DETAILED ACTION
All rejections and objections not mentioned below have been withdrawn.
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
Acknowledgment is made of applicant’s claim for priority. The certified copy has been filed in parent Application No. 63/059,705, filed on 7/31/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/29/2023 is being considered by the examiner.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 15, 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over BACHOVCHIN (BACHOVCHIN et al., US20170119901A1, 2017-05-04, previously provided) as evidenced by PubChem (PubChem Mk-2206, 2008, previous provided) in view of Li(Li et al., Multi-targeted therapy of cancer by niclosamide: A new application for an old drug, Volume 349, Issue 1, 10 July 2014, Pages 8-14, previous provided) in view of Brennen ( Brennen et al., Evaluation of Fibroblast Activation Protein-Alpha (FAP) as a Diagnostic Marker and Therapeutic Target in Prostate Cancer, December 2009, previous provided) further in view of Sobhani (Sobhani, N., Generali, D., D’Angelo, A. et al. Current status of androgen receptor-splice variant 7 inhibitor niclosamide in castrate-resistant prostate-cancer. Invest New Drugs 36, 1133–1137 (2018), previous provided) .
The reference BACHOVCHIN teaches the following compound (figure 15A) and “In certain embodiments, the cytotoxic compound or cytostatic compound is an inhibitor of the activity of one or more of the isoforms of the serine/threonine kinase, Akt (also known as PKB; hereinafter referred to as “Akt”), such as a substituted naphthyridine compounds. Exemplary Akt inhibitors in the clinic for which FAP-activated prodrugs are contemplated by the present invention include, but are not limited to: Perifosine (KRX-0401) by AEterna Zentaris; MK-2206 by Merck; and GSK-2141795 by GlaxoSmithKline. For example, the Akt inhibitor moiety of the subject prodrugs can be represented by the following formula…” [0195]. The reference also teaches “A prodrug for fibroblast activation protein (FAP)-dependent release of an agent, comprising a FAP substrate covalently linked to an agent via a bond or a self-immolative linker; wherein the agent is a cytotoxic or cytolytic drug; upon cleavage by FAP of the FAP substrate, the prodrug releases the agent”(reference claim 2). Wherein, A=6-membered heteroaryl, R2=R3=F, R1=H, linker =
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, drug= MK-2206. This helps to teach claims 1, 2, 3, 4, 5, 6, 8.
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The reference PubChem provides evidence for the structure of MK-2206 (section 1.1):
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The reference BACHOVCHIN teaches “The term “self-eliminating linker” or “self-immolative linker” refers to a temporary extender, spacer, or placeholder unit attaching two or more molecules together by chemical bonds that are cleaved under defined conditions to release the two molecules. In general, a self-eliminating or self-immolative linker may be linear or branched, and may link two or more of the same molecules together, or may link two or more different molecules together. A self-immolative moiety may be defined as a bifunctional chemical group which is capable of covalently linking together two spaced chemical moieties into a normally stable molecule, releasing one of said spaced chemical moieties from the molecule by means of enzymatic cleavage; and following said enzymatic cleavage, spontaneously cleaving from the remainder of the bifunctional chemical group to release the other of said spaced chemical moieties. In accordance with the present invention, the self-immolative moiety is covalently linked at one of its ends, directly or indirectly through a Spacer unit, to the FAP substrate by an amide bond and covalently linked at its other end to a chemical reactive site (functional group) pending from the drug. The conjugate is in the absence of an enzyme (i.e., FAP) capable of cleaving the amide bond of the self-immolative moiety. The self-eliminating or self-immolative linker may degrade, decompose, or fragment under, for example, physiological conditions, acidic conditions, basic conditions, or in the presence of specific chemical agents. Examples of self-eliminating linkers include, but are not limited to, p-aminobenzyloxycarbonyl (PABC) and 2,4-bis(hydroxymethyl)aniline. Exemplary self-immolative linkers can be found in, for example, U.S. Pat. No. 7,754,681 (incorporated by reference)” [298]. This helps to teach claim 7.
