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 .
Priority
The present application, filed January 4, 2021, is a national stage application of
PCT/JP2020/040974, filed October 30, 2020, which claims priority to foreign priority
application JP2019-200256, filed November 1, 2019.
Claims 35-38 and 47-58 are drawn to a method of treating cancer or enhancing or eliciting an immune response comprising administering a therapeutically effective amount of a compound of formula (II-A) or (III-A), a therapeutic support composition, and a therapeutically effective amount of one or more immunomodulatory agents.
The subject matter of claims 35-38 and 47-58 is not supported by provisional application 62/871051, filed July 5, 2019. 62/871051 teaches payload D may be TLR agonists and STING agonists, which are each immunomodulatory agents (p. 22, [0085] and [0086]), but does not teach a method requiring administration of a therapeutically effective amount of a compound of formula (II-A) or (III-A), a therapeutic support composition, and a therapeutically effective amount of one or more immunomodulatory agents. Provisional application 62/971196, filed February 6, 2020, does support the method of claim 35 (for example, see [0007]) and its dependent claims. Therefore, claims 35-38 and 47-58 are examined with the effective filing date of February 6, 2020.
Claim 43 claims a method of treating cancer in a subject, or enhancing or eliciting an immune response against a second tumor in a subject, comprising administering a therapeutically effective amount of a compound of formula (II-A) or (III-A) and locally administering, at a first tumor in the subject, a therapeutic support composition comprising a support and a tetrazine-containing group of formula as shown.
The subject matter of claim 43 is not supported by provisional application 62/871051, filed July 5, 2019, or provisional application 62/971196, filed February 6, 2020. Neither 62/871051 nor 62/971196 disclose a method of enhancing or eliciting an immune response against a second tumor in a subject, as recited in claim 43. Provisional application 62/981401, filed February 25, 2020, discloses a method for inhibiting secondary tumor formation (for example, see pp. 1-2, [0005]). Therefore, claim 43 is examined with an effective filing date of February 25, 2020.
Claims 44-46 claim a method of inhibiting tumor metastasis in a subject at risk of
tumor metastasis comprising administering a therapeutically effective amount of a compound of formula (II-A) or (III-A) and locally administering, at a first tumor in the subject, a therapeutic support composition comprising a support and a tetrazine-containing group of a formula as shown in the claim.
The subject matter of claims 44-46 is not supported by provisional application 62/871051, filed July 5, 2019, or provisional application 62/971196, filed February 6, 2020. Neither 62/871051 nor 62/971196 disclose a method of inhibiting tumor metastasis in a subject at risk of tumor metastasis comprising administering a therapeutically effective amount of a compound of formula (II-A) or (III-A) and locally administering, at a first tumor in the subject, a therapeutic support composition comprising a support and a tetrazine-containing group of a formula as shown in the claim. Provisional application 62/981401, filed February 25, 2020, discloses a method for inhibiting tumor metastasis in a subject at risk of tumor metastasis comprising administering a therapeutically effective amount of a compound of formula (II-A) or (III-A) and locally administering, at a first tumor in the subject, a therapeutic support composition comprising a support and a tetrazine-containing group of a formula as shown. Therefore, claims 44-46 are examined with an effective filing date of February 25, 2020.
In summary:
Claims 35-38 and 47-58 are examined with the effective filing date of February 6, 2020.
Claims 43-46 are examined with the effective filing date of February 25, 2020.
Election/Restrictions
Applicant’s election without traverse of Group III, encompassed by present claims 35-38 and 43-58, in the reply filed on July 14, 2025, is acknowledged.
Status of the Application
Applicant’s communication, received July 14, 2025, wherein claims 1, 11, 15-17, 22, 27, 29, 32, and 39-42 are canceled and new claims 47-58 are added, is acknowledged.
Claims 35-38 and 43-58 are pending and examined on the merits herein.
Claim Objections
Claim 35 is objected to because of the following informalities:
Claim 35 recites “c) a therapeutically effective amount one or more immunomodulatory agents, or a pharmaceutically acceptable salt thereof.” This should read: “c) a therapeutically effective amount of one or more immunomodulatory agents, or a pharmaceutically acceptable salt thereof.”
Appropriate correction is required.
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.
Claims 35-37 and 47-50 are rejected under 35 U.S.C. 103 as being unpatentable over Oneto (Publication no. WO 2017044983 A1; cited in IDS received June 28, 2022) in view of Robillard (Publication no. WO 2014081301 A1; cited in IDS received June 28, 2022) and Jing (Jing, W.; et al. Journal for Immunotherapy of Cancer 2019, vol. 7, pp. 1-18; cited in PTO-892).
Jing was published online April 29, 2019, and thus qualifies as eligible prior art under 35 U.S.C. 102(a)(1).
Claim 35 claims a method of treating cancer or enhancing or eliciting an immune response comprising administering to a subject in need thereof: a) a therapeutically effective amount of a compound of formula (II-A) or (III-A), b) a therapeutic support composition comprising a support and a tetrazine-containing group of the formula shown, and c) a therapeutically effective amount one or more immunomodulatory agents.
Claim 36 depends from claim 35 and requires the method of enhancing or eliciting an immune response wherein the administration of a), b ), and c) enhances or elicits an immune response against a cancer in the subject.
Claim 37 depends from claim 35 and requires the method is the method of treating cancer. Claim 47 depends from claim 37 and requires the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, colon cancer or pancreatic cancer, claim 48 requires the cancer is a solid tumor, claim 49 requires the cancer is a soft tissue sarcoma, and claim 50 requires the immunomodulatory agent(s) is a stimulator of interferon genes (STING) agonist.
Oneto teaches and claims a method of treating or preventing a condition or disorder, comprising administering to a subject in need thereof a functionalized payload and/or therapeutic support composition according to any one of claims 1-50, which are discussed below (p. 139, claim 51). Oneto further claims wherein the condition or disorder is a cancer (p. 139, claim 52), wherein the cancer is a soft tissue sarcoma (p. 139, claim 53), wherein the cancer is a solid tumor (p. 139, claim 54), and wherein the cancer is the cancer is melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioblastoma, lung cancer, soft tissue carcinoma, fibrosarcoma, osteosarcoma, or pancreatic cancer (p. 139, claim 55).
Oneto teaches support compositions comprising the tetrazine containing group of the formulas shown (p. 62, [0175]; see structures), which have R1 as the same groups recited in present claim 35. Oneto teaches a specific therapeutic support composition of the structure below (p. 65). In this example, the tetrazine group is the structure shown on the right in claim 35, R20 is alkyl (methyl), and the support is alginate as shown.
PNG
media_image1.png
199
218
media_image1.png
Greyscale
Oneto further teaches and claims specific payloads that include chemotherapeutics. Specifically, Oneto claims compounds with payloads that include, for example gemcitabine, 5-fluorouracil, daunorubicin, and doxorubicin (pp. 126-129, claim 42) (emphasis added). These functionalized payloads satisfy all limitations of the compound of formula (II-A) or formula (III-A) except for the additional substituent(s) required by these compounds.
Oneto does not teach trans-cyclooctene compounds that satisfy the limitations of formula (II-A) or formula (III-A) as required by present claim 35. In addition, Oneto does not teach administration of a therapeutically effective amount one or more immunomodulatory agents with a) and b), as recited in claim 35, or wherein the immunomodulatory agent is a STING agonist, as recited in claim 50.
Robillard teaches a kit for the administration and activation of a prodrug that comprises a Masking Moiety linked, directly or indirectly, to a Trigger moiety, which in turn is linked to a Drug, and an Activator for the Trigger moiety. Robillard teaches the Trigger moiety comprises a dienophile and the Activator comprises a diene, whereby the dienophile is an eight-membered non-aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. Robillard teaches the trigger and the activator undergo a fast, bio-orthogonal reaction resulting in the release of the masking moiety, and activation of the drug (cover page, Abstract, lines 1-5). Robillard teaches specific dienophiles include, for example, the compound
PNG
media_image2.png
124
72
media_image2.png
Greyscale
(p. 30, fifth row of structures) which satisfies the requirements of the cyclooctene group recited in formula (II-A) of claim 35, wherein R1A is C1 alkyl, L2 is -C(O)-, and R1B is OH.
Robillard teaches an example of tetrazine-induced release of doxorubicin from TCO-1 doxorubicin (p. 87, lines 16-17), which involves reaction of a trans-cyclooctene group carrying a doxorubicin payload with a tetrazine group to release doxorubicin from trans-cyclooctene (p. 88, lines 6-8). This is taken as teaching that a chemotherapy may be delivered using the method of Robillard.
Jing teaches that administration of a STING agonist potently changed the tumor architecture, altered the immune profile, and increased the survival of tumor-bearing mice with pancreatic cancer (p. 1, Abstract, lines 1-5). Specifically, Jing teaches an example in which KPC syngrafts were implanted subcutaneously in immunocompetent mice to model immune suppressed human pancreatic cancer. Jing teaches that single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma, and thus they assayed the potential for STING agonists to provide an additive effect when combined with standard-of-care cytotoxic chemotherapy, gemcitabine, which is a nucleoside analog chemotherapy used for multiple cancers that exerts direct anti-tumor activity and may possess tumor immunotherapeutic effects (p. 4, right column, Results section, lines 13-23). Jing teaches administration of gemcitabine prior to administration of the STING agonist DMXAA (p. 4, right column, Results section, lines 23-26 to p. 5, left column, line 1). Jing teaches that gemcitabine delayed tumor progression and resulted in a reduced tumor burden relative to a non-treated tumor with a ~ 1-week survival benefit in their model, and that when intra-tumoral administration of DMXAA was initiated 12-days after tumor implantation, alone or in combination with gemcitabine, nearly all tumors regressed, resulting in significantly reduced tumor burden and smaller tumors upon analysis at days 19–20 (p. 5, left column, lines 2-11). Jing concludes that the combination of gemcitabine and DMXAA treatment resulted in pronounced tumor regression and better survival, consistent with an additive effect of the dual treatment strategy (p. 5, left column, lines 11-14).
