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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 20, 2026 has been entered.
DETAILED ACTION
Claims 1 – 16 are pending in this application, wherein claim 1 is amended.
Claims 1 – 16 are currently examined.
Priority
This application is a national stage application of PCT/IB2020/050651, filed January 28, 2020, which claims benefit of foreign priority document ZA2019/00623, filed January 30, 2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Rejections
The rejection of claims 1 – 16 in the previous Office Action, dated March 19, 2026, under 35 U.S.C. 103 as being unpatentable over Badana et al. in view of Alawin et al. and Yamaguchi et al. has been considered and is withdrawn in view of the amended claim 1.
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 1 – 3 and 11 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over Badana et al. (Journal of Breast Cancer, 2016, Vol. 19, Issue 4, cited in the PTO-892 on March 19, 2026) in view of Alawin et al. (The Journal of Nutritional Biochemistry, 2016, Vol. 27, Issue 2016, page 266 – 277, cited in the PTO-892 on March 19, 2026), Yokoo et al. (PLOS ONE, 2015, Vol. 10, Issue 11, cited in the PTO-892 on April 26, 2024), and Wittkowski et al. (PLOS ONE, 2018, Vol. 13, Issue 7, PTO-892).
Badana et al. disclose that lipid raft integrity is required for survival of triple negative breast cancer cells (Title). Badana et al. found in the study that the cholesterol-depleting agent, MβCD, efficiently depletes membrane cholesterol and causes concentration dependent (0.1 – 0.5 mM) cytotoxicity compared to nystatin and filipin III in TNBC cell lines. The disclosure corresponds to the claimed inhibition of growth of the triple negative breast cancer. MβCD also causes cell cycle arrest at the G2M phase and apoptosis in MDA-MB 231 cells and in MDA-MB 468 cells. The disclosure corresponds to the claimed apoptosis of cancer cells of the triple negative breast cancer. Badana et al. conclude that MβCD-induced cholesterol removal enhances alterations in lipid raft integrity, which reduces TNBC cell survival (Abstract). Thus, the disclosure corresponds to the claimed treatment of triple negative breast cancer by inhibiting growth of the triple negative breast cancer and causing apoptosis of cancer cells thereof.
However, Badana et al. do not teach the use of 2-hydroxypropyl-β-cyclodextrin (HPβCD) for the treatment of TNBC. Badana et al. also do not teach administering HPβCD in an amount that is not toxic to the subject, a medicament consisting essentially of HPβCD and not including an additional active pharmaceutical ingredient other than HPβCD, administration of HPβCD by parenteral or non-parenteral routes, or selection of subject having a TNBC tumor greater than 20 mm3.
Alawin et al. teach that hydroxypropyl-β-cyclodextrin (HPβCD) is an agent that disrupts lipid raft integrity (Abstract).
Yokoo et al. disclose that HPβCD itself may act as an anticancer agent by directly modulating cholesterol homeostasis in cancer cells (page 2, para. 4). Yokoo et al. found that HPβCD significantly inhibits the growth of various leukemic cell lines in a dose- and time-dependent manner (page 6, para. 5). The IC50 values of HPβCD after 72 hours of exposure are 3.86 – 10.09 mM in the tested leukemia cell lines, whereas HPβCD did not significantly interfere with the growth of normal human primary hepatocytes at concentrations up to 15 mM, and the IC50 for hepatocytes is 18 mM (page 6, para. 6; page 7, Table 1). The disclosure corresponds to the administration of HPβCD in an amount effective to inhibit growth of cancer cells while exhibiting lower toxicity toward normal cells. Yokoo et al. disclose that HPβCD reduces intracellular cholesterol and inhibits cell growth through G2/M cell-cycle arrest and apoptosis (Abstract). Thus, the disclosure corresponds to the administration of HPβCD in an amount effective to cause apoptosis of cancer cells. Yokoo et al. further evaluate HPβCD as a single anticancer agent in vivo by intraperitoneally administering 50 mM HPβCD (695.5 mg/kg) or 150 mM HPβCD (2086.5 mg/kg) to leukemia mouse models. HPβCD-treated mice survive