The reference also teaches “ A pharmaceutical composition, comprising a prodrug of claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier” (reference claim 16). This helps to teach claim 11.
The reference also teaches “An aspect of the invention is a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a prodrug of the invention, or a pharmaceutically acceptable salt thereof” [0089]. This helps to teach claim 12.
The reference BACHOVCHIN teaches “The compounds of the invention may also be administered in conjunction with an anti-cancer therapy. Anti-cancer therapies include cancer medicaments, radiation, and surgical procedures. As used herein, a “cancer medicament” refers to an agent which is administered to a subject for the purpose of treating a cancer. As used herein, “treating a cancer” includes preventing the development of a cancer, reducing the symptoms of cancer, and/or inhibiting the growth of an established cancer. In one embodiment, “treating a cancer” means reducing the symptoms of cancer and/or inhibiting the growth of an established cancer, whether at a primary site or metastatic. Various types of medicaments for the treatment of cancer are described herein. For the purpose of this specification, cancer medicaments are classified as chemotherapeutic agents, immunotherapeutic agents, cancer vaccines, hormone therapy, and biological response modifiers” [0345-0346]. This helps to teach claim 15.
The reference BACHOVCHIN teaches “The term “subject” as used herein refers to a living mammal. In an embodiment, a subject is a mouse, rat, hamster, guinea pig, rabbit, cat, dog, goat, sheep, pig, horse, cow, or non-human primate. In another embodiment, a subject is a human” [0296]. This helps to teach claim 16.
The reference BACHOVCHIN does not teach the drugs of claim 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 15, 16 or the prostate cancer of claims 13-14.
The reference Li teaches “The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified niclosamide as a potential anticancer agent by various high-throughput screening campaigns. Niclosamide not only inhibits the Wnt/b-catenin, mTORC1, STAT3, NF-jB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. A number of studies have established the anticancer activities of niclosamide in both in vitro and in vivo models. Moreover, the inhibitory effects of niclosamide on cancer stem cells provide further evidence for its consideration as a promising drug for cancer therapy. This article reviews various aspects of niclosamide as they relate to its efficacy against cancer and associated molecular mechanisms”(abstract) and “Anti-cancer activity of niclosamide has been demonstrated in human breast cancer [10,11,18,48,49), prostate cancer…”(page 11). The reference also teaches the structure of niclosamide (figure 1). This helps to teach claims 9, 10, 13, 14.
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The reference Brennen teaches “One defining characteristic of these carcinoma-associated fibroblasts, or myofibroblasts, is the expression of fibroblast activation protein-alpha (FAP). FAP is a membrane-bound serine protease that has both dipeptidase, as well as, gelatinase and collagenase activity. FAP is not expressed in healthy adults, but has been shown to be selectively expressed on myofibroblasts in the stroma surrounding >90% of epithelial cancers examined, including 7/7 human prostate cancer specimens, with minimal to no expression in either cancerous epithelial or adjacent normal tissues. FAP has been implicated in tumor promotion through studies demonstrating increases in tumor incidence, growth, and microvessel density using in vivo models. In contrast, other studies have shown that expression of FAP decreased tumorigenicity in vivo suggesting that the physiologic response to FAP may be dependent upon the exact context of its expression. Our goal is to evaluate FAP expression patterns and enzymatic activity in both normal prostate tissue and at various stages of oncogenic transformation (i.e. PIA, PIN, Localized and Advanced Cancer) to determine tumor stage in which FAP expression may play a role. A second objective is to exploit this expression in the treatment of prostate cancer by developing therapies targeted for activation by FAP. This will be accomplished by identifying selective peptide substrates for the proteolytic activity of FAP and coupling these peptides to a highly cytotoxic agent, thapsigargin, to generate prodrugs that are only activated in prostate tumors where FAP is expressed”(page 4). This helps to teach claims 9, 10, 13 and 14.