Jing further teaches that the regression and survival benefit observed in STING agonist treated mice was consistent with activation of adaptive immune responses, wherein a reversal in the CD4:CD8 T cell ratio was observed. This is reflective of an increase in CD8+ lymphocytes within tumors treated with DMXAA, either alone or in combination with gemcitabine (p. 5, right column, lines 1-8). Jing concludes that it appears that STING agonist administration after gemcitabine treatment results in systemic anti-tumor immune responses (p. 5, right column, lines 18-20).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify the modify the trans-cyclooctene compounds carrying a chemotherapeutic agent taught by Oneto for treating cancer with a trans-cyclooctene substituent taught by Robillard. One of ordinary skill in the art would have been motivated to modify the modify the trans-cyclooctene compounds carrying a chemotherapeutic agent taught by Oneto for treating cancer with a trans-cyclooctene substituent taught by Robillard because Oneto teaches a method of treating or preventing a condition or disorder, comprising administering to a subject in need thereof a functionalized payload and/or therapeutic support composition, and specifically teaches that the method may be applied treating cancer, because Oneto teaches in their general formula that the trans-cyclooctene group may be substituted, and because Robillard teaches exemplary trans-cyclooctene agents for delivering chemotherapeutic payloads that are modified with, for example, a methyl group and carboxylic acid, as shown above. In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Oneto teaches embodiments that satisfy all limitations of the compounds of formula (II-A) and formula (III-A) as recited in claim 35, and Robillard teaches additional therapeutic agents conjugated to trans-cyclooctene that include substituents that satisfy the requirements of R1a, L2, and R1b, one of ordinary skill in the art would have recognized that the substituted trans-cyclooctene group taught by Robillard may be substituted for the trans-cyclooctene group taught by Oneto with a reasonable expectation that the substituted trans-cyclooctene group of Robillard will give predictable results when administered as part of the method of Oneto.
Regarding the administration of the additional immunomodulatory agent required by claim 35, it would have been prima facie obvious to administer a STING agonist, such as the STING agonist DMXAA, as part of the method obvious over Oneto and Robillard for the purposes of treating cancer. One of ordinary skill in the art would have been motivated to administer a STING agonist, such as the STING agonist DMXAA, as part of the method obvious over Oneto and Robillard for the purposes of treating cancer, because Oneto expressly suggests their method may be used to deliver gemcitabine and to treat pancreatic cancer, and because Jing teaches that administration of DMXAA with gemcitabine results in a tumor regression, reduced tumor burden and smaller tumors, and that this occurs by stimulating a systemic anti-tumor immune response. In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because Oneto and Robillard render obvious a method for treating cancer using the claimed compounds, and because Jing teaches the benefit of STING agonists with gemcitabine for reducing tumor burden and promoting a systemic anti-tumor immune response, one of ordinary skill in the art would have recognized that administration of a STING agonist may benefit the method obvious over Oneto in view of Robillard by promoting a systemic anti-tumor immune response. Moreover, because Jing teaches the immune response from administering gemcitabine and the STING agonist, one of ordinary skill in the art would have expected to elicit an immune response against cancer using this method.
Regarding the treatment of soft tissue sarcoma, because Oneto teaches the method for the treatment of soft tissue sarcoma, one of ordinary skill in the art would have reasonably considered that an additional therapy known to enhance the anticancer activity of gemcitabine by inducing a systemic anticancer response would also be effective in treating soft tissue sarcoma when administered with a) and b) of claim 35 obvious over Oneto and Robillard.
Therefore the invention taken as a whole is prima facie obvious.
Claims 35, 37-38, 47-49, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Oneto in view of Robillard and Pratesi (Pratesi, G.; et al. Cancer Research 2005, vol. 65, pp. 6388-6393; cited in PTO-892).
Claim 35 claims a method of treating cancer or enhancing or eliciting an immune response comprising administering to a subject in need thereof: a) a therapeutically effective amount of a compound of formula (II-A) or (III-A), b) a therapeutic support composition comprising a support and a tetrazine-containing group of the formula shown, and c) a therapeutically effective amount one or more immunomodulatory agents.
Claim 37 depends from claim 35 and requires the method is the method of treating cancer. Claim 38 depends from claim 35 and claims the immunomodulatory agent is a toll-like receptor (TLR) agonist. Claim 47 depends from claim 37 and requires the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, colon cancer or pancreatic cancer, claim 48 requires the cancer is a solid tumor, claim 49 requires the cancer is a soft tissue sarcoma.
Claim 51 depends from claim 38 and requires the TLR agonist is a TLR9 agonist.
Oneto teaches as described in the above rejections under 35 U.S.C. 103.
Oneto does not teach trans-cyclooctene compounds that satisfy the limitations of formula (II-A) or formula (III-A) as required by present claim 35. Oneto does not teach a method that requires administering a therapeutically effective amount of one or more immunomodulatory agents, as required by claim 35 and its dependents, and wherein the immunomodulatory agent is a TLR agonist and a TLR9 agonist, as required by claims 38 and 51.
Robillard teaches as described int the above rejection under 35 U.S.C. 103.
Pratesi teaches CpG-oligodeoxynucleotides (CpG-ODN) exhibit potent immunostimulatory activity by binding with Toll-like receptor 9 (TLR9) (p. 6388, Abstract, lines 1-3). Pratesi teaches that based on the finding that TLR9 is highly expressed and functional in pancreatic tissue, they evaluated the antitumor effects of chemotherapy combined with CpG-ODNs in the orthotopic mouse model of a human pancreatic tumor xenograft (p. 6388, Abstract, lines 3-7). Pratesi teaches that CpG-ODNs alone had little effect on tumor growth, whereas gemcitabine alone significantly delayed the median time of disease onset and of bulky disease development, but did not enhance survival time. Finally, Pratesi teaches that when the gemcitabine regimen was followed by administration of CpG-ODNs, development of bulky disease was delayed, survival time was significantly improved compared with gemcitabine-treated mice (p. 6388, Abstract, lines 10-18), and that autoptic examination showed tumor spread in the peritoneal cavity was reduced to a greater extent than with gemcitabine alone (p. 6388, Abstract, lines 19-21). Pratesi concludes by stating that the clear improvement of survival observed in an orthotopic murine model of human pancreatic cancer by the combined use of CpG-ODNs with chemotherapy suggests the promise of this therapeutic regimen in the clinical setting (p. 6388, Abstract, lines 24-28). As evidenced by Sommariva (Sommariva, M.; et al. Cancer Research 2011, vol. 71, pp. 6382-6390; cited in PTO-892), CpG-ODN are a Toll-like receptor 9 (TLR9) agonist (p. 6382, Abstract, lines 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify the modify the trans-cyclooctene compounds carrying a chemotherapeutic agent taught by Oneto for treating cancer with a trans-cyclooctene substituent taught by Robillard. One of ordinary skill in the art would have been motivated to modify the modify the trans-cyclooctene compounds carrying a chemotherapeutic agent taught by Oneto for treating cancer with a trans-cyclooctene substituent taught by Robillard because Oneto teaches a method of treating or preventing a condition or disorder, comprising administering to a subject in need thereof a functionalized payload and/or therapeutic support composition, and specifically teaches that the method may be applied treating cancer, because Oneto teaches in their general formula that the trans-cyclooctene group may be substituted, and because Robillard teaches exemplary trans-cyclooctene agents for delivering chemotherapeutic payloads that are modified with, for example, a methyl group and carboxylic acid, as shown above. In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Oneto teaches embodiments that satisfy all limitations of the compounds of formula (II-A) and formula (III-A) as recited in claim 35, and Robillard teaches additional therapeutic agents conjugated to trans-cyclooctene that include substituents that satisfy the requirements of R1a, L2, and R1b, one of ordinary skill in the art would have recognized that the substituted trans-cyclooctene group taught by Robillard may be substituted for the trans-cyclooctene group taught by Oneto with a reasonable expectation that the substituted trans-cyclooctene group of Robillard will give predictable results when administered as part of the method of Oneto.
Regarding the addition of an immunomodulatory agent, it would have been prima facie obvious to administer a TLR9 agonist, such as the TLR9 agonist CPG-ODN, as part of the method obvious over Oneto and Robillard for the purposes of treating cancer. One of ordinary skill in the art would have been motivated to administer a TLR9 agonist, such as the TLR9 agonist CPG-ODN, as part of the method obvious over Oneto and Robillard for the purposes of treating cancer because Oneto expressly suggests their method may be used to deliver gemcitabine and treat pancreatic cancer, and because Pratesi teaches that combination therapy comprising gemcitabine and CPG-ODN increased survival time compared with gemcitabine-treated mice. In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because Oneto and Robillard render obvious a method for treating cancer, and because Pratesi teaches the benefit of a TLR9 agonist for increasing survival time in mice with human pancreatic tumor xenografts, one of ordinary skill in the art would have recognized that administration of a TLR9 agonist may benefit the method obvious over Oneto in view of Robillard by further extending the survival time of the subject with cancer.
Regarding the treatment of soft tissue sarcoma, because Oneto teaches the method for the treatment of soft tissue sarcoma, one of ordinary skill in the art would have reasonably considered that an additional therapy known to enhance the anticancer activity of gemcitabine with improved survival times and reduced tumor spread would also be effective in treating soft tissue sarcoma when administered with a) and b) of claim 35 obvious over Oneto and Robillard.