longer than vehicle-treated mice, with statistically significant improvement in overall survival reported in the tested leukemia models (page 11, para. 1; page 12, Fig. 6). The disclosure of intraperitoneal administration of HPβCD as the anticancer agent corresponds to the medicament formulated as a pharmaceutical composition, as recited in claims 2 and 14, and administration of the medicament by a parenteral route, as recited in claim 3. Yokoo et al. additionally report that HPβCD-treated mice exhibit no gross lesions, hemolysis, or anemia and no observed changes in lung histology, and conclude that HPβCD is well tolerated in mice with low toxicity (page 13, para. 1). Thus, the same in vivo doses of HPβCD that produced anticancer efficacy are also tolerated by the treated animals. Yokoo further conclude that systemic HPβCD administration has limited toxicity where examined (page 15, para. 3). These disclosures correspond to administration of an effective amount of HPβCD that is not toxic to the subject, as recited in claims 1 and 13. Yokoo et al. further teach that single use of HPβCD effectively inhibits growth of various leukemia cells and that systemic administration of HPβCD suppresses leukemia progression and improves survival in murine leukemia models (page 13, para. 4; page 14, para. 1). Thus, Yokoo et al. teach that HPβCD may be used as the active anticancer agent without requiring an additional active pharmaceutical ingredient, which corresponds to the limitation “does not include any additional active pharmaceutical ingredient other than the HPβCD” of claim 1. Yokoo et al. also disclose that HPβCD did not significantly interfere with growth of normal human primary hepatocytes at concentrations up to 15 mM and that systemic administration of HPβCD to mice had no significant adverse effects (page 6, para. 5; Abstract). Thus, the disclosure also reads on the limitation “the amount is not toxic” of claim 1.
Wittkowski et al. disclose the use of cyclodextrins in breast cancer and teach that β-cyclodextrins have demonstrated activity in breast cancer models (Abstract). Wittkowski et al. discuss the teachings of Guerra et al., which is about the previously reported inhibition of migration of human MDA-MB-231 breast cancer cells by cyclodextrin-mediated cholesterol depletion (page 14, para. 6). Wittkowski et al. further evaluate HPβCD in wound-healing experiments using MDA-MB-23a ER-negative and MCF-7 ER-positive human breast cancer cell lines and found that HPβCD inhibits migration of the breast cancer cells (page 16, Fig. 6). In particular, HPβCD is tested directly in MDA-MB-231 cells, the same triple-negative breast cancer cell line evaluated by Badana et al. Thus, this disclosure provides a breast cancer specific evidence supporting the biological activity of HPβCD in MDA-MB-231 cells.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Badana et al. by substituting HPβCD for MβCD as the cholesterol-depleting cyclodextrin for treatment of TNBC because Badana et al. teach that depletion of membrane cholesterol by MβCD disrupts lipid raft integrity in TNBC cells and results in reduced TNBC cell survival, G2/M cell-cycle arrest, and apoptosis, Alawin et al. teach that HPβCD is capable of disrupting lipid raft integrity, Yokoo et al. further establish that HPβCD itself reduces intracellular cholesterol and produces significant inhibition of cancer cell growth through G2/M cell cycle arrest and apoptosis, and Wittkowski et al. additionally demonstrate biological activity of HPβCD in MDA-MB-231 breast cancer cells, which is the same breast cancer cell line evaluated by Badana et al. Accordingly, the combined teachings would have suggested HPβCD as an alternative cholesterol depleting cyclodextrin for obtaining the growth-inhibitory and apoptosis effects taught by Badana et al. in TNBC cells. One of ordinary skill in the art would have been motivated to make such a modification because the prior art collectively identifies disruption of cholesterol dependent lipid raft integrity as an approach of reducing survival of TNBC cells and identifies HPβCD as a cyclodextrin capable of acting through the same cholesterol-dependent