The reference Sobhani teaches “Castrate-Resistant Prostate-Cancer (CRPC) is one of the most common malignancies occurring in men. Unfortunately, even if several recently approved agents clinically improved the outcome of CRPC patients, none of these is curative especially for a splice version of the Androgen Receptor (AR) AR-V7, which is a variant of the receptor constitutively activated and does not require the presence of androgens for the activation AR down-stream pathways. Since high AR-V7 expression is one of the most common features of CRPC, targeting this receptor variant is considered as one of the most promising strategies for treating this disease. Therefore anti-AR-V7 molecules could lead to a potential shift in paradigm in the treatment of CRPC. Niclosamide, an already FDA-approved antihelminthic drug, was identified as a potent AR-V7 inhibitor in prostate cancer cells. Due to the recent positive preclinical results, niclosamide may be an interesting and novel type of targeted treatments for CRPC”(Summary) and “Antonarakis ES et al. showed that ARV7 is highly expressed in circulating tumour cells (CTC), as quantified with RT-PCR [50], and it is associated with resistance to abiraterone and enzalutamide in metastatic CRPC patients [42–44]”(page 1135). This helps to teach 14.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified BACHOVCHIN with Li because BACHOVCHIN teaches a method of using a prodrug wherein different drugs can be attached for cancer treatment and Li teaches a drug (niclosamide) for cancer treatment and thus it would be obvious to substitute equivalents for the same purpose of treating cancer. One would have a reasonable expectation of success because niclosamide is known to treat prostate cancer including Castrate-Resistant Prostate-Cancer as taught by Li and Sobhani and because Brennen teaches that treatment of prostate cancer can be done by developing therapies targeted for activation by FAP because FAP is selectively expressed in human prostate cancer. BACHOVCHIN teaches “A prodrug for fibroblast activation protein (FAP)-dependent release of an agent, comprising a FAP substrate covalently linked to an agent via a bond or a self-immolative linker; wherein the agent is a cytotoxic or cytolytic drug; upon cleavage by FAP of the FAP substrate, the prodrug releases the agent”(reference claim 2). It would have been obvious to modify Li with Sobhani because both teach niclosamide is known to treat prostate cancer and with Brennen because it also teaches prostate cancer. It would have been also obvious to modify BACHOVCHIN with Brennen because they both teach cancer treatment directed by FAP. Thus one would have a reasonable expectation of success to treat cancer because BACHOVCHIN teaches targeting FAP with a prodrug, which will select for prostate cancer cells(taught by Brennen) , and Li and Sobhani teach niclosamide as a treatment of prostate cancer. One would be motivated to do so to direct a prostate cancer treatment drug to prostate cancer.
Claim(s) 1-8, 10-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over BACHOVCHIN (BACHOVCHIN et al., US20170119901A1, 2017-05-04, previous provided) as evidenced by PubChem (PubChem Mk-2206, 2008, previous provided) in view of Li(Li et al., Multi-targeted therapy of cancer by niclosamide: A new application for an old drug, Volume 349, Issue 1, 10 July 2014, Pages 8-14, previous provided) in view of Brennen ( Brennen et al., Evaluation of Fibroblast Activation Protein-Alpha (FAP) as a Diagnostic Marker and Therapeutic Target in Prostate Cancer, December 2009, previous provided) further in view of Sobhani (Sobhani, N., Generali, D., D’Angelo, A. et al. Current status of androgen receptor-splice variant 7 inhibitor niclosamide in castrate-resistant prostate-cancer. Invest New Drugs 36, 1133–1137 (2018), previous provided) further in view of Riber (Riber et al., Self-Immolative Linkers Literally Bridge Disulfide Chemistry and the Realm of Thiol-Free Drugs, Adv. Healthcare Mater. 2015, 4, 1887–1890, previous provided).