Therefore the invention taken as a whole is prima facie obvious.
Claims 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Oneto in view of Robillard, Jing, and Khan (Oneto, J. M. M.; et al. ACS Central Science 2016, vol. 2, pp. 476-482; cited in IDS received June 28, 2022).
Claim 44 claims a method of inhibiting tumor metastasis in a subject at risk of tumor metastasis comprising: a) administering a compound of formula (II-A) or (III-A) thereof to the subject, and b) locally administering, at a first tumor in the subject, a therapeutic support composition comprising a support and a tetrazine-containing group of the formula as shown in the claim. Claim 45 depends from claim 44 and requires further administering a therapeutically effective amount of one or more immunomodulatory agents. Claim 46 depends from claim 45 and requires the one or more immunomodulatory agents is from one of the groups recited in the claim.
Oneto teaches as described in the above rejection under 35 U.S.C. 103. In addition, Oneto teaches that the disclosed methods provide the ability to place particles as disclosed at the time of the biopsy, and subsequently enable the practitioner to deliver through to the biopsy site chemokines (agents that attract cancerous cells and/or immune cells) and adjuvants to enhance the immune system with fewer side effects, as well as chemotherapeutics agents combined with immunotherapy agents (p. 89 [00252], lines 1-5) (emphasis added). Oneto teaches the chemotherapy agent would treat the solid tumor or specific location, while the enhanced response of the immunotherapy would help with distant metastatic sites (lines 6-8). This is taken as teaching that a combined chemotherapy and immunotherapy approach would be useful for inhibiting metastasis.
Oneto does not teach trans-cyclooctene compounds that satisfy the limitations of formula (II-A) or formula (III-A) as required by present claim 44. In addition, Oneto does not teach an embodiment wherein the therapeutic support composition is locally administered for the purposes of inhibiting metastasis, as required by claim 44, or administration of an additional immunomodulatory agent as recited in claims 45-46.
Robillard and Jing teach as described in the above rejections under 35 U.S.C. 103.
Khan teaches in vivo bioorthogonal chemistry for the concentration and activation of systemic pro-drugs. As one example, Khan teaches a “catch and release” approach, wherein a tetrazine-modified alginate is administered at the site of a tumor, and a TCO-modified drug is released at the site of a tumor by reaction with the tetrazine group (p. 477, Figure 1). Khan further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies, specifically connecting this to the treatment of distant micrometastasis (p. 480, left column, second full paragraph, lines 12-15).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify the trans-cyclooctene compounds carrying a chemotherapeutic agent taught by Oneto with a substituent for the purposes of inhibiting tumor metastasis. One of ordinary skill in the art would have been motivated to modify the trans-cyclooctene compounds carrying a chemotherapeutic agent taught by Robillard with a substituent for the purposes of inhibiting tumor metastasis because Oneto teaches a method of treating or preventing a condition or disorder, comprising administering to a subject in need thereof a functionalized payload and/or therapeutic support composition and suggests that the method may be applied to inhibiting tumor metastasis, because Oneto teaches in their general formula that the trans-cyclooctene group may be substituted, and because Robillard teaches example trans-cyclooctene agents for delivering chemotherapeutic payloads that are modified with, for example, a methyl group and carboxylic acid.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Oneto teaches embodiments that satisfy all limitations of the compounds of formula (II-A) and formula (III-A) as recited in claim 44, and Robillard teaches additional therapeutic agents conjugated to trans-cyclooctene that include substituents that satisfy the requirements of formula (II-A) in claim 44, one of ordinary skill in the art would have recognized that the substituted trans-cyclooctene agent taught by Robillard may be substituted for the trans-cyclooctene agent taught by Oneto with a reasonable expectation that the substituted trans-cyclooctene agent will give predictable results when administered as part of the method of Oneto.
Regarding the method of inhibiting tumor metastasis as required by present claims 44-46, because Oneto teaches the benefits of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, and because Jing teaches that administration of a STING agonist promotes a systemic anti-tumor immune response, one of ordinary skill in the art would have recognized that administration of an immunomodulating compound, such as a STING agonist, together with a) and b) as recited in claim 44, may be effective in inhibiting metastases.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, and because Oneto teaches the benefit of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, one ordinary skill in the art would have recognized that administration of an immunomodulatory drug in addition to a) and b) of claim 44, wherein b) is locally administered as taught by Khan, may be effective in inhibiting metastasis.
Therefore the invention taken as a whole is prima facie obvious.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Oneto in view of Robillard, Jing, Khan, and Geiger (Geiger, T. R.; et al. Biochimica et Biophysica Acta 2009, vol. 1796, pp. 293-308; cited in PTO-892).
Claim 43 claims a method of treating cancer or enhancing or eliciting an immune response against a second tumor in a subject, comprising administering to a subject in need thereof: a) a therapeutically effective amount of a compound of formula (II-A) or (III-A), b) a therapeutic support composition comprising a support and a tetrazine-containing group of the formula shown, and wherein the subject has a second tumor and the administration of a) and the administration of b) inhibits growth of the second tumor; and/or enhances or elicits an immune response against the second tumor.
Oneto teaches as described in the above rejection under 35 U.S.C. 103.
Oneto does not teach trans-cyclooctene compounds that satisfy the limitations of formula (II-A) or formula (III-A) as required by present claim 43. In addition, Oneto does not teach a method that requires administering a) and b) above to a patient with a second tumor, wherein the claimed method inhibits growth of the second tumor and/or enhances or elicits an immune response against the second tumor, as required by claim 43.
Robillard, Jing, and Khan teach as described in the above rejections under 35 U.S.C. 103.
Geiger teaches mechanisms of metastasis. Specifically, Geiger teaches that the classical view on the metastatic cascade includes: 1. EMT and breach of the basement membrane barrier; 2. dissociation of tumor cells from the bulk tumor; 3. invasion of the neighboring tissue; 4. Intravasation into pre-existing and newly formed blood and lymph vessels; 5. transport through vessels; 6. extravasation from vessels; 7. Establishment of disseminated cells (which can stay dormant for a prolonged period of time) at a secondary anatomical site; and 8. outgrowth of
micrometastases and macrometastases/secondary tumors (p. 293, first paragraph, lines 1-10) (emphasis added).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify the trans-cyclooctene compounds carrying a chemotherapeutic agent taught by Oneto with a substituent for the purposes of inhibiting tumor metastasis. One of ordinary skill in the art would have been motivated to modify the trans-cyclooctene compounds carrying a chemotherapeutic agent taught by Robillard with a substituent for the purposes of inhibiting tumor metastasis because Oneto teaches a method of treating or preventing a condition or disorder, comprising administering to a subject in need thereof a functionalized payload and/or therapeutic support composition and suggests that the method may be applied to inhibiting tumor metastasis, because Oneto teaches in their general formula that the trans-cyclooctene group may be substituted, and because Robillard teaches example trans-cyclooctene agents for delivering chemotherapeutic payloads that are modified with, for example, a methyl group and carboxylic acid.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Oneto teaches embodiments that satisfy all limitations of the compounds of formula (II-A) and formula (III-A) as recited in claim 44, and Robillard teaches additional therapeutic agents conjugated to trans-cyclooctene that include substituents that satisfy the requirements of formula (II-A) in claim 44, one of ordinary skill in the art would have recognized that the substituted trans-cyclooctene agent taught by Robillard may be substituted for the trans-cyclooctene agent taught by Oneto with a reasonable expectation that the substituted trans-cyclooctene agent will give predictable results when administered as part of the method of Oneto.
Regarding the method of inhibiting growth of a second tumor as required by present claim 43, because Oneto teaches the benefits of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, because Jing teaches that administration of a STING agonist promotes a systemic anti-tumor immune response, and because Geiger teaches the secondary tumors as part of metastasis, one of ordinary skill in the art would have recognized that administration of an immunomodulating compound, such as a STING agonist, together with a) and b) as recited in claim 43, may be effective in inhibiting metastases and treating secondary tumors.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, and because Oneto teaches the benefit of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, one ordinary skill in the art would have recognized that administration of an immunomodulatory drug in addition to a) and b) of claim 44, wherein b) is locally administered as taught Khan, may be effective in inhibiting metastasis and treating secondary tumors.
Therefore the invention taken as a whole is prima facie obvious.
Claims 35-38, 47-49, and 52-58 are rejected under 35 U.S.C. 103 as being unpatentable over Yee (Publication no. WO 2018187740 A1; cited in IDS received July 28, 2022) in view of Hershberg (Publication no. WO 2012045090 A2; cited in PTO-892).
Yee was published October 11, 2018 and thus qualifies as eligible prior art under 35 U.S.C. 102(a)(1) given the effective filing dates of these claims described in the above priority section.
Claim 35 claims a method of treating cancer or enhancing or eliciting an immune response comprising administering to a subject in need thereof: a) a therapeutically effective amount of a compound of formula (II-A) or (III-A), b) a therapeutic support composition comprising a support and a tetrazine-containing group of the formula shown, and c) a therapeutically effective amount one or more immunomodulatory agents.
Claim 36 depends from claim 35 and requires the method of enhancing or eliciting an immune response wherein the administration of a), b ), and c) enhances or elicits an immune response against a cancer in the subject.
Claim 37 depends from claim 35 and requires the method is the method of treating cancer. Claim 38 depends from claim 35 and claims the immunomodulatory agent is a toll-like receptor (TLR) agonist. Claim 47 depends from claim 37 and requires the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, colon cancer or pancreatic cancer, claim 48 requires the cancer is a solid tumor, claim 49 requires the cancer is a soft tissue sarcoma.
