further highlights the need for modified CDN STING ligands owing to the susceptibility of natural ligand cGAMP to degradation (§ Introduction, ¶3).
Baird does not teach that the cyclic dinucleotide has the structure illustrated in instant claim 1. This deficiency is cured by Yoshikawa.
Yoshikawa teaches a cyclic dinucleotide termed “Example 14” or “Ex14” having identical structure as that of the instant claims (Table 1-3, reproduced below).
PNG
media_image1.png
203
918
media_image1.png
Greyscale
Yoshikawa teaches that compound Ex14 functions as a STING agonist (Tables 3-4) and has improved cell permeability, EC50, and serum stability when compared to the natural STING ligand cGAMP (¶1701, Table 6).
Yoshikawa teaches that administration of compound Ex14 in a mouse model of colon cancer exhibited an anti-tumor effect (¶1709; Fig. 9, 11).
Yoshikawa teaches that the disclosed CDNs are suitable for use in treating a variety of cancers including, for example, melanoma and metastatic urothelial cancer (Table 7).
It would have been obvious to one of ordinary skill in the art to substitute the cyclic dinucleotide of Baird with the cyclic dinucleotide compound Ex14 taught by Yoshikawa, resulting in a method of treating cancer comprising a combination of radiation and the instantly claimed compound. The skilled artisan would have been motivated to make this substitution because Baird highlights that CDNs are unstable and Yoshikawa teaches that compound Ex14 has improved pharmacological properties, including stability, relative to native cGAMP. There would have been a reasonable expectation of success because Yoshikawa teaches that, like the cyclic dinucleotide of Baird, compound Ex14 functions as a STING agonist and confers anti-tumor activity, and because Baird teaches that radiotherapy synergizes with the anti-tumor activity of a STING agonist.
Claims 2-8, 14-17, 32, 37, 39-40, 43-44, 46, 52-53, 55, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Baird et al. 2016 (Cancer research, 76(1), 50-61.; PTO-892), herein “Baird”, and Yoshikawa et al. 2018 (WO 2018/100558 A2; IDS dated 08/15/2024), herein “Yoshikawa”, as applied to claims 1, 10, 19, 31, and 55 above, and further in view of Cemerski et al. 2018 (WO 2018/118664; IDS dated 08/15/2024), herein “Cemerski”, and Weichselbaum et al. 2017 (Nature reviews Clinical oncology, 14(6), 365-379.; PTO-892), herein “Weichselbaum”.
The teachings of Baird and Yoshikawa are summarized above.
In addition, Baird teaches the caveat that treatment with a CDN STING agonist can result in PDL1 upregulation on cancer cells (Pg. 60, ¶2).
Yoshikawa further teaches that the disclosed cyclic dinucleotide compounds may be administered concurrently with immunotherapeutic agents (¶1490), which, regarding instant Claims 3-5 and 7-8, include anti-CTLA4 antibodies such as ipilimumab, anti-PD1 antibodies such as pembrolizumab, and anti-PD-L1 antibodies (¶1497).
However, neither Baird nor Yoshikawa expressly teach the combination of all three radiation, immune checkpoint inhibitors, and CDN STING agonist therapy nor the particular dosing/schedule encompassed by the instant claims. These deficiencies are cured by Cemerski and Weichselbaum.
Cemerski teaches a method of treating cancer comprising administering synthetic CDN STING agonists in combination with immune checkpoint inhibitors (Abstract; Example 2).
Cemerski teaches that said combination therapy may be used prior to, during, or after radiation treatment (¶0174).
Regarding instant Claims 3-6, Cemerski teaches that the checkpoint inhibitor can be an anti-PD-1 antibody such as pembrolizumab (¶0095) or an anti-PD-L1 antibody such as MEDI4739 (¶0090).
Regarding instant Claims 14-17 and 62, Cemerski teaches that the CDN STING agonist and checkpoint inhibitor can be administered separately or in conjunction, that each agent may be administered prior to, separately, or subsequent to the other agent, and that the CDN/checkpoint inhibitor combination therapy may be administered after radiation (¶0207; ¶0174).
Regarding instant Claims 32, 37, and 39-40, 43, and 46, Cemerski teaches the treatment cycle is 21 days, that the first dose is administered on Cycle 1/Day 1, and that the STING agonist is administered once a week for the first three treatment cycles (i.e. administered on Day 1, Day 8, and Day 15) (¶0249), and that the checkpoint inhibitor is administered once every three weeks (¶0254).
Regarding instant Claim 52, Cemersky teaches the checkpoint inhibitor is administered at a fixed dose of 200mg (¶0254).