The reference BACHOVCHIN teaches the following compound (figure 15A) and “In certain embodiments, the cytotoxic compound or cytostatic compound is an inhibitor of the activity of one or more of the isoforms of the serine/threonine kinase, Akt (also known as PKB; hereinafter referred to as “Akt”), such as a substituted naphthyridine compounds. Exemplary Akt inhibitors in the clinic for which FAP-activated prodrugs are contemplated by the present invention include, but are not limited to: Perifosine (KRX-0401) by AEterna Zentaris; MK-2206 by Merck; and GSK-2141795 by GlaxoSmithKline. For example, the Akt inhibitor moiety of the subject prodrugs can be represented by the following formula…” [0195]. The reference also teaches “A prodrug for fibroblast activation protein (FAP)-dependent release of an agent, comprising a FAP substrate covalently linked to an agent via a bond or a self-immolative linker; wherein the agent is a cytotoxic or cytolytic drug; upon cleavage by FAP of the FAP substrate, the prodrug releases the agent”(reference claim 2). Wherein, A=6-membered heteroaryl, R2=R3=F, R1=H, linker =
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, drug= MK-2206. This helps to teach claims 1, 2, 3, 4, 5, 6, 8.
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The reference PubChem provides evidence for the structure of MK-2206 (section 1.1):
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The reference BACHOVCHIN teaches “The term “self-eliminating linker” or “self-immolative linker” refers to a temporary extender, spacer, or placeholder unit attaching two or more molecules together by chemical bonds that are cleaved under defined conditions to release the two molecules. In general, a self-eliminating or self-immolative linker may be linear or branched, and may link two or more of the same molecules together, or may link two or more different molecules together. A self-immolative moiety may be defined as a bifunctional chemical group which is capable of covalently linking together two spaced chemical moieties into a normally stable molecule, releasing one of said spaced chemical moieties from the molecule by means of enzymatic cleavage; and following said enzymatic cleavage, spontaneously cleaving from the remainder of the bifunctional chemical group to release the other of said spaced chemical moieties. In accordance with the present invention, the self-immolative moiety is covalently linked at one of its ends, directly or indirectly through a Spacer unit, to the FAP substrate by an amide bond and covalently linked at its other end to a chemical reactive site (functional group) pending from the drug. The conjugate is in the absence of an enzyme (i.e., FAP) capable of cleaving the amide bond of the self-immolative moiety. The self-eliminating or self-immolative linker may degrade, decompose, or fragment under, for example, physiological conditions, acidic conditions, basic conditions, or in the presence of specific chemical agents. Examples of self-eliminating linkers include, but are not limited to, p-aminobenzyloxycarbonyl (PABC) and 2,4-bis(hydroxymethyl)aniline. Exemplary self-immolative linkers can be found in, for example, U.S. Pat. No. 7,754,681 (incorporated by reference)” [298]. This helps to teach claim 7.
The reference also teaches “ A pharmaceutical composition, comprising a prodrug of claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier” (reference claim 16). This helps to teach claim 11.
The reference also teaches “An aspect of the invention is a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a prodrug of the invention, or a pharmaceutically acceptable salt thereof” [0089]. This helps to teach claim 12.
The reference BACHOVCHIN teaches “The compounds of the invention may also be administered in conjunction with an anti-cancer therapy. Anti-cancer therapies include cancer medicaments, radiation, and surgical procedures. As used herein, a “cancer medicament” refers to an agent which is administered to a subject for the purpose of treating a cancer. As used herein, “treating a cancer” includes preventing the development of a cancer, reducing the symptoms of cancer, and/or inhibiting the growth of an established cancer. In one embodiment, “treating a cancer” means reducing the symptoms of cancer and/or inhibiting the growth of an established cancer, whether at a primary site or metastatic. Various types of medicaments for the treatment of cancer are described herein. For the purpose of this specification, cancer medicaments are classified as chemotherapeutic agents, immunotherapeutic agents, cancer vaccines, hormone therapy, and biological response modifiers” [0345-0346]. This helps to teach claim 15.
The reference BACHOVCHIN teaches “The term “subject” as used herein refers to a living mammal. In an embodiment, a subject is a mouse, rat, hamster, guinea pig, rabbit, cat, dog, goat, sheep, pig, horse, cow, or non-human primate. In another embodiment, a subject is a human” [0296]. This helps to teach claim 16.
The reference BACHOVCHIN does not teach the drugs of claim 9, the compounds of claim 10 or the prostate cancer of claims 13-14.