Claim 52 depends from claim 35 and requires the compound has formula (II-A') and therapeutic support composition, as shown in the claims. Claims 53-57 further limit the compound of formula (II-A’), and claim 58 requires the tetrazine-containing group is incorporated into the hyaluronic acid from 10% to 50%.
Yee teaches cyclooctene conjugates of therapeutic agents that have improved aqueous solubility and can release the agents upon contact with a tetrazine-containing biomaterial to provide site-selective delivery of agents at the location of the tetrazine-containing biomaterial in a subject (cover page, Abstract, lines 1-3).
Yee teaches several conjugates comprising cyclooctene conjugated to therapeutic agents. As one example, Yee teaches the compound TCO-Acid-MMAE, which has a carboxylic acid-substituted trans-cyclooctene conjugated to monomethyl auristatin E (MMAE) (p. 111, Example 11; structure shown below), which is a peptide-based antimitotic agent (p. 52, see bottom figure). This compound satisfies all limitations of the compound of formula (II) recited in the present claim 35, and the compound of formula (II-A’) recited in claim 52.
PNG
media_image3.png
142
333
media_image3.png
Greyscale
Yee further teaches an embodiment wherein trans-cyclooctene is modified with glycine and conjugated to the therapeutic agent doxorubicin (p. 112, synthetic scheme for Example 12; synthesis described in [00377]; structure shown below). This compound also satisfies all limitations of the compound of formula (II) recited in the present claim 35, and the compound of formula (II-A’) recited in claims 52-58.
PNG
media_image4.png
189
171
media_image4.png
Greyscale
Furthermore, relating to the general structure of formula (I-A) recited in claim 1 of Yee (p. 136, claim 1), Yee claims variable group L2 as -C(O)- (p. 137, claim 5) and R1b may be -N(H)CHR1eCO2H, with R1e as -CH2CO2H (p. 138, claim 6), which are substituents at the same position as the carboxylic acid in TCO-Acid-MMAE above and in the position of glycine in TCO-Gly-Dox above. These definitions of L2 and R1b claimed by Yee would provide an aspartic acid substituent on the trans-cyclooctene group in place of the glycine group of TCO-Gly-Dox above.
Finally, Yee teaches an embodiment wherein trans-cyclooctene is modified with aspartic acid and conjugated to the therapeutic agent daptomycin (p. 113, Synthetic scheme at top of page; synthesis described in [00378]; structure shown below). This structure has the carboxylic acid substituent of trans-cyclooctene condensed with aspartic acid.
PNG
media_image5.png
185
236
media_image5.png
Greyscale
In addition, Yee teaches and claims a method of treating a condition or disorder comprising administering a therapeutically effective amount of the compound of any of claims 14-16 or the pharmaceutical composition of claim 19 and a therapeutic support composition, the therapeutic support composition comprising a biocompatible support and a tetrazine-containing group of formula as shown in the claim (p. 146, claim 25), which has the same limitations of the tetrazine-containing group recited in the present claims 35 and 52. TCO-Acid-MMAE and TCO-Gly-Dox have payloads as pharmaceutical agents, as required by claim 14 of Yee (p. 142), and thus falls within the scope of the method claimed by Yee.
Yee further teaches specific structures of the therapeutic support composition comprising a tetrazine-containing group. As one example, Oneto claims a therapeutic support composition of formula II as shown below, wherein G2 is a tetrazine group as shown in the claims.
PNG
media_image6.png
143
246
media_image6.png
Greyscale
Yee further teaches and claims the therapeutic support compositions shown in claims 23 and 24 wherein G2 is as shown (p. 144, claims 23 and 24).
In addition, Yee teaches the therapeutic support compositions may comprise units as shown below (p. 63, [00192]; p. 64, second structure), which satisfies all limitations of b) of present claim 52.
PNG
media_image7.png
191
233
media_image7.png
Greyscale
Moreover, Yee teaches the tetrazine-containing group can be incorporated into the hyaluronic acid from about 0.1 % to about 80% as measured by the percent of carboxylic acids being linked or conjugated to the tetrazine-containing group, such as about 1% to about 75%, about 5% to about 75%, about 10% to about 50%, or about 40% to about 75% (p. 64, [00195], line 2 to p. 65, line 3).
Yee further teaches and claims the method of claim 25 (described above), wherein the condition or disorder is cancer (p. 145, claim 26), wherein the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer (p. 146, claim 27), wherein the cancer is a solid tumor (p. 146, claim 28), wherein the cancer is a soft tissue sarcoma (p. 146, claim 29), and wherein the soft tissue sarcoma is a fibrosarcoma, rhabdomyosarcoma, or Ewing's sarcoma (p. 146, claim 30). These are the same cancers recited in present claims 47-50.
Finally, Yee teaches that the disclosed methods provide the ability to place particles as
disclosed herein at the time of the biopsy, and when the results return, the practitioner can deliver
through to the biopsy site chemokines (agents that attract cancerous cells and/or immune cells) and adjuvants to enhance the immune system with fewer side effects as well as chemotherapeutics agents combined with immunotherapy agents (p. 82, [00244], line 1 to p. 83, line 2) (emphasis added). Yee teaches the chemotherapy agent would treat the solid tumor or specific location, while the enhanced response of the immunotherapy would help with distant metastatic sites.
Hershberg teaches a combination therapy comprising a TLR8 agonist and an anticancer
agent for use in the treatment of cancer. Hershberg teaches that their invention is directed generally to a combination therapy comprising administration of a benzo[b]azepine TLR8 agonist and one or more additional treatment modalities such as an anti-cancer agent ( e.g., doxorubicin) for use in treating, alleviating, or preventing cancer, preferably solid tumors (such as sarcomas, carcinomas, and lymphomas) (p. 2, [07], lines 1-4). Hershberg teaches that in preferred embodiments, the TLR8 agonist VTX-2337 and doxorubicin are used for the treatment of cancer and the cancer is selected from the group consisting of ovarian cancer, breast cancer, head and neck cancer, renal cancer, bladder cancer, hepatocellular cancer, colorectal cancer, melanoma, and lymphoma, or any combination thereof (p. 3, lines 4-8).
Hershberg teaches an example wherein a tumor-bearing mouse model with human immune system (HIS) was transplanted with human HLA-A2+ OVCAR5 ovarian cancer tumors; and treated with pegylated liposomal doxorubicin (Doxil or PLD), VTX-2337, or the two agents in combination. Hershberg teaches that VTX-2337 and Doxil treatment independently induced tumor-infiltrating human leukocytes and restricted growth of human ovarian tumor xenografts in a dose-dependent manner, while the combination of the two drugs induced the highest frequency of tumor-infiltrating human leukocytes and potently restricted growth of ovarian tumors. Hershberg teaches that combined activation of innate and adaptive immunity by VTX-2337 and Doxil, as well as sensitization of tumor cells by Doxil to adaptive and innate immune effector mechanisms was at the basis of the observed interactions suppressing tumor growth (p. 36, lines 5-11). In addition, Hershberg teaches that VTX-2337 induced dose-dependent activation of human CD14+ and CD11e+ cells in vivo, and that transient, dose-dependent upregulation of human Th1 cytokines but also IL-10 was observed in the plasma of mice treated with VTX-2337 (p. 35, [0122], line 13 to p. 36, line 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer VTX-2337 in combination with the TCO-modified doxorubicin and the therapeutic support composition taught by Yee for the purposes of treating cancer. One of ordinary skill in the art would have been motivated to administer VTX-2337 in combination with the TCO-modified doxorubicin and the therapeutic support composition taught by Yee for the purposes of treating cancer because Yee teaches the method above for treating cancer, including wherein the anticancer drug delivered is doxorubicin, and because Hershberg teaches co-administration of doxorubicin and the TLR8 agonist VTX-2337 is more effective for inhibiting ovarian tumor growth than administration of either therapy alone. In addition, because Hershberg teaches the response of the anti-tumor immune system due this therapy, one of ordinary skill in the art would have expected the method obvious over Yee in view of Hershberg to elicit an immune response against cancer.
In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because Yee renders obvious a method for treating cancer by co-administering a) and b) as recited in claims 35-37, 47-49, and 52-58 with the anticancer therapy doxorubicin, and because Hershberg teaches the benefits of combination therapy of doxorubicin and the TLR8 agonist VTX-2337, one of ordinary skill in the art would have recognized that administration of the TLR8 agonist may benefit the method obvious over Yee by further reducing tumor cell growth in a subject.
Regarding the cancers of claims 47-49, because Yee teaches their method may be administered for the cancers recited in claims 47-49, and because Hershberg teaches their method may be used for treating solid tumors such as sarcomas, carcinomas, and lymphomas (p. 2, [07], lines 4), one of ordinary skill in the art would have reasonably considered administering the method obvious over Yee in view of Hershberg for the purposes of treating cancers such as ovarian cancer, solid tumors, and soft tissue sarcomas.
Regarding the requirement of claim 58 wherein the tetrazine-containing group is incorporated into the hyaluronic acid from 10% to 50%, because Yee teaches the tetrazine-containing group can be incorporated into the hyaluronic acid from about 0.1 % to about 80% as measured by the percent of carboxylic acids being linked or conjugated to the tetrazine-containing group, such as about 1% to about 75%, about 5% to about 75%, about 10% to about 50%, or about 40% to about 75% as measured by the % of carboxylic acids being linked or conjugated to the tetrazine-containing group, one of ordinary skill in the art would have contemplated different levels of incorporation of tetrazine into hyaluronic acid, including levels between 10 and 50%, as recited by Yee, and would have adjusted the level of tetrazine incorporation to optimize release of the drug from the TCO-conjugates when treating cancer.
Therefore the invention taken as a whole is prima facie obvious.
Claim 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Yee in view of Khan and Hershberg.