Weichselbaum teaches that radiation activates the immune response by release of cGAMP ligand and downstream STING pathway activation, and that STING pathway activation is essential for radiation-induced anti-tumor responses (Fig. 1; Pg. 369, § The STING signalling pathway).
Weichselbaum teaches that PD-L1 is elevated on tumor cells following radiation, potentially leading to radiation induced tumor equilibrium, and that addition of immune checkpoint inhibitors could be an effective strategy to shift the tumor out of equilibrium (Fig. 1; Pg. 371, Col. 2).
Weichselbaum teaches that, in keeping with this hypothesis, administration of an anti-PD-L1 antibody following radiation resulted in substantial tumor regression and increased CD8+ T-cell infiltration (Pg. 372, Col 2, last ¶).
Regarding instant Claim 44, Weichselbaum teaches that the timing of checkpoint inhibitor treatment following radiation is critical (Pg. 373, Col. 2, ¶1), and teaches of many ongoing clinical trials investigating the combination of radiation with checkpoint inhibitors, several of which comprise administering the checkpoint inhibitor, for example, “up to 2 days” after radiation (Pg. 372, Col. 2, ¶1), “within 1 week” of radiation (Pg. 375, Table 1 cont.), and wherein radiation is administered on “days -2, -1, and 0” of the treatment cycle (Pg. 374, Table 1).
Because Cemerski teaches a method of treating cancer comprising administering checkpoint inhibitors in combination with CDN STING agonists, and Weichselbaum teaches methods of treating cancer comprising administering checkpoint inhibitors in combination with radiation, it would have been obvious to one of ordinary skill in the art to further administer a checkpoint inhibitor in combination with the combined radiation/CDN STING agonist therapy taught by Baird and Yoshikawa – wherein the CDN STING agonist “Ex14” taught by Yoshikawa is administered in combination with a checkpoint inhibitor following radiation therapy.
The skilled artisan would have been motivated to employ said combined radiation/CDN STING agonist/checkpoint inhibitor therapy because Baird and Weichselbaum teach that tumor expression of PD-L1 is elevated following STING agonist treatment and radiation, respectively, and that radiation therapy synergizes with either CDN STING agonist therapy or checkpoint inhibitors, respectively.
There would have been a reasonable expectation of success because Yoshikawa teaches that CDN STING agonist compound “Ex14” can be administered in combination with checkpoint inhibitors such as those tarteting CTLA-4, PD-1, or PD-L1, Cemerski teaches that radiation can be administered before combined CDN STING/checkpoint inhibitor therapy, and Weichselbaum teaches that the mechanism by which immune checkpoint inhibition and radiotherapy synergize is through STING pathway activation.
Regarding instant Claim 44, it would have been obvious to one of ordinary skill in the art that the radiation could be administered between day -8 and -1 of the treatment cycle taught by Cemerski and summarized above. The skilled artisan would have been motivated to administer radiation within a week of starting said treatment cycles given the suggesting by Weichselbaum that the timing of administering checkpoint inhibitor therapy following radiation is critical. There would have been a reasonable expectation of success because Cemerski teaches that radiation can be administered prior to combined CDN/checkpoint therapy, and Weichselbaum teaches several ongoing clinical trials employ a protocol wherein the radiation is administered shortly before administering the checkpoint inhibitors (e.g. “within 1 week”, “up to 2 days”, or on “days -2, -1 and 0”).
Further, regarding instant Claim 53, Yoshikawa does not teach the particular doses at which compound 14 is administered.
However, Cemerski teaches that the cyclic dinucleotide STING agonist is administered at a dose within the range of 10µg-270µg, with particular examples of 10µg, 90µg, and 270µg (¶0251-0253), a range which overlaps with several doses encompassed by the instant claims (e.g. 0.05 mg, 0.1 mg, and 0.2 mg).
Cemerski further teaches that the maximum tolerated dose is determined by stepwise dose escalation within the 10µg-270µg range (Example 2).
It would have been obvious to one of ordinary skill in the art that the cyclic dinucleotide STING agonist compound of the instant claims could be administered in the amount of, for example, 0.05 mg, 0.1 mg, or 0.2 mg. The skilled artisan would appreciate that discovery of the appropriate dose is the result of routine optimization, such as by dose escalation as taught by Cemerski. There would have been a reasonable expectation of success given the overlapping dose ranges taught by Cemerski and the shared chemical class/mechanism of action of the cyclic dinucleotide STING agonist of Cemerski and that of the instant claims.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Baird et al. 2016 (Cancer research, 76(1), 50-61.; PTO-892), herein “Baird”, and Yoshikawa et al. 2018 (WO 2018/100558 A2; IDS dated 08/15/2024), herein “Yoshikawa”, as applied to claims 1, 10, 19, 31, and 55 above, and further in view of Lee et al. 2018 (Translational lung cancer research, 7(2), 180.; PTO-892), herein “Lee”.