mechanism. In particular, Alawin et al. provide reason to select HPβCD because HPβCD disrupts lipid raft integrity, while Yokoo et al. demonstrate that HPβCD is not merely capable of affecting the same cellular target, but actually depletes intracellular cholesterol and produces the relevant downstream anticancer effects of growth inhibition, G2/M arrest, and apoptosis. Wittkowski et al. further provide reason to apply HPβCD in the breast cancer context by demonstrating activity of HPβCD in MDA-MB-231 breast cancer cells. Thus, one of ordinary skill in the art would have been motivated to select HPβCD in place of MβCD in Badana et al. in order to obtain the known cholesterol depletion-mediated anticancer effects using HPβCD, which is independently shown by Yokoo et al. to produce cholesterol-depletion-mediated anticancer effects and by Wittkowski et al. to exhibit biological activity in MDA-MB-231 breast cancer cells. One of ordinary skill in the art would also have had a reasonable expectation of success to achieve inhibition of TNBC growth and apoptosis of TNBC cells upon substitution of HPβCD for MβCD because Badana et al. establish that cholesterol depletion and disruption of lipid raft integrity produce growth inhibition and apoptosis in TNBC cells; Alawin et al. establish that HPβCD disrupts lipid raft integrity; Yokoo et al. experimentally demonstrate that HPβCD reduces intracellular cholesterol and causes growth inhibition, G2/M cell-cycle arrest, and apoptosis in cancer cells; and Wittkowski et al. demonstrate activity of HPβCD in MDA-MB-231 breast cancer cells. Yokoo et al. further demonstrate in vivo anticancer efficacy of HPβCD administered as the anticancer agent at 50 mM (695.5 mg/kg) and 150 mM (2086.5 mg/kg) by intraperitoneal administration, with HPβCD-treated mice exhibiting significantly improved survival relative to vehicle-treated mice. Yokoo et al. further report that systemic administration of HPβCD produced no significant adverse effects. Thus, Yokoo et al. provide evidence that HPβCD may be administered at anticancer effective amounts that are also tolerated by the treated animals. In view of these teachings, one of ordinary skill in the art would have reasonably expected that administration of an amount of HPβCD effective to inhibit TNBC growth and cause apoptosis while being tolerated by the subject according to the modified method of Badana et al. would inhibit TNBC growth and cause apoptosis of TNBC cells without requiring an additional active pharmaceutical ingredient.
With respect to claim 2, it would have been obvious for one of ordinary skill in the art to formulate HPβCD medicament as a pharmaceutical composition suitable for administration to a subject because Yokoo et al. teach administration of HPβCD as an anticancer agent in vivo. One of ordinary skill in the art would have had reason to formulate HPβCD in a form suitable for administration in order to deliver the HPβCD to the subject for its intended therapeutic effect, with a reasonable expectation of success to administer HPβCD based on the in vivo administration demonstrated by Yokoo et al.
Claims 4, 6 – 8, and 14 – 15 are rejected under 35 U.S.C. 103 as being unpatentable over Badana et al. (Journal of Breast Cancer, 2016, Vol. 19, Issue 4, cited in the PTO-892 on March 19, 2026) in view of Alawin et al. (The Journal of Nutritional Biochemistry, 2016, Vol. 27, Issue 2016, page 266 – 277, cited in the PTO-892 on March 19, 2026), Yokoo et al. (PLOS ONE, 2015, Vol. 10, Issue 11, cited in the PTO-892 on April 26, 2024), and Wittkowski et al. (PLOS ONE, 2018, Vol. 13, Issue 7, PTO-892) as applied to claims 1 – 3 and 11 – 13 above, and further in view of Matsuo et al. (Molecular Genetics and Metabolism, 2013, Vol. 108, Issue 1, page 76 – 81, PTO-892).
Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. teach the limitations discussed above.
However, Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. do not teach the parenteral administrations recited in claims 4 and 15. Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. do not teach the pharmaceutical composition comprises an excipient, as recited in claims 6 – 8 and 14.