The reference Li teaches “The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified niclosamide as a potential anticancer agent by various high-throughput screening campaigns. Niclosamide not only inhibits the Wnt/b-catenin, mTORC1, STAT3, NF-jB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. A number of studies have established the anticancer activities of niclosamide in both in vitro and in vivo models. Moreover, the inhibitory effects of niclosamide on cancer stem cells provide further evidence for its consideration as a promising drug for cancer therapy. This article reviews various aspects of niclosamide as they relate to its efficacy against cancer and associated molecular mechanisms”(abstract) and “Anti-cancer activity of niclosamide has been demonstrated in human breast cancer [10,11,18,48,49), prostate cancer…”(page 11). The reference also teaches the structure of niclosamide (figure 1). This helps to teach claims 9, 10, 13, 14.
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The reference Brennen teaches “One defining characteristic of these carcinoma-associated fibroblasts, or myofibroblasts, is the expression of fibroblast activation protein-alpha (FAP). FAP is a membrane-bound serine protease that has both dipeptidase, as well as, gelatinase and collagenase activity. FAP is not expressed in healthy adults, but has been shown to be selectively expressed on myofibroblasts in the stroma surrounding >90% of epithelial cancers examined, including 7/7 human prostate cancer specimens, with minimal to no expression in either cancerous epithelial or adjacent normal tissues. FAP has been implicated in tumor promotion through studies demonstrating increases in tumor incidence, growth, and microvessel density using in vivo models. In contrast, other studies have shown that expression of FAP decreased tumorigenicity in vivo suggesting that the physiologic response to FAP may be dependent upon the exact context of its expression. Our goal is to evaluate FAP expression patterns and enzymatic activity in both normal prostate tissue and at various stages of oncogenic transformation (i.e. PIA, PIN, Localized and Advanced Cancer) to determine tumor stage in which FAP expression may play a role. A second objective is to exploit this expression in the treatment of prostate cancer by developing therapies targeted for activation by FAP. This will be accomplished by identifying selective peptide substrates for the proteolytic activity of FAP and coupling these peptides to a highly cytotoxic agent, thapsigargin, to generate prodrugs that are only activated in prostate tumors where FAP is expressed”(page 4). This helps to teach claims 9, 10, 13 and 14.
The reference Sobhani teaches “Castrate-Resistant Prostate-Cancer (CRPC) is one of the most common malignancies occurring in men. Unfortunately, even if several recently approved agents clinically improved the outcome of CRPC patients, none of these is curative especially for a splice version of the Androgen Receptor (AR) AR-V7, which is a variant of the receptor constitutively activated and does not require the presence of androgens for the activation AR down-stream pathways. Since high AR-V7 expression is one of the most common features of CRPC, targeting this receptor variant is considered as one of the most promising strategies for treating this disease. Therefore anti-AR-V7 molecules could lead to a potential shift in paradigm in the treatment of CRPC. Niclosamide, an already FDA-approved antihelminthic drug, was identified as a potent AR-V7 inhibitor in prostate cancer cells. Due to the recent positive preclinical results, niclosamide may be an interesting and novel type of targeted treatments for CRPC”(Summary) and “Antonarakis ES et al. showed that ARV7 is highly expressed in circulating tumour cells (CTC), as quantified with RT-PCR [50], and it is associated with resistance to abiraterone and enzalutamide in metastatic CRPC patients [42–44]”(page 1135). This helps to teach 14.
The reference Riber teaches “ The ultimate goal of controlled, intracellular drug delivery is to get the drug to the target cell without spilling the contents in transit and then release the entire payload upon cell entry. One of the most powerful platforms to achieve this relies on the intracellular disulfide reshuffling as a trigger for drug release form the engineered prodrugs. However, utility of disulfide reshuffling for drug release is naturally applicable only to the thiol containing molecules— ultimately leaving nearly all commercialized drugs beyond the scope of this platform. This is a drastic limitation. A cunning new tool of organic chemistry is fast entering the mainstream of prodrug design: the self-immolative linkers. This platform allows overcoming the natural chemical barrier and makes it possible to link virtually any drug to its carrier via a disulfide bond and engineer a specific intracellular release. It is a game-changing accomplishment of modern organic chemistry. The scope and limitations of this novel opportunity for medicinal chemistry and nanomedicine are outlined”(abstract). They also give the following example of disulfide reshuffling (figure 3) as well as the fact that additional carbons be attached where the R group is located ( reference figure 2). This helps to teach claim 10.