The teachings of Baird and Yoshikawa are summarized above.
Baird and Yoshikawa do not teach that the radiation is particle radiation. This deficiency is cured by Lee.
Lee teaches that proton beam therapy (PBT) is an increasingly common form of radiation therapy wherein rather than conventional photon radiation, a beam of charged particles is employed to deliver the radiation (Abstract).
Lee teaches that the majority of the radiation dose delivered by PBT is concentrated at the “Bragg peak”, which better spares normal tissue from radiation damage (Pg. 182-183, § Physics of protons).
Lee teaches that conventional photon radiation is associated with an increase in Trex expression, which downregulates STING ligands and attenuates cancer cell immunogenicity (Pg. 183, last ¶). In this context, Lee suggests that PBT can provide an additional tool in maximizing anti-tumor immunogenic responses induced by radiation therapy (Pg. 184, ¶1).
It would have been obvious to one of ordinary skill in the art to substitute the radiation in the combination radiation/CDN STING agonist therapy as taught by Baird and Yoshikawa with proton beam therapy taught by Lee. The skilled artisan would have been motivated to do so because Lee teaches that PBT causes less off-target radiation damage to healthy tissue. There would have been a reasonable expectation of success because Lee teaches that PBT may mitigate the immunosuppressive effects associated with conventional photon radiation.
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.
Claims 1-6, 10, 14-17, 19, 31-23, 37-40, 43-44, 46, 52-53, 55, and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,403,154 (PTO-892) in view of Baird et al. 2016 (Cancer research, 76(1), 50-61.; PTO-892), herein “Baird”, Cemerski et al. 2018 (WO 2018/118664; IDS dated 08/15/2024), herein “Cemerski”, and Weichselbaum et al. 2017 (Nature reviews Clinical oncology, 14(6), 365-379.; PTO-892), herein “Weichselbaum”.
The claims of ‘154 are drawn to a method of treating cancer comprising administering “Compound No. 14” (see structure below) in combination with a checkpoint inhibitor.
Compound No. 14:
PNG
media_image2.png
224
277
media_image2.png
Greyscale
Regarding instant Claims 3-6, ‘154 claims 7-8 are drawn to the method comprising, for example, anti-PD-1 antibody pembrolizumab or anti-PD-L1 antibody durvalumab.
Regarding instant Claims 14-15, ‘154 claim 13 is drawn to the method wherein Compound No. 14 and the checkpoint inhibitor are administered concurrently or sequentially in separate pharmaceutical compositions.
Regarding instant Claims 19 and 31, ‘154 claims 3-6 are drawn to methods of treating cancer wherein the cancer is, for example, lung cancer or a metastatic solid tumor.
Regarding instant Claim 32, ‘154 claim 14-15 are drawn to the method wherein the checkpoint inhibitor is administered, for example, once every three weeks.
Regarding instant Claim 37, ‘154 claim 16 is drawn to the method wherein the checkpoint inhibitor is administered on Day 1 or Day 2 of a treatment cycle.
Regarding instant Claims 39, 43, and 46, ‘154 claim 17 is drawn to the method wherein the treatment cycle is 14, 21, 28, or 84 days.
Regarding instant Claim 40, ‘154 claim 18-19 are drawn to the method wherein Compound No. 14 is administered on days 1, 8, and 15 of a treatment cycle.
Regarding instant Claim 52, ‘154 claim 10 is drawn to the method wherein the checkpoint inhibitor is administered in an amount of 200mg.
Regarding instant Claim 53, ‘154 claims 11-12 are drawn to the method wherein Compound No. 14 is administered in an amount from 0.2mg-1.2mg.
The claims of ‘154 are not drawn to the method further comprising radiation therapy nor the particular nature, dosing or timing of said radiation therapy. These limitations are rendered obvious by Baird, Cemerski, and Weichselbaum.
Baird teaches a method of treating cancer comprising administering a cyclic dinucleotide (CDN) STING agonist (RR-CDG) in combination with radiation therapy (Abstract; Fig. 1). Baird further teaches that while radiation therapy alone was ineffective, the combined therapy was synergistic resulting in tumor regression at lower doses of the STING agonist than required as a single agent (§ Results – dose-dependent synergy between RR-CDG and RT).
Regarding instant Claim 10, Baird teaches mice were irradiated with CT-guided beams using the XStrahl SARRP platform (i.e. external beam radiation) (§ RT of tumors).
Regarding instant Claim 19, Baird teaches the combined CDN/radiation treatment is effective at treating mice bearing 3LL tumors, a lung cancer (Pg. 53, ¶1).