Claim 44 claims a method of inhibiting tumor metastasis in a subject at risk of tumor metastasis comprising: a) administering a compound of formula (II-A) or (III-A) thereof to the subject, and b) locally administering, at a first tumor in the subject, a therapeutic support composition comprising a support and a tetrazine-containing group of the formula as shown in the claim.
Yee teaches as described in the above rejection under 35 U.S.C. 103. Specifically, Yee teaches that the disclosed methods provide the ability to place particles as disclosed herein at the time of the biopsy, and when the results return, the practitioner can deliver through to the biopsy site chemokines (agents that attract cancerous cells and/or immune cells) and adjuvants to enhance the immune system with fewer side effects, as well as chemotherapeutics agents combined with immunotherapy agents (p. 82, [00244], line 1 to p. 83, line 2) (emphasis added). Yee teaches the chemotherapy agent would treat the solid tumor or specific location, while the enhanced response of the immunotherapy would help with distant metastatic sites.
Yee does not expressly teach a method of inhibiting metastasis by administering a administering a compound of formula (II-A) or (III-A) thereof to the subject, and b) locally administering, at a first tumor in the subject, a therapeutic support composition comprising a support and a tetrazine-containing group of the formula as shown in the claim. Yee also does not expressly teach the administration of an immunomodulatory agent, as recited in claims 45-46.
Hershberg and Khan teach as described in the above rejections under 35 U.S.C. 103.
It would have been prima facie obvious to practice the method of Yee for the purposes of inhibiting tumor metastasis in a subject at risk of tumor metastasis comprising: a) administering a compound of formula (II-A) or (III-A) thereof to the subject, and b) locally administering, at a first tumor in the subject, a therapeutic support composition comprising a support and a tetrazine-containing group of the formula as shown in the claim. One of ordinary skill in the art would have been motivated to practice the method of Yee for the purposes of inhibiting tumor metastasis in a subject because Yee suggests that administration of a chemotherapeutic agent and immunotherapy agent may be used to treat a tumor at a specific location and to help with distant metastases, and Hershberg teaches the increased immune response following administration of the TLR agonist one of ordinary skill in the art would have recognized that said TLR agonist may be benefit the method of Yee for inhibiting metastases.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, and because Yee teaches the benefit of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, one ordinary skill in the art would have recognized that administration of an immunomodulatory drug in addition to a) and b) of claim 44, wherein b) is locally administered as taught Khan, may be effective in inhibiting metastasis.
Therefore the invention taken as a whole is prima facie obvious.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Yee in view of Hershberg, Khan, and Geiger.
Claim 43 claims a method of treating cancer or enhancing or eliciting an immune response against a second tumor in a subject, comprising administering to a subject in need thereof: a) a therapeutically effective amount of a compound of formula (II-A) or (III-A), b) a therapeutic support composition comprising a support and a tetrazine-containing group of the formula shown, and wherein the subject has a second tumor and the administration of a) and the administration of b) inhibits growth of the second tumor; and/or enhances or elicits an immune response against the second tumor.
Yee teaches as described in the above rejections under 35 U.S.C. 103. Specifically, Yee teaches that the disclosed methods provide the ability to place particles as disclosed herein at the time of the biopsy, and when the results return, the practitioner can deliver through to the biopsy site chemokines (agents that attract cancerous cells and/or immune cells) and adjuvants to enhance the immune system with fewer side effects, as well as chemotherapeutics agents combined with immunotherapy agents (p. 82, [00244], line 1 to p. 83, line 2) (emphasis added). Yee teaches the chemotherapy agent would treat the solid tumor or specific location, while the enhanced response of the immunotherapy would help with distant metastatic sites.
Yee does not expressly teach a method of treating cancer or enhancing or eliciting an immune response against a second tumor in a subject, comprising administering to a subject in need thereof a) and b) as recited in the claims.
Khan and Geiger teach as described in the above rejection under 35 U.S.C. 103.
It would have been prima facie obvious to practice the method of Yee for the purposes of treating a second tumor in a subject by administering a) and b) as described in the claims, together with an immunomodulatory compound. One of ordinary skill in the art would have been motivated to practice the method of Yee for the purposes of treating a second tumor in a subject by administering a) and b) as described in the claims, together with an immunomodulatory compound because Yee suggests that administration of a chemotherapeutic agent and immunotherapy agent may be used to both treat a tumor at a specific location and to help with distant metastases, because Hershberg teaches the benefits of treatment with doxorubicin and a TLR8 agonist for treating cancer and inducing an immune response, and because Geiger teaches secondary tumors as a result of metastasis. Therefore, one of ordinary skill in the art would have considered practicing the method of treating cancer taught by Yee and administering the compound of formula (II-A) or (III-A) with therapeutic support composition, together with an immunomodulating compound such as the TLR8 agonist taught by Hershberg, for the purposes of inhibiting the growth of secondary tumors that arise due to metastasis.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, and because Yee teaches the benefit of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, one ordinary skill in the art would have recognized that administration of an immunomodulatory drug in addition to a) and b) of claim 44, wherein b) is locally administered as taught Khan, may be effective in inhibiting metastasis and secondary tumors.
Regarding the method of treating a secondary tumor, because Yee teaches the chemotherapy agent would treat the solid tumor or specific location, while the enhanced response of the immunotherapy would help with distant metastatic sites, and because Geiger teaching that metastasis results in secondary tumors, one of ordinary skill in the art would have practiced the method obvious over Yee in view of Hershberg, Khan, and Geiger on secondary tumors, because said method may be effective in treating distant metastatic sites, such as secondary tumors that arise due to metastasis.
Therefore the invention taken as a whole is prima facie obvious.
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 35-37 and 44-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9, 15-17, and 23 of U.S. Patent No. 10,828,373 (reference patent, herein referred to as ‘373) in view of Oneto, Robillard, Jing, and Khan.
The present application and ‘373 are each assigned to Tambo Inc.
Claim 1 of ‘373 claims a functionalized payload of the formula as shown in the claims. Claims 2-5 of ‘373 further limit the functionalized payload of claim 1, and claim 6 claims the functionalized payload of claim 5 which has the formula as shown therein. Claim 9 claims group D is selected from a group that includes, for example, the anticancer agents doxorubicin and gemcitabine, and claim 23 requires D as doxorubicin.
Claim 15 of ‘373 claims a method of treating a cancer, comprising administering to a subject in need thereof a support composition comprising a tetrazine-containing group as shown, which have the same structure as the support composition required in the present claims, and a functionalized payload of claim 2. Claim 16 requires the support composition is hyaluronic acid, claim 17 requires the cancer is soft tissue sarcoma, melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioblastoma, lung cancer, soft tissue carcinoma, fibrosarcoma, osteosarcoma, or pancreatic cancer.
The claims of ‘373 do not claim a compound of formula (II-A) or (III-A) or a method of enhancing or eliciting an immune response or administration of an additional immunomodulatory agent, as required by the present claim 35 and its dependent claims. In addition, the claims do not claim a method of inhibiting tumor metastasis in a subject at risk of tumor metastasis, as required by present claims 44-46.
Oneto, Robillard, Jing, and Khan teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a functionalized payload of the claims of ‘373, wherein the methyl ester substituent is a carboxylic acid as taught in the TCO conjugates of Robillard, together with an immunomodulatory agent, because the claims of ‘373 teach functionalized payloads analogous to those of the present claims, only differing in the specific TCO substituents, and in view of Robillard, other TCO substituents would be expected to be tolerated as part of this method. In addition, it would have been prima facie obvious to modify the method of treating cancer claimed by ‘373 and administer an immunomodulatory agent, such as a STING agonist, because Jing teaches the benefits of a STING agonist for enhancing the effect of gemcitabine in treating cancer and inducing a systemic anti-tumor response.
Regarding the inhibition of tumor metastasis as required by present claims 44-46, because the claims of ‘373 claim a method of treating cancer, and because Oneto suggests the method with an immunotherapy may be effective for inhibiting metastasis, and because Jing teaches co-administration of gemcitabine and a STING agonist promotes a systemic immune system response one of ordinary skill in the art would have contemplated practicing the method for the purposes of inhibiting metastasis.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, one of ordinary skill in the art would have recognized that the method obvious over the claims of ‘373, Oneto, Robillard, Jing and Khan, including local administration of the therapeutic support composition, may be administered for the purposes of inhibiting metastasis.
Claims 35, 37-38 and 47-49, and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9, 15-17, and 23 of ‘373 in view of Oneto, Robillard, and Pratesi.
The claims of ‘373 claim as described in the above non-statutory double patenting rejection.
The claims of ‘373 do not claim a compound of formula (II-A) or (III-A) or a method of enhancing or eliciting an immune response or administration of an additional immunomodulatory agent, as required by the present claim 35 and its dependent claims. In addition, the claims of ‘373 do not claim a method of inhibiting tumor metastasis in a subject at risk of tumor metastasis, as required by present claims 44-46.
Oneto, Robillard, and Pratesi teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a functionalized payload of the claims of ‘373, wherein the methyl ester substituent is a carboxylic acid as taught in the TCO conjugates of Robillard, together with an immunomodulatory agent, because the claims of ‘373 teach functionalized payloads analogous to those of the present claims, only differing in the specific TCO substituents, and in view of Robillard, other TCO substituents would be expected to be tolerated as part of this method. In addition, it would have been prima facie obvious to modify the method of treating cancer claimed by ‘373 and administer an immunomodulatory agent, such as a TLR9 agonist, because Pratesi teaches the benefits of a TLR9 agonist for enhancing the effect of gemcitabine in treating cancer.
Claim 43 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9, 15-17, and 23 of ‘373 (reference patent, herein referred to as ‘373) in view of Oneto, Robillard, Jing, Khan, and Geiger.