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified BACHOVCHIN with Li because BACHOVCHIN teaches a method of using a prodrug wherein different drugs can be attached for cancer treatment and Li teaches a drug (niclosamide) for cancer treatment and thus it would be obvious to substitute equivalents for the same purpose of treating cancer. One would have a reasonable expectation of success because niclosamide is known to treat prostate cancer including Castrate-Resistant Prostate-Cancer as taught by Li and Sobhani and because Brennen teaches that treatment of prostate cancer can be done by developing therapies targeted for activation by FAP because FAP is selectively expressed in human prostate cancer. BACHOVCHIN teaches “A prodrug for fibroblast activation protein (FAP)-dependent release of an agent, comprising a FAP substrate covalently linked to an agent via a bond or a self-immolative linker; wherein the agent is a cytotoxic or cytolytic drug; upon cleavage by FAP of the FAP substrate, the prodrug releases the agent”(reference claim 2). It would have been obvious to modify Li with Sobhani because both teach niclosamide is known to treat prostate cancer and with Brennen because it also teaches prostate cancer. It would have been also obvious to modify BACHOVCHIN with Brennen because they both teach cancer treatment directed by FAP. Thus one would have a reasonable expectation of success to treat cancer because BACHOVCHIN teaches targeting FAP with a prodrug, which will select for prostate cancer cells(taught by Brennen) , and Li and Sobhani teach niclosamide as a treatment of prostate cancer. One would be motivated to do so to direct a prostate cancer treatment drug to prostate cancer.
It would also have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the above references with Riber because Riber teaches self-immolative linkers of drug delivery the same as BACHOVCHIN. Thus one would have a reasonable expectation for success because the linkers are both self-immolative linkers and the reference claims “This platform allows overcoming the natural chemical barrier and makes it possible to link virtually any drug to its carrier via a disulfide bond and engineer a specific intracellular release”(abstract) and one would be motivated to do so to control intracellular drug delivery is to get the drug to the target cell without spilling the contents in transit.
Response to Arguments
Applicant's arguments filed 11/05/2025 have been fully considered but they are not persuasive.
The applicant argues a lack of motivation with a reasonable expectation of success to obtain the instant invention. This argument is not persuasive because one could be motivated to make and use the compounds of the instant invention from the motivation to treat cancer which is taught BACHOVCHIN which teaches the compound of instant formula (I) that is a FAP substrate to help direct drug delivery for cancer treatment. Brennen teaches that FAP is highly expressed in prostate cancer and Li teaches niclosamide for the treatment of prostate cancer. Thus one would have been motivated to treat cancer by the combination of these references since one would have a reasonable expectation of improved prostate cancer treatment by targeting FAP which is highly expressed in prostate cancer. Thus one would thus be motivated to help target FAP by combining the FAP targeting compound of BACHOVCHIN via well known linkers (other references discussed above) with a drug (niclosamide) known for treatment of prostate cancer. Since all compounds parts are known to do each of these jobs individually one would thus have a reasonable expectation of success for the combination.
The applicant also argues that that the reference Riber does not help to teach the specific compounds of claim 10 because Riber is only general cited for linkers and not specific compounds. This argument is not persuasive because in view of the rest of the references the other parts of the compounds of claim 10 are obvious besides the linker and Riber teaches that the linkers needed for claim 10 are also obvious as they are common linkers used for this specific purpose of drug release. Furthermore, technically, Riber isn’t even needed for an obviousness rejection of claim 10 because BACHOVCHIN teaches a linker of claim 10 as well see Figure 15 A above.
Conclusion
Claims 1-8 and 10-16 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.A.S./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627
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