Regarding instant Claim 31, Baird teaches that Panc02 tumors are spontaneously metastatic and that combined CDN/radiation treatment eliminated metastatic disease – in contrast to radiation alone (Pg. 54, Col. 2, ¶1).
Regarding instant Claim 55, Baird teaches that the radiation was dosed at 10 Gy (Pg. 53, ¶1). Regarding the limitation that said dose is a “fraction” dose, Baird notes that the radiation dose was administered in as single “suboptimal” dose (Pg. 52, last ¶). Because the instant specification defines the term “fraction dose” as “the dose of radiation administered in each individual fraction” (¶0125) and states that the radiation can be administered “in 1 fraction” (¶0079), the single suboptimal dose taught by Baird appears to meet this limitation. Moreover, Baird teaches that “Fractionation of radiation over 5–7 weeks of daily treatment is a superior technique to ensure selective cancer versus normal cell death” (Pg. 58, last ¶).
Baird further highlights the need for modified CDN STING ligands owing to the susceptibility of natural ligand cGAMP to degradation (§ Introduction, ¶3).
In addition, Baird teaches the caveat that treatment with a CDN STING agonist can result in PDL1 upregulation on cancer cells (Pg. 60, ¶2).
Cemerski teaches a method of treating cancer comprising administering synthetic CDN STING agonists in combination with immune checkpoint inhibitors (Abstract; Example 2).
Cemerski teaches that said combination therapy may be administered after radiation treatment (¶0174).
Weichselbaum teaches that radiation activates the immune response by release of cGAMP ligand and downstream STING pathway activation, and that STING pathway activation is essential for radiation-induced anti-tumor responses (Fig. 1; Pg. 369, § The STING signalling pathway).
Weichselbaum teaches that PD-L1 is elevated on tumor cells following radiation, potentially leading to radiation induced tumor equilibrium, and that addition of immune checkpoint inhibitors could be an effective strategy to shift the tumor out of equilibrium (Fig. 1; Pg. 371, Col. 2).
Weichselbaum teaches that, in keeping with this hypothesis, administration of an anti-PD-L1 antibody following radiation resulted in substantial tumor regression and increased CD8+ T-cell infiltration (Pg. 372, Col 2, last ¶).
Regarding instant Claim 44, Weichselbaum teaches that the timing of checkpoint inhibitor treatment following radiation is critical (Pg. 373, Col. 2, ¶1), and teaches of many ongoing clinical trials investigating the combination of radiation with checkpoint inhibitors, several of which comprise administering the checkpoint inhibitor, for example, “up to 2 days” after radiation (Pg. 372, Col. 2, ¶1), “within 1 week” of radiation (Pg. 375, Table 1 cont.), and wherein radiation is administered on “days -2, -1, and 0” of the treatment cycle (Pg. 374, Table 1).
Because Baird teaches a method of treating cancer comprising administering a CDN STING agonist in combination with radiation, Weichselbaum teaches methods of treating cancer comprising administering checkpoint inhibitors in combination with radiation, and Cemerski teaches that a method of administering CDN STING agonist in combination with a checkpoint inhibitor can be performed after radiation therapy, it would have been obvious to modify the claims of ‘154 – which are drawn to a method of administering CDN STING agonist Compound No. 14 in combination with checkpoint inhibitors – to further comprise administration of radiation.
The skilled artisan would have been motivated to employ said combined radiation/CDN STING agonist/checkpoint inhibitor therapy because Baird and Weichselbaum teach that tumor expression of PD-L1 is elevated following STING agonist treatment and radiation, respectively, and that radiation therapy synergizes with either CDN STING agonist therapy or checkpoint inhibitors, respectively.
There would have been a reasonable expectation of success because Cemerski teaches that radiation can be administered before combined CDN STING/checkpoint inhibitor therapy, and Weichselbaum teaches that the mechanism by which immune checkpoint inhibition and radiotherapy synergize is through STING pathway activation.
Further, regarding instant Claim 44, it would have been obvious to one of ordinary skill in the art that the radiation could be administered between day -8 and -1 of the treatment cycle encompassed by the claims of ‘154. The skilled artisan would have been motivated to administer radiation within a week of starting said treatment cycles given the suggesting by Weichselbaum that the timing of administering checkpoint inhibitor therapy following radiation is critical. There would have been a reasonable expectation of success because Cemerski teaches that radiation can be administered prior to combined CDN/checkpoint therapy, and Weichselbaum teaches that several ongoing clinical trials employ a protocol wherein the radiation is administered shortly before administering the checkpoint inhibitors (e.g. “within 1 week”, “up to 2 days”, or on “days -2, -1 and 0”).