The claims of ‘373 claim as described in the above non-statutory double patenting rejections.
The claims of ‘373 do not claim a compound of formula (II-A) or (III-A), a method of treating a second tumor in a subject, or locally administering the therapeutic support composition, all as required by claim 43.
Oneto, Robillard, Jing, Khan, and Geiger teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a) and b) recited in claim 43 to a patient with a secondary tumor for the purposes of treating cancer and inhibiting growth of the second tumor because ‘373 claims a method of treating cancer, Oneto teaches a method of treating or preventing a condition or disorder comprising administering to a subject in need thereof a functionalized payload and/or therapeutic support composition, teaches in their general formula that the trans-cyclooctene group may be substituted, and teaches that the method may be applied to inhibiting tumor metastasis, and because Robillard teaches example trans-cyclooctene agents for delivering chemotherapeutic payloads that are modified with, for example, a methyl group and carboxylic acid as required by claim 43.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Oneto teaches embodiments that satisfy all limitations of the compounds of formula (II-A) and formula (III-A) as recited in claim 43, and Robillard teaches additional therapeutic agents conjugated to trans-cyclooctene that include substituents that satisfy the present claims, one of ordinary skill in the art would have recognized that the substituted trans-cyclooctene agent taught by Robillard may be substituted for the trans-cyclooctene agent taught by Oneto with a reasonable expectation that the substituted trans-cyclooctene agent will give predictable results when administered as part of the method of Oneto.
Regarding the method of inhibiting growth of a second tumor as required by present claim 43, because Oneto teaches the benefits of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, because Jing teaches that administration of a STING agonist promotes a systemic anti-tumor immune response, and because Geiger teaches the secondary tumors as part of metastasis, one of ordinary skill in the art would have recognized that administration of an immunomodulating compound, such as a STING agonist, together with a) and b) as recited in claim 44, may be effective in inhibiting metastases and treating secondary tumors.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, and because Oneto teaches the benefit of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, one ordinary skill in the art would have recognized that administration of an immunomodulatory drug in addition to a) and b) of claim 44, wherein b) is locally administered as taught Khan, may be effective in inhibiting metastasis and treating secondary tumors.
Claims 35-38, 47-49, and 52-58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9, 15-17, and 23 of ‘373 in view of Yee and Hershberg.
The claims of ‘373 claim as described in the above non-statutory double patenting rejections.
The claims of ‘373 do not claim a compound of formula (II-A) or (III-A) or a method of enhancing or eliciting an immune response or administration of an additional immunomodulatory agent, as required by the present claim 35 and its dependent claims. In addition, the claims do not claim a method of inhibiting tumor metastasis in a subject at risk of tumor metastasis, as required by present claims 44-46.
Yee and Hershberg teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a functionalized payload of the claims of ‘373, wherein the substituent is instead a glycine or aspartic acid substituent, as taught by Yee, together with an immunomodulatory agent, because the claims of ‘373 claim functionalized payloads analogous to those of the present claims, only differing in the specific TCO substituents, and Yee teaches further teaches methods of treating cancer with embodiments that include, for example, TCO modified with glycine or aspartic acid. In addition, it would have been obvious to modify the method of treating cancer claimed by ‘373 and administer an immunomodulatory agent, such as a TLR agonist taught by Hershberg, because Hershberg teaches the benefits of combined doxorubicin and TLR8 agonist for treating cancer and eliciting an immune response against cancer.
Finally, it would have been obvious to practice the method of treating cancer obvious over the claims of ‘373, Yee, and Hershberg, using a hyaluronic acid modified with tetrazine groups incorporated into the hyaluronic acid from 10 to 50%, as suggested by Yee, because said substitution of tetrazine may provide robust release of an anticancer payload at a site of a tumor.
Claims 35-38, 44-49, and 52-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 13, 15, 16, and 18 of U.S. Patent No. 11,253,600 (reference patent, herein referred to as ‘600) in view of Oneto, Khan, and Hershberg.
The present application and ‘600 are each assigned to Tambo Inc.
Claim 1 of ‘600 claims a compound of formula (I-A) as shown. Claim 4 requires R1a as CH3, claim 5 requires L-2 as -C(O)- and claim 6 claims R1b is selected from a group that includes N(H)CH2CO2H and N(H)CHR1cCO2H, wherein R1C is CH2CO2H. Together, these substituents of R1a and R1b render obvious the substituents the compound of formula (II-A) of the present claims, in addition to the compound of formula (II-A’) in claims 52-57.
Claim 13 claims the payload is a therapeutic agent, claim 15 claims the therapeutic agent is a payload selected from the group recited in the claims, which includes doxorubicin and gemcitabine, and claim 16 claims the compound is as shown, which has doxorubicin conjugated to trans-cyclooctene modified with methyl and glycine groups. This compound satisfies the limitations of the compound of formula (II-A) and the compound of formula (II-A’) as recited in claims 52-57.
PNG
media_image8.png
258
272
media_image8.png
Greyscale
Claim 18 of ‘600 claims a method of enhancing or eliciting an immune response comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount enhances or elicits an immune response against a cancer in the subject.
The claims of ‘600 do not claim administering also administering the required therapeutic support composition and an immunomodulatory agent, as required by the present claims.
Oneto, Khan, and Hershberg teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a therapeutic support composition and additional immunomodulatory drug because the claims of ‘600 claim a method of enhancing or eliciting an immune response against cancer by administering a TCO-payload conjugate, Oneto teaches a related method for treating cancer by administering related TCO-payload conjugates and therapeutic support compositions of the present claims, and because Hershberg teaches the benefits of a TLR8 agonist administered in combination with doxorubicin, and thus one of ordinary skill in the art would have contemplated administering a TLR8 agonist to enhance the immune response and method of treating cancer obvious over the claims of ‘600, Oneto, and Hershberg.
Regarding the method of inhibiting tumor metastasis as required by present claims 44-46, because the claims of ‘600 claim a method of eliciting an immune response against cancer, and because Oneto teaches the same method of treating cancer may be reasonably applied to metastases, one of ordinary skill in the art would have contemplated practicing the method for the purposes of inhibiting metastasis. In addition, because Hershberg teaches the benefits of a TLR8 agonist administered in combination with doxorubicin, specifically teaching the enhanced immune response that occurs when administering the TLR8 agonist, the method with co-administration of a TLR8 agonist would also reasonably inhibit metastasis.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, and because Oneto teaches the benefit of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, one ordinary skill in the art would have recognized that administration of an immunomodulatory drug in addition to a) and b) of claim 44, wherein b) is locally administered as taught Khan, may be effective in inhibiting metastasis.
Claims 35-37, 44-50, and 52-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 13, 15, 16, and 18 of ‘600 (reference patent, herein referred to as ‘600) in view of Oneto, Jing, and Khan.
The claims of ‘600 claim as described the above non-statutory double patenting rejection.
The claims of ‘600 do not claim administering also administering the required therapeutic support composition and an immunomodulatory agent, a method of inhibiting metastases by administering a TCO conjugate, therapeutic support composition, and immunomodulatory agent, and wherein the immunomodulatory agent is a STING agonist, as required by the present claims.
Oneto, Jing, and Khan teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a therapeutic support composition and additional immunomodulatory drug because the claims of ‘600 claim a method of enhancing or eliciting an immune response against cancer by administering a TCO-payload conjugate, Oneto teaches a related method for treating cancer by administering related TCO-payload conjugates and therapeutic support compositions of the present claims, and because Jing teaches the benefits of administration of gemcitabine with a STING agonist for promoting a systemic anti-tumor response, and thus one of ordinary skill in the art would have contemplated administering a STING agonist to enhance the immune response and method of treating cancer obvious over the claims of ‘600, Oneto, and Jing.
Regarding the method of inhibiting tumor metastasis as required by present claims 44-46, because the claims of ‘600 claim a method of eliciting an immune response against cancer, and because Oneto teaches the same method of treating cancer may be reasonably applied to tumor metastases, one of ordinary skill in the art would have contemplated practicing the method for the purposes of inhibiting metastasis. In addition, because Jing teaches co-administration of gemcitabine and a STING agonist promotes a systemic immune system response, the method with co-administration of a STING agonist would also reasonably inhibit tumor metastases.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, and because Oneto teaches the benefit of chemotherapy and immunotherapy for stimulating the immune system and treating metastasis, one ordinary skill in the art would have recognized that administration of an immunomodulatory drug in addition to a) and b) of claim 44, wherein b) is locally administered as taught Khan, may be effective in inhibiting metastasis.
Claims 35, 37-38, 47-49, and 51-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 13, 15, 16, and 18 of ‘600 (reference patent, herein referred to as ‘600) in view of Oneto and Pratesi.
The claims of ‘600 claim as described in the above non-statutory double patenting rejection.
The claims of ‘600 do not claim administering also administering the required therapeutic support composition and an immunomodulatory agent, and wherein the immunomodulatory agent is a TLR9 agonist, as required by the present claim 35.
Oneto and Pratesi teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a therapeutic support composition and additional immunomodulatory drug for the purposes of treating cancer because the claims of ‘600 claim a method of enhancing or eliciting an immune response against cancer by administering a TCO-payload conjugate, Oneto teaches a related method for treating cancer by administering related TCO-payload conjugates and therapeutic support compositions of the present claims, and Pratesi teaches the benefits of administration of gemcitabine with a TLR9 agonist for increasing subject survival time and reducing tumor spread, and thus one of ordinary skill in the art would have contemplated administering a TLR9 agonist to enhance the immune response and method of treating cancer obvious over the claims of ‘600, Oneto, and Pratesi.
Claim 58 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 13, 15, 16, and 18 of ‘600 in view of Oneto, Khan, and Pratesi as applied to claims 35, 37-38, 47-49, and 51-57 above, and further in view of Yee.