Matsuo et al. teach therapeutic administration of HPβCD to human subjects having Niemann-Pick Type C disease (Abstract). Matsuo et al. disclose that 20% HPβCD solution is prepared by dissolving HPβCD in distilled water and that the HPβCD solution is subsequently diluted to the required concentration with saline prior to administration (page 77, Left Col., para. 3). Matsuo et al. further disclose intravenous infusion of the resulting HPβCD solution, beginning at 80 mg/kg per dose and gradually increasing to 2 g/kg per dose or 2.5 g/kg per dose in the respective patients (page 77, Left Col., para. 4). Thus, Matsuo et al. teach HPβCD as the therapeutically active agent formulated in a pharmaceutical composition with an aqueous vehicle and administered intravenously, without an additional active pharmaceutical ingredient. The disclosures correspond to the pharmaceutical composition comprising an excipient and no additional active pharmaceutical ingredient other than HPβCD recited in claims 6 – 8 and 14 and the intravenous route recited in claims 4 and 15.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the HPβCD treatment rendered obvious by the combined teachings of Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. by formulating HPβCD with an aqueous pharmaceutically acceptable vehicle and administering the resulting pharmaceutical composition intravenously in view of Matsuo et al. for obtaining the pharmaceutical composition and intravenous administration recited in claims 4, 6 – 8, and 14 – 15 because Matsuo et al. teach therapeutic administration of HPβCD to human subjects and disclose preparing a 20% HPβCD solution by dissolving HPβCD in distilled water, diluting the solution to the required concentration with saline prior to use, and administering HPβCD by intravenous infusion. One of ordinary skill in the art would have had a reason to use the formulation and intravenous administration taught by Matsuo et al. because Matsuo et al. demonstrate that HPβCD may be formulated in an aqueous pharmaceutical vehicle and therapeutically administered to human subjects by intravenous infusion. One of ordinary skill in the art would have had a reasonable expectation of success because Matsuo et al. actually administer the formulated HPβCD intravenously to human subjects. Thus, application of the known HPβCD formulation and intravenous administration of Matsuo et al. to the HPβCD anticancer treatment rendered obvious by the combined teachings of Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. would have predictably provided and administrable HPβCD pharmaceutical composition comprising an aqueous vehicle and no additional active pharmaceutical ingredient, administered by the intravenous route.
Claims 5, 9, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Badana et al. (Journal of Breast Cancer, 2016, Vol. 19, Issue 4, cited in the PTO-892 on March 19, 2026) in view of Alawin et al. (The Journal of Nutritional Biochemistry, 2016, Vol. 27, Issue 2016, page 266 – 277, cited in the PTO-892 on March 19, 2026), Yokoo et al. (PLOS ONE, 2015, Vol. 10, Issue 11, cited in the PTO-892 on April 26, 2024), Wittkowski et al. (PLOS ONE, 2018, Vol. 13, Issue 7, PTO-892), and Matsuo et al. (Molecular Genetics and Metabolism, 2013, Vol. 108, Issue 1, page 76 – 81, PTO-892) as applied to claims 1 – 4, 6 – 8, and 11 – 15 above, and further in view of Yalçın et al. (Journal of Pharmaceutical Sciences, 2016. Vol. 105, Issue 8, page 2372 – 2380, PTO-892).
Badana et al., Alawin et al., Yokoo et al., Wittkowski et al., and Matsuo et al. teach the limitations discussed above.
Badana et al., Alawin et al., Yokoo et al., Wittkowski et al., and Matsuo et al. do not teach the pharmaceutical composition is administered via non-parenteral administration routes as recited in claims 5 and 16.