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,403,154 (PTO-892) in view of Baird et al. 2016 (Cancer research, 76(1), 50-61.; PTO-892), herein “Baird”, Cemerski et al. 2018 (WO 2018/118664; IDS dated 08/15/2024), herein “Cemerski”, and Weichselbaum et al. 2017 (Nature reviews Clinical oncology, 14(6), 365-379.; PTO-892), herein “Weichselbaum”, as applied to Claim 1 above, and further in view of Lee et al. 2018 (Translational lung cancer research, 7(2), 180.; PTO-892), herein “Lee”.
The claims of ‘154 and the teachings of Baird, Cemerski, and Weichselbaum are summarized above.
The claims of ‘154 in view of Baird, Cemerski, and Weichselbaum are not drawn to a method wherein the radiation is particle radiation. This deficiency is cured by Lee.
Lee teaches that proton beam therapy (PBT) is an increasingly common form of radiation therapy wherein rather than conventional photon radiation, a beam of charged particles is employed to deliver the radiation (Abstract).
Lee teaches that the majority of the radiation dose delivered by PBT is concentrated at the “Bragg peak”, which better spares normal tissue from radiation damage (Pg. 182-183, § Physics of protons).
Lee teaches that conventional photon radiation is associated with an increase in Trex expression, which downregulates STING ligands and attenuates cancer cell immunogenicity (Pg. 183, last ¶). In this context, Lee suggests that PBT can provide an additional tool in maximizing anti-tumor immunogenic responses induced by radiation therapy (Pg. 184, ¶1).
It would have been obvious to one of ordinary skill in the art to substitute the radiation in the combination radiation/CDN STING agonist therapy according to the claims of ‘154 in view of Baird, Cemerski, and Weichselbaum with proton beam therapy taught by Lee. The skilled artisan would have been motivated to do so because Lee teaches that PBT causes less off-target radiation damage to healthy tissue. There would have been a reasonable expectation of success because Lee teaches that PBT may mitigate the immunosuppressive effects associated with conventional photon radiation.
Claims 7-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,403,154 (PTO-892) in view of Baird et al. 2016 (Cancer research, 76(1), 50-61.; PTO-892), herein “Baird”, Cemerski et al. 2018 (WO 2018/118664; IDS dated 08/15/2024), herein “Cemerski”, and Weichselbaum et al. 2017 (Nature reviews Clinical oncology, 14(6), 365-379.; PTO-892), herein “Weichselbaum”, as applied to Claims 1-2 above, and further in view of Yoshikawa et al. 2018 (WO 2018/100558 A2; IDS dated 08/15/2024), herein “Yoshikawa”.
The claims of ‘154 and the teachings of Baird, Cemerski, and Weichselbaum are summarized above.
The claims of ‘154 in view of Baird, Cemerski, and Weichselbaum are not drawn to a combined treatment method wherein the checkpoint inhibitor comprises an anti-CTLA-4 antibody such as ipilimumab. This limitation is rendered obvious in view of Yoshikawa.
Yoshikawa teaches a cyclic dinucleotide termed “Example 14” or “Ex14” having identical structure as that of the instant claims and the claims of ‘154 (Table 1-3).
Yoshikawa teaches that compound Ex14 functions as a STING agonist (Tables 3-4) and has improved cell permeability, EC50, and serum stability when compared to the natural STING ligand cGAMP (¶1701, Table 6).
Yoshikawa teaches that administration of compound Ex14 in a mouse model of colon cancer exhibited an anti-tumor effect (¶1709; Fig. 9, 11).
Yoshikawa teaches that the disclosed CDNs are suitable for use in treating a variety of cancers including, for example, melanoma and metastatic urothelial cancer (Table 7).
Yoshikawa teaches that the disclosed CDN compounds may be administered concurrently with immunotherapeutic agents (¶1490), which, regarding instant Claims 7-8, include anti-CTLA4 antibodies such as ipilimumab, anti-PD1 antibodies such as pembrolizumab, and anti-PD-L1 antibodies (¶1497).
In addition to the teachings summarized above, Weichselbaum further teaches that patients treated by radiotherapy and followed up with ipilimumab treatment displayed a trend towards improved overall survival, particularly in those with bone metastases, and that combined radiotherapy with anti-CTLA-4 treatment is efficacious owing to stress-induced markers on surviving tumor cells that make them susceptible to NK-cell-mediated cytotoxicity (Pg. 372, Col. 2, ¶1).