The claims of ‘600 claim as described in the above non-statutory double patenting rejection.
Oneto, Khan, and Pratesi teach as described in the above rejections under 35 U.S.C. 103.
The claims of ‘600 do not require the tetrazine-containing group is incorporated
into the hyaluronic acid from 10% to 50%, as recited in present claim 58.
Yee teaches as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to practice the method of treating cancer obvious over the claims of ‘600, Oneto, Khan, and Pratesi, as described in the above non-statutory double patenting rejection, using a hyaluronic acid modified with tetrazine groups incorporated into the hyaluronic acid from 10 to 50%, as suggested by Yee, because said substitution of tetrazine may provide robust release of an anticancer payload at a site of a tumor.
Claim 43 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 13, 15, 16, and 18 of ‘600 in view of Oneto, Jing, Khan, and Geiger.
The claims of ‘600 claim as described in the above non-statutory double patenting rejection.
The claims of ‘600 do not claim a method of treating cancer in a subject with a second tumor by administering a) and b) as required by the present claim 43.
Oneto, Jing, Khan, and Geiger teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to practice the method of claim 43 because ‘600 claims a method of treating cancer using a compound that satisfies the limitations of the compound of formula (II-A) of claim 43, Oneto suggests their related method may be used with an immunotherapy for the purposes of inhibiting metastasis, Jing teaches the benefits of STING agonists when administered with gemcitabine for inducing a systemic anti-tumor response, and Geiger teaches secondary tumors as a result of metastasis. Accordingly, one of ordinary skill in the art would have contemplated administering the method claimed by ‘600 with an immunomodulatory agent, such as a STING agonist, to treat a secondary tumor that arose via metastasis, because said method may be effective in treating said secondary tumor.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, one of ordinary skill in the art would have recognized that the method obvious over the claims of ‘600, Oneto, Jing, Khan, and Geiger may be administered for the purposes of treating secondary tumors that arise via metastasis.
Claims 35-38, 44-49, and 52-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, 13, and 14 of U.S. Patent No. 12,296,017 (reference patent, herein referred to as ‘017) in view of Oneto, Hershberg, and Khan.
The present application and ‘017 are each assigned to Tambo Inc.
Claim 1 of ‘017 claims a method of treating a cancer or bacterial infection comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I-A) as shown and a therapeutic support composition with formula as shown. Claim 2 claims the method is a method of treating is a cancer and the therapeutic agent is an anticancer agent, claim 3 claims the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer, claim 4 claims the cancer is a solid tumor, claim 5 claims the cancer is a soft tissue sarcoma, claim 10 claims the biocompatible support comprises substituted hyaluronic acid units of formula (II) as shown, claim 13 claims the anticancer agent is doxorubicin, and claim 14 claims the compound of formula (I-A) is the conjugate below, which has doxorubicin conjugated to trans-cyclooctene modified with methyl and glycine groups. This TCO moiety satisfies the requirements of the present claim of formula (II-A’) of claims 52-57.
PNG
media_image9.png
252
269
media_image9.png
Greyscale
The claims of ‘017 do not claim administering the immunomodulatory agent, a method of enhancing or eliciting an immune response, a method of inhibiting metastases by administering a TCO conjugate, therapeutic support composition, and immunomodulatory agent, and wherein the immunomodulatory agent is a TLR agonist, as required by the present claims.
Oneto, Hershberg, and Khan teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a therapeutic support composition and additional immunomodulatory drug because the claims of ‘017 claim a method of treating cancer by administering a compound of formula (I-A) and therapeutic support composition, because Oneto teaches the benefits of enhancing the immune system when treating cancer and metastases, and because Hershberg teaches the benefits of a TLR8 agonist administered in combination with doxorubicin for treating cancer. Thus one of ordinary skill in the art would have contemplated administering a TLR8 agonist to enhance the immune response and method of treating cancer obvious over the claims of ‘017, Oneto, and Hershberg.
Regarding the method of inhibiting tumor metastasis as required by present claims 44-46, because the claims of ‘017 claim a method of treating cancer, and because Oneto teaches the same method of treating cancer may be reasonably applied to tumor metastases, one of ordinary skill in the art would have contemplated practicing the method for the purposes of inhibiting metastasis. In addition, because Hershberg teaches the benefits of a TLR8 agonist administered in combination with doxorubicin, specifically teaching the enhanced immune response that occurs when administering the TLR8 agonist, the method with co-administration of a TLR8 agonist would also reasonably be expected to inhibit tumor metastases.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, one of ordinary skill in the art would have recognized that the method obvious over the claims of ‘017, Oneto, Hershberg, and Khan may be administered for the purposes of inhibiting metastasis.
Claim 58 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, 13, and 14 of ‘017 in view of Oneto, Hershberg, and Khan as applied to claims 35-38, 44-49, and 52-57 above, and further in view of Yee.
The claims of ‘017 claim as described in the above non-statutory double patenting rejection.
Oneto, Hershberg, and Khan teach as described in the above rejections under 35 U.S.C. 103.
The claims of ‘017 do not require the tetrazine-containing group is incorporated
into the hyaluronic acid from 10% to 50%, as recited in present claim 58.
Yee teaches as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to practice the method of treating cancer obvious over the claims of ‘017, Oneto, Hershberg, and Khan as described in the above non-statutory double patenting rejection, using a hyaluronic acid modified with tetrazine groups incorporated into the hyaluronic acid from 10 to 50%, as suggested by Yee, because said substitution of tetrazine may provide robust release of an anticancer payload at a site of a tumor.
Claims 35, 37-38, 47-49, and 52-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, 13, and 14 of ‘017 in view of Oneto and Pratesi.
The present application and ‘017 are each assigned to Tambo Inc.
The claims of ‘017 claim as described in the above non-statutory double patenting rejection.
The claims of ‘017 do not claim administering the immunomodulatory agent, a method of enhancing or eliciting an immune response, a method of inhibiting metastases by administering a TCO conjugate, therapeutic support composition, and immunomodulatory agent, and wherein the immunomodulatory agent is a TLR9 agonist, as required by the present claims.
Oneto and Pratesi teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a therapeutic support composition and additional immunomodulatory drug because the claims of ‘017 claim a method of treating cancer by administering a compound of formula (I-A) and therapeutic support composition, because Oneto teaches the benefits of enhancing the immune system when treating cancer and metastases by delivering payloads of both gemcitabine and doxorubicin, and because Pratesi teaches the benefits of a TLR9 agonist administered in combination with gemcitabine for treating cancer. Thus one of ordinary skill in the art would have contemplated administering a TLR9 agonist to enhance the method of treating cancer obvious over the claims of ‘017, Oneto, and Pratesi.
Claims 35-38 and 47-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, 13, and 14 of ‘017 in view of Oneto and Jing.
The present application and ‘017 are each assigned to Tambo Inc.
The claims of ‘017 claim as described in the above non-statutory double patenting rejection.
The claims of ‘017 do not claim administering the immunomodulatory agent, a method of enhancing or eliciting an immune response, a method of inhibiting metastases by administering a TCO conjugate, therapeutic support composition, and immunomodulatory agent, and wherein the immunomodulatory agent is a STING agonist, as required by the present claims.
Oneto and Jing teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer a therapeutic support composition and additional immunomodulatory drug because the claims of ‘017 claim a method of treating cancer by administering a compound of formula (I-A) and therapeutic support composition, because Oneto teaches the benefits of enhancing the immune system when treating cancer and metastases by delivering payloads of both gemcitabine and doxorubicin, and because Jing teaches the benefits of a STING agonist administered in combination with gemcitabine for treating cancer and inducing a systemic anti-tumor response. Thus one of ordinary skill in the art would have contemplated administering a STING agonist to enhance the method of treating cancer obvious over the claims of ‘017, Oneto, and Jing.
Claim 43 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, 13, and 14 of ‘017 in view of Oneto, Hershberg, Khan, and Geiger.
The claims of ‘017 claim as described in the above non-statutory double patenting rejection.
The claims of ‘017 do not claim a method of treating cancer in a subject with a second tumor by administering a) and b) as required by the present claim 43.
Oneto, Hershberg, Khan, and Geiger teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to practice the method of claim 43 because ‘017 claims a method of treating cancer using a compound that satisfies the limitations of the compound of formula (II-A) of claim 43, Oneto suggests their related method may be used with an immunotherapy for the purposes of inhibiting metastasis, Hershberg teaches the benefits of TLR agonists when administered with doxorubicin, and Geiger teaches secondary tumors as a result of metastasis. Accordingly, one of ordinary skill in the art would have contemplated administering the method claimed by ‘017 with an immunomodulatory agent, such as a TLR agonist, to treat a secondary tumor that arose via metastasis, because said method may be effective in treating said secondary tumor.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, one of ordinary skill in the art would have recognized that the method obvious over the claims of ‘017, Oneto, Hershberg, Khan, and Geiger may be administered for the purposes of treating secondary tumors that arise via metastasis.
Claims 35-37 and 44-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54, 55, and 67 of co-pending U.S. patent application 18/705504 (reference application, herein referred to as ‘504) in view of Oneto, Jing, and Khan.
The present application and ‘504 are each assigned to Tambo, Inc.
Claim 54 of ‘504 claims a method of treating cancer or enhancing or eliciting an immune response, the method comprising administering to a subject in need thereof, a therapeutically effective amount of the targeting moiety of claim 1 and a conjugate comprising payload linked to one or more trans-cyclooctene moieties. Claim 55 claims the conjugate is of Formula X as shown in the claim, which includes the trans-cyclooctene substituents as required by the present claims. Claim 67 claims further comprising administering a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
The claims of ‘504 do not require the payload of formula X as an anti-cancer payload, as required by the present claims.