Yalçın et al. teach HPβCD formulated as polymeric microspheres based on chitosan or sodium alginate and designed for nasal administration (Abstract). Yalçın et al. further teach that cyclodextrins, including HPβCD, have potential therapeutic use as neuroprotective agents based upon the ability to extract and deplete cholesterol from cell membranes, and evaluate the neuroprotective effects of the HPβCD-containing microspheres following nasal administration in vivo (page 2373, Left Col., para. 2). The disclosure of nasal administration corresponds to the intranasal route recited in claims 5 and 16. The disclosure of HPβCD formulated with chitosan or sodium alginate further corresponds to a pharmaceutical composition comprising an excipient as recited in claim 9.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the HPβCD treatment rendered obvious by the combined teachings of Badana et al., Alawin et al., Yokoo et al, and Wittkowski et al. by formulating HPβCD with a pharmaceutically acceptable excipient and administering the resulting pharmaceutical composition intranasally, in view of Yalçın et al. for obtaining the pharmaceutical composition and non-parenteral administration recited in claims 5, 9, and 16 because Yalçın et al. teach formulating HPβCD in polymeric microspheres comprising chitosan or sodium alginate and administering the HPβCD-containing formulation by the nasal route. One of ordinary skill in the art would have had a reason to use the formulation and intranasal administration taught by Yalçın et al. because Yalçın et al. demonstrate that HPβCD may be formulated with pharmaceutically acceptable polymeric carriers and successfully delivered by nasal route for a therapeutic purpose. One of ordinary skill in the art would have had a reasonable expectation of success because Yalçın et al. actually administer the HPβCD-containing microspheres nasally in vivo and demonstrate biological effects associated with the administered HPβCD formulation. Thus, application of the known HPβCD formulation and nasal administration taught by Yalçın et al. to the HPβCD anticancer treatment rendered obvious by the combined teachings of Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. would have predictably provided an HPβCD pharmaceutical composition comprising an excipient and administered by an intranasal route, as recited in claims 5, 9, and 16.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Badana et al. (Journal of Breast Cancer, 2016, Vol. 19, Issue 4, cited in the PTO-892 on March 19, 2026) in view of Alawin et al. (The Journal of Nutritional Biochemistry, 2016, Vol. 27, Issue 2016, page 266 – 277, cited in the PTO-892 on March 19, 2026), Yokoo et al. (PLOS ONE, 2015, Vol. 10, Issue 11, cited in the PTO-892 on April 26, 2024), and Wittkowski et al. (PLOS ONE, 2018, Vol. 13, Issue 7, PTO-892) as applied to claims 1 – 3 and 11 – 13 above, and further in view of Ayala de la Peña et al. (Clinical and Translational Oncology, 2018, Vol. 21, Issue 1, page 18 – 30, PTO-892) and Anbalagan et al. (Molecular Cancer Therapeutics, 2012, Vol. 11, Issue 9, PTO-892).
Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. teach the limitations discussed above.
Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. do not teach the subject has triple negative breast cancer that is in a stage wherein the subject has tumors of a size greater than 20 mm3.
Ayala de la Peña et al. teach clinical guidelines for treatment of early-stage breast cancer (Title), including TNBC (page 26, Right Col.). Ayala de la Peña et al. teach that conventional chemotherapy remains the mainstay of adjuvant systemic treatment for most patients with early TNBC and further provide treatment recommendations based upon TNBC tumor size. In particular, Ayala de la Peña et al. teach that no adjuvant chemotherapy is recommended for tumors equal to or less than 0.5 cm (pT1a), whereas for tumors of 0.6 – 1 cm, administration of adjuvant chemotherapy is to be discussed and balanced. Ayala de la Peña et al. further teach that neoadjuvant therapy in TNBC results in pathological complete response rates of 30 – 40% and recommend sequential anthracyclines and taxanes for the vast majority of patients receiving neoadjuvant therapy (page 26, Right Col., para. 2 – 3). Thus, Ayala de la Peña et al. teach that the size of an established TNBC tumor is a recognized consideration in determining whether a subject should receive systemic anticancer treatment.