It would have been obvious to one of ordinary skill in the art that the checkpoint inhibitor of the combined CDN STING agonist/checkpoint inhibitor/radiation therapy of the claims of ‘154 in view of Baird, Cemerski, and Weichselbaum could comprise the anti-CTLA-4 antibody ipilimumab. The skilled artisan would have been motivated to employ ipilimumab in view of the teachings of Weichselbaum demonstrating improved outcomes in combination with radiation. There would have been a reasonable expectation of success because Yoshikawa teaches that the CDN STING agonist encompassed by the instant claims and those of ‘154 is suitable for combination with checkpoint inhibitors including anti-CTLA-4 antibodies.
Claims 1, 10, 19, 31, and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, and 12 of U.S. Patent No. 10,980,825 (IDS dated 08/15/2024), in view of Baird et al. 2016 (Cancer research, 76(1), 50-61.; PTO-892), herein “Baird”, and Yoshikawa et al. 2018 (WO 2018/100558 A2; IDS dated 08/15/2024), herein “Yoshikawa”.
‘825 claims 1, 2, and 5 are drawn to a compound having identical structure to that of the instant claims (reproduced below):
PNG
media_image3.png
218
261
media_image3.png
Greyscale
‘825 claim 12 is drawn to a method of treating a patient with cancer comprising administering said compound wherein activation of STING by said compound suppresses cancer cell growth.
The claims of ‘825 are not drawn to particular cancer types nor combination therapies including the claimed compound administered with radiation. These limitations are rendered obvious by Baird and Yoshikawa.
Baird teaches a method of treating cancer comprising administering a cyclic dinucleotide (CDN) STING agonist (RR-CDG) in combination with radiation therapy (Abstract; Fig. 1). Baird further teaches that while radiation therapy alone was ineffective, the combined therapy was synergistic resulting in tumor regression at lower doses of the STING agonist than required as a single agent (§ Results – dose-dependent synergy between RR-CDG and RT).
Regarding instant Claim 10, Baird teaches mice were irradiated with CT-guided beams using the XStrahl SARRP platform (i.e. external beam radiation) (§ RT of tumors).
Regarding instant Claim 19, Baird teaches the combined CDN/radiation treatment is effective at treating mice bearing 3LL tumors, a lung cancer (Pg. 53, ¶1).
Regarding instant Claim 31, Baird teaches that Panc02 tumors are spontaneously metastatic and that combined CDN/radiation treatment eliminated metastatic disease – in contrast to radiation alone (Pg. 54, Col. 2, ¶1).
Regarding instant Claim 55, Baird teaches that the radiation was dosed at 10 Gy (Pg. 53, ¶1). Regarding the limitation that said dose is a “fraction” dose, Baird notes that the radiation dose was administered in as single “suboptimal” dose (Pg. 52, last ¶). Because the instant specification defines the term “fraction dose” as “the dose of radiation administered in each individual fraction” (¶0125) and states that the radiation can be administered “in 1 fraction” (¶0079), the single suboptimal dose taught by Baird appears to meet this limitation. Moreover, Baird teaches that “Fractionation of radiation over 5–7 weeks of daily treatment is a superior technique to ensure selective cancer versus normal cell death” (Pg. 58, last ¶).
Baird further highlights the need for modified CDN STING ligands owing to the susceptibility of natural ligand cGAMP to degradation (§ Introduction, ¶3).
Yoshikawa teaches a cyclic dinucleotide termed “Example 14” or “Ex14” having identical structure as that of the instant claims and ‘825 claim 5(Table 1-3, reproduced below).
Yoshikawa teaches that compound Ex14 functions as a STING agonist (Tables 3-4) and has improved cell permeability, EC50, and serum stability when compared to the natural STING ligand cGAMP (¶1701, Table 6).
Yoshikawa teaches that administration of compound Ex14 in a mouse model of colon cancer exhibited an anti-tumor effect (¶1709; Fig. 9, 11).
Yoshikawa teaches that the disclosed CDNs are suitable for use in treating a variety of cancers including, for example, melanoma and metastatic urothelial cancer (Table 7).
It would have been obvious to one of ordinary skill in the art to substitute the cyclic dinucleotide of Baird with the cyclic dinucleotide compound Ex14 taught by Yoshikawa, resulting in a method of treating cancer comprising a combination of radiation and administration of the compound of ‘825. The skilled artisan would have been motivated to make this substitution because Baird highlights that CDNs are unstable and Yoshikawa teaches that compound Ex14 has improved pharmacological properties, including stability, relative to native cGAMP. There would have been a reasonable expectation of success because Yoshikawa teaches that, like the cyclic dinucleotide of Baird, compound Ex14 functions as a STING agonist and confers anti-tumor activity, and because Baird teaches that radiotherapy synergizes with the anti-tumor activity of a STING agonist.