Oneto, Jing, and Khan teach as described in the above rejection under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to select gemcitabine as the payload when practicing the method claimed by ‘504, because Oneto teaches examples of gemcitabine linked to trans-cyclooctene. In addition, one of ordinary skill in the art, in view of ‘504 claiming administration of an additional immunomodulatory agent, would have considered administering a STING agonist, because Jing teaches the benefits of administration of gemcitabine with a STING agonist for promoting a systemic anti-tumor response.
Regarding the method of inhibiting tumor metastasis as required by present claims 44-46, because the claims of ‘504 claim a method of treating cancer, and because Oneto teaches the same method of treating cancer may be reasonably applied to tumor metastases, one of ordinary skill in the art would have contemplated practicing the method for the purposes of inhibiting metastasis. In addition, because Jing teaches co-administration of gemcitabine and a STING agonist promotes a systemic immune system response, the method with co-administration of a STING agonist would also reasonably inhibit tumor metastases.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, one of ordinary skill in the art would have recognized that the method obvious over the claims of ‘504, Oneto, Jing, and Khan may be administered for the purposes of inhibiting metastasis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Claims 35-37, 44-50, and 52-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54, 55, and 67 of ‘504 in view of Yee, Khan, and Jing.
The claims of ‘504 claim as described in the above non-statutory double patenting rejection.
The claims of ‘504 do not require the payload of formula X as an anti-cancer payload, as required by the present claims.
Yee, Khan, and Jing teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to select gemcitabine as the payload when practicing the method claimed by ‘504, because Yee teaches examples of gemcitabine and doxorubicin linked to trans-cyclooctene with the substituents required by claims 52-58. In addition, in view of ‘504 claiming administration of an additional immunomodulatory agent, one of ordinary skill in the art would have considered administering a STING agonist, because Jing teaches the benefits of administration of gemcitabine with a STING agonist for promoting a systemic anti-tumor response.
Regarding the method of inhibiting tumor metastasis as required by present claims 44-46, because the claims of ‘504 claim a method of treating cancer, and because Yee teaches the same method of treating cancer may be reasonably applied to tumor metastases, one of ordinary skill in the art would have contemplated practicing the method for the purposes of inhibiting metastasis. In addition, because Jing teaches co-administration of gemcitabine and a STING agonist promotes a systemic immune system response, the method with co-administration of a STING agonist would also reasonably inhibit tumor metastases.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, one of ordinary skill in the art would have recognized that the method obvious over the claims of ‘504, Yee, Khan, and Jing may be administered for the purposes of inhibiting metastasis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Claims 35, 37-38, 47-49, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54, 55, and 67 of ‘504 in view of Oneto and Pratesi.
The present application and ‘504 are each assigned to Tambo, Inc.
Claim 54 of ‘504 claims a method of treating cancer or enhancing or eliciting an immune response, the method comprising administering to a subject in need thereof, a therapeutically effective amount of the targeting moiety of claim 1 and a conjugate comprising payload linked to one or more trans-cyclooctene moieties. Claim 55 claims the conjugate is of Formula X as shown in the claim, which includes the trans-cyclooctene substituents as required by the present claims. Claim 67 claims further comprising administering a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
The claims of ‘504 do not require the payload of formula X as an anti-cancer payload, as required by the present claims.
Oneto and Pratesi teach as described in the above rejection under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to select gemcitabine as the payload when practicing the method claimed by ‘504, because Oneto teaches examples of gemcitabine linked to trans-cyclooctene. In addition, one of ordinary skill in the art, in view of ‘504 claiming administration of an additional immunomodulatory agent, would have considered administering a TLR9 agonist, because Pratesi teaches the benefits of administration of gemcitabine with a TLR9 agonist for reducing tumor burden and tumor spread.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Claims 35, 37-38, 47-49, and 52-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54, 55, and 67 of ‘504 in view of Yee and Pratesi.
The present application and ‘504 are each assigned to Tambo, Inc.
Claim 54 of ‘504 claims a method of treating cancer or enhancing or eliciting an immune response, the method comprising administering to a subject in need thereof, a therapeutically effective amount of the targeting moiety of claim 1 and a conjugate comprising payload linked to one or more trans-cyclooctene moieties. Claim 55 claims the conjugate is of Formula X as shown in the claim, which includes the trans-cyclooctene substituents as required by the present claims. Claim 67 claims further comprising administering a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
The claims of ‘504 do not require the payload of formula X as an anti-cancer payload, as required by the present claims.
Yee and Pratesi teach as described in the above rejection under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to select gemcitabine as the payload when practicing the method claimed by ‘504, because Yee teaches examples of gemcitabine and doxorubicin linked to trans-cyclooctene. In addition, one of ordinary skill in the art, in view of ‘504 claiming administration of an additional immunomodulatory agent, would have considered administering a TLR9 agonist, because Pratesi teaches the benefits of administration of gemcitabine with a TLR9 agonist for reducing tumor burden and tumor spread.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Claim 43 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54, 55, and 67 of ‘504 in view of Oneto, Jing, Khan, and Geiger.
The claims of ‘504 claim as described in the above non-statutory double patenting rejection.
The claims of ‘504 do not claim a method of treating cancer in a subject with a second tumor, and do not require the payload of formula X as an anti-cancer payload, as required by the present claim 43.
Oneto, Jing, Khan, and Geiger teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to select gemcitabine as the payload when practicing the method claimed by ‘504, because Oneto teaches examples of gemcitabine and doxorubicin linked to trans-cyclooctene. In addition, one of ordinary skill in the art, in view of ‘504 claiming administration of an additional immunomodulatory agent, would have considered administering a TLR9 agonist, because Jing teaches the benefits of administration of gemcitabine with a STING agonist for promoting a systemic anti-tumor response.
Regarding the limitation wherein the therapeutic support composition is locally administered at the first tumor in a subject, because Oneto teaches chemotherapeutics agents combined with immunotherapy agents may be delivered at the site of a biopsy, one of ordinary skill in the art would have reasonably considered administering the chemotherapy and therapeutic support composition locally to treat the initial tumor.
Regarding the administration of the immunomodulatory agent, because Oneto teaches the enhanced response of the immunotherapy would help with distant metastatic sites, one of ordinary skill in the art would have recognized that an immunomodulatory agent may be administered for the purposes of enhancing the immune response for inhibiting metastasis at sites other than the solid tumor.
Regarding the method of treating a secondary tumor, because Oneto teaches the chemotherapy agent would treat the solid tumor or specific location, while the enhanced response of the immunotherapy would help with distant metastatic sites, and in view of Geiger teaching that metastasis results in secondary tumors, one of ordinary skill in the art would have reasonably contemplated the method obvious over Oneto in view of Khan and Jing for treating secondary tumors because said method may be effective in treating distant metastatic sites, such as secondary tumors that arise due to metastasis.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, one of ordinary skill in the art would have recognized that the method obvious over the claims of ‘504, Oneto, Khan, and Jing may be administered for the purposes of inhibiting the growth a second tumor.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Claim 43 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54, 55, and 67 of ‘504 in view of Yee, Jing, Khan and Geiger.
The claims of ‘504 claim as described in the above non-statutory double patenting rejection.
The claims of ‘504 do not claim a method of treating cancer in a subject with a second tumor, and do not require the payload of formula X as an anti-cancer payload, as required by the present claim 43.
Yee, Jing, Khan, and Geiger teach as described in the above rejections under 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to select gemcitabine as the payload when practicing the method claimed by ‘504, because Yee teaches examples of gemcitabine and doxorubicin linked to trans-cyclooctene. In addition, one of ordinary skill in the art, in view of ‘504 claiming administration of an additional immunomodulatory agent, would have considered administering a STING agonist, because Jing teaches the benefits of administration of gemcitabine with a STING agonist for promoting a systemic anti-tumor response.
Regarding the limitation wherein the therapeutic support composition is locally administered at the first tumor in a subject, because Yee teaches chemotherapeutics agents combined with immunotherapy agents may be delivered at the site of a biopsy, one of ordinary skill in the art would have reasonably considered administering the chemotherapy and therapeutic support composition locally to treat the initial tumor.
Regarding the administration of the immunomodulatory agent, because Yee teaches the enhanced response of the immunotherapy would help with distant metastatic sites, one of ordinary skill in the art would have recognized that an immunomodulatory agent may be administered for the purposes of enhancing the immune response for inhibiting metastasis at sites other than the solid tumor.
Regarding the method of treating a secondary tumor, because Yee teaches the chemotherapy agent would treat the solid tumor or specific location, while the enhanced response of the immunotherapy would help with distant metastatic sites, and in view of Geiger teaching that metastasis results in secondary tumors, one of ordinary skill in the art would have reasonably practiced the method obvious over Yee in view of Khan and Jing because said method may be effective in treating distant metastatic sites, such as secondary tumors that arise due to metastasis.
Regarding the local administration of the therapeutic support composition, because Khan teaches implanting an alginate-based tetrazine at the site of a tumor, and further teaches that the low level of systemic toxicity of the approach would not preclude the concomitant use of systemic doxorubicin or alternative immunotherapies that may be effective against distant micrometastases, one of ordinary skill in the art would have recognized that the method obvious over the claims of ‘504, Yee, Khan, Jing, and Geiger may be administered for the purposes of inhibiting metastasis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN BRANDSEN whose telephone number is (703)756-4780. The examiner can normally be reached Monday - Friday from 9:00 am to 5:00 pm.
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, Scarlett Goon can be reached at (571)270-5241. 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.
/B.M.B./ Examiner, Art Unit 1693
/ERIC OLSON/ Primary Examiner, Art Unit 1693
Prosecution Insights