Anbalagan et al. teach treatment of established triple negative breast cancer tumors using MDA-MB-231 human breast cancer xenografts (Abstract). Anbalagan et al. teach that treatment is initiated when the MDA-MB-231 tumors reached a palpable volume of ~80 – 100 mm3 and demonstrate that administration of KX-01 significantly inhibits growth of the established MDA-MB-231 tumors, including a 79.0% reduction in tumor volume at 5 mg/kg relative to vehicle (page 6, para. 1). Thus, Anbalagan et al. teach selecting subjects having established MDA-MB-231 TNBC tumors having volumes of approximately 80 – 100 mm3, which are greater than the 20 mm3 tumor volume recited in claim 10, for administration of anticancer treatment, and demonstrate that tumors of such size remain amenable to therapeutic intervention.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the HPβCD treatment of TNBC rendered obvious by the combined teachings of Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. by administering the treatment to a subject having an established TNBC tumor greater than 20 mm3 in view of Ayala de la Peña et al. and Anbalagan et al. because Ayala de la Peña et al. teach that tumor size is a recognized consideration in determining whether a subject having TNBC should receive systemic anticancer treatment, while Anbalagan et al. teach selecting subjects having established MDA-MB-231 TNBC tumors of approximately 80 – 100 mm3 for anticancer treatment, which are greater than the 20 mm3 tumor volume recited in claim 10. Thus, the combined teachings provide a reason to apply the HPβCD treatment of TNBC discussed above to a subject having an established TNBC tumor greater than 20 mm3, rather than limiting such treatment to subjects having smaller tumors. One of ordinary skill in the art would have been motivated to make such a modification because Ayala de la Peña et al. explicitly identify tumor size as relevant to selection of systemic treatment for TNBC and Anbalagan et al. demonstrate that established MDA-MB-231 TNBC tumors having volumes of approximately 80 – 100 mm3 remain amenable to therapeutic intervention. Accordingly, one of ordinary skill in the art seeking to treat TNBC according to the combined teachings of Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. would have had reason to administer the HPβCD treatment to subjects having established TNBC tumors within the greater than 20 mm3 range because tumor size is a recognized consideration in selecting subjects for systemic TNBC treatment and established MDA-MB-231 TNBC tumors having volumes greater than 20 mm3 are known to be amenable to therapeutic intervention. One of ordinary skill in the art would also have had a reasonable expectation of success because Anbalagan et al. demonstrate that established MDA-MB-231 TNBC tumors having volumes of approximately 80 – 100 mm3 are amenable to anticancer treatment, as supported by significant inhibition of tumor growth following treatment. Thus, the presence of an established TNBC tumor having a volume greater than 20 mm3 would not have been expected to prevent a therapeutic response. Further, for the reasons discussed above, the combined teachings of Badana et al., Alawin et al., Yokoo et al., and Wittkowski et al. provide a reasonable expectation that administration of HPβCD would inhibit TNBC growth and cause apoptosis of TNBC cells. Accordingly, one of ordinary skill in the art would have reasonably expected administration of HPβCD to a subject having an established TNBC tumor greater than 20 mm3 to produce the claimed growth inhibitory and apoptotic effects.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed July 20, 2026, have been fully considered. The present rejection relies upon a different combination of references from the prior rejection of record. Accordingly, Applicant’s arguments directed specifically to deficiencies in the prior combination of Badana et al., Alawin et al., and Yamaguchi et al. have been considered in view of the present rejection. The substance of Applicant’s arguments concerning the asserted lack of a reasonable expectation of success, the differences between MβCD and HPβCD, the teachings of Yamaguchi et al., the asserted toxicity of HPβCD, and the previously presented arguments concerning Yokoo et al. and Guerra et al. are addressed below in view of the prior art as a whole.
Applicant argues that the claims as amended require administration of HPβCD as the sole active pharmaceutical ingredient in an amount that (1) inhibits growth of triple negative breast cancer, (2) causes apoptosis of TNBC cancer cells, and (3) is non-toxic to the subject. Applicant contends that the prior rejection fails to establish a reasonable expectation that the combination of Badana et al., Alawin et al., and Yamaguchi et al. would satisfy each of these limitations and asserts that a reasoned explanation, rather than a conclusory statement, is required to support a finding of obviousness. However, the argument has been considered but is not persuasive with respect to the present rejection. Unlike the prior rejection, the present rejection does not rely upon Alawin et al. alone to bridge the effects observed for MβCD by Badana et al. to the claimed use of HPβCD. Instead, the present rejection further relies upon Yokoo et al. and Wittkowski et al. to address the deficiency identified by Applicant. In particular, Yokoo et al. provide HPβCD specific evidence of the claimed growth inhibitory and apoptotic effects, while Wittkowski et al