Claims 2-8, 14-17, 32, 37, 39-40, 43-44, 46, 52-53, 55, and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, and 12 of U.S. Patent No. 10,980,825 (IDS dated 08/15/2024), in view of Baird et al. 2016 (Cancer research, 76(1), 50-61.; PTO-892), herein “Baird”, and Yoshikawa et al. 2018 (WO 2018/100558 A2; IDS dated 08/15/2024), herein “Yoshikawa”, as applied to claims 1, 10, 19, 31, and 55 above, and further in view of Cemerski et al. 2018 (WO 2018/118664; IDS dated 08/15/2024), herein “Cemerski”, and Weichselbaum et al. 2017 (Nature reviews Clinical oncology, 14(6), 365-379.; PTO-892), herein “Weichselbaum”.
The teachings of Baird and Yoshikawa are summarized above.
In addition, Baird teaches the caveat that treatment with a CDN STING agonist can result in PDL1 upregulation on cancer cells (Pg. 60, ¶2).
Yoshikawa further teaches that the disclosed cyclic dinucleotide compounds may be administered concurrently with immunotherapeutic agents (¶1490), which, regarding instant Claims 3-5 and 7-8, include anti-CTLA4 antibodies such as ipilimumab, anti-PD1 antibodies such as pembrolizumab, and anti-PD-L1 antibodies (¶1497).
However, neither Baird nor Yoshikawa expressly teach the combination of all three radiation, immune checkpoint inhibitors, and CDN STING agonist therapy nor the particular dosing/schedule encompassed by the instant claims. These deficiencies are cured by Cemerski and Weichselbaum.
Cemerski teaches a method of treating cancer comprising administering synthetic CDN STING agonists in combination with immune checkpoint inhibitors (Abstract; Example 2).
Cemerski teaches that said combination therapy may be used prior to, during, or after radiation treatment (¶0174).
Regarding instant Claims 3-6, Cemerski teaches that the checkpoint inhibitor can be an anti-PD-1 antibody such as pembrolizumab (¶0095) or an anti-PD-L1 antibody such as MEDI4739 (¶0090).
Regarding instant Claims 14-17 and 62, Cemerski teaches that the CDN STING agonist and checkpoint inhibitor can be administered separately or in conjunction, that each agent may be administered prior to, separately, or subsequent to the other agent, and that the CDN/checkpoint inhibitor combination therapy may be administered after radiation (¶0207; ¶0174).
Regarding instant Claims 32, 37, and 39-40, 43, and 46, Cemerski teaches the treatment cycle is 21 days, that the first dose is administered on Cycle 1/Day 1, and that the STING agonist is administered once a week for the first three treatment cycles (i.e. administered on Day 1, Day 8, and Day 15) (¶0249), and that the checkpoint inhibitor is administered once every three weeks (¶0254).
Regarding instant Claim 52, Cemersky teaches the checkpoint inhibitor is administered at a fixed dose of 200mg (¶0254).
Weichselbaum teaches that radiation activates the immune response by release of cGAMP ligand and downstream STING pathway activation, and that STING pathway activation is essential for radiation-induced anti-tumor responses (Fig. 1; Pg. 369, § The STING signalling pathway).
Weichselbaum teaches that PD-L1 is elevated on tumor cells following radiation, potentially leading to radiation induced tumor equilibrium, and that addition of immune checkpoint inhibitors could be an effective strategy to shift the tumor out of equilibrium (Fig. 1; Pg. 371, Col. 2).
Weichselbaum teaches that, in keeping with this hypothesis, administration of an anti-PD-L1 antibody following radiation resulted in substantial tumor regression and increased CD8+ T-cell infiltration (Pg. 372, Col 2, last ¶).
Regarding instant Claim 44, Weichselbaum teaches that the timing of checkpoint inhibitor treatment following radiation is critical (Pg. 373, Col. 2, ¶1), and teaches of many ongoing clinical trials investigating the combination of radiation with checkpoint inhibitors, several of which comprise administering the checkpoint inhibitor, for example, “up to 2 days” after radiation (Pg. 372, Col. 2, ¶1), “within 1 week” of radiation (Pg. 375, Table 1 cont.), and wherein radiation is administered on “days -2, -1, and 0” of the treatment cycle (Pg. 374, Table 1).
Because Cemerski teaches a method of treating cancer comprising administering checkpoint inhibitors in combination with CDN STING agonists, and Weichselbaum teaches methods of treating cancer comprising administering checkpoint inhibitors in combination with radiation, it would have been obvious to one of ordinary skill in the art to further administer a checkpoint inhibitor in combination with the combined radiation/CDN STING agonist therapy taught by Baird and Yoshikawa – wherein the CDN STING agonist “Ex14” taught by Yoshikawa is administered in combination with a checkpoint inhibitor following radiation therapy.
The skilled artisan would have been motivated to employ said combined radiation/CDN STING agonist/checkpoint inhibitor therapy because Baird and Weichselbaum teach that tumor expression of PD-L1 is elevated following STING agonist treatment and radiation, respectively, and that radiation therapy synergizes with either CDN STING agonist therapy or checkpoint inhibitors, respectively.
There would have been a reasonable expectation of success because Yoshikawa teaches that CDN STING agonist compound “Ex14” can be administered in combination with checkpoint inhibitors such as those tarteting CTLA-4, PD-1, or PD-L1, Cemerski teaches that radiation can be administered before combined CDN STING/checkpoint inhibitor therapy, and Weichselbaum teaches that the mechanism by which immune checkpoint inhibition and radiotherapy synergize is through STING pathway activation.
Regarding instant Claim 44, it would have been obvious to one of ordinary skill in the art that the radiation could be administered between day -8 and -1 of the treatment cycle taught by Cemerski and summarized above. The skilled artisan would have been motivated to administer radiation within a week of starting said treatment cycles given the suggesting by Weichselbaum that the timing of administering checkpoint inhibitor therapy following radiation is critical. There would have been a reasonable expectation of success because Cemerski teaches that radiation can be administered prior to combined CDN/checkpoint therapy, and Weichselbaum teaches several ongoing clinical trials employ a protocol wherein the radiation is administered shortly before administering the checkpoint inhibitors (e.g. “within 1 week”, “up to 2 days”, or on “days -2, -1 and 0”).
Further, regarding instant Claim 53, Yoshikawa does not teach the particular doses at which compound 14 is administered.
However, Cemerski teaches that the cyclic dinucleotide STING agonist is administered at a dose within the range of 10µg-270µg, with particular examples of 10µg, 90µg, and 270µg (¶0251-0253), a range which overlaps with several doses encompassed by the instant claims (e.g. 0.05 mg, 0.1 mg, and 0.2 mg).
Cemerski further teaches that the maximum tolerated dose is determined by stepwise dose escalation within the 10µg-270µg range (Example 2).
It would have been obvious to one of ordinary skill in the art that the cyclic dinucleotide STING agonist compound of the instant claims could be administered in the amount of, for example, 0.05 mg, 0.1 mg, or 0.2 mg. The skilled artisan would appreciate that discovery of the appropriate dose is the result of routine optimization, such as by dose escalation as taught by Cemerski. There would have been a reasonable expectation of success given the overlapping dose ranges taught by Cemerski and the shared chemical class/mechanism of action of the cyclic dinucleotide STING agonist of Cemerski and that of the instant claims.
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, and 12 of U.S. Patent No. 10,980,825 (IDS dated 08/15/2024), in view of Baird et al. 2016 (Cancer research, 76(1), 50-61.; PTO-892), herein “Baird”, and Yoshikawa et al. 2018 (WO 2018/100558 A2; IDS dated 08/15/2024), herein “Yoshikawa”, as applied to claims 1, 10, 19, 31, and 55 above, and further in view of Lee et al. 2018 (Translational lung cancer research, 7(2), 180.; PTO-892), herein “Lee”.
The teachings of Baird and Yoshikawa are summarized above.
The claims of ‘825 in view of Baird and Yoshikawa are not drawn to a method comprising particle radiation. This deficiency is cured by Lee.
Lee teaches that proton beam therapy (PBT) is an increasingly common form of radiation therapy wherein rather than conventional photon radiation, a beam of charged particles is employed to deliver the radiation (Abstract).
Lee teaches that the majority of the radiation dose delivered by PBT is concentrated at the “Bragg peak”, which better spares normal tissue from radiation damage (Pg. 182-183, § Physics of protons).
Lee teaches that conventional photon radiation is associated with an increase in Trex expression, which downregulates STING ligands and attenuates cancer cell immunogenicity (Pg. 183, last ¶). In this context, Lee suggests that PBT can provide an additional tool in maximizing anti-tumor immunogenic responses induced by radiation therapy (Pg. 184, ¶1).
It would have been obvious to one of ordinary skill in the art to substitute the radiation in the combination radiation/CDN STING agonist therapy as taught by Baird and Yoshikawa with proton beam therapy taught by Lee. The skilled artisan would have been motivated to do so because Lee teaches that PBT causes less off-target radiation damage to healthy tissue. There would have been a reasonable expectation of success because Lee teaches that PBT may mitigate the immunosuppressive effects associated with conventional photon radiation.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRYAN WILLIAM HECK whose telephone number is (703)756-4701. The examiner can normally be reached Mon-Fri 8:00am - 5:30pm.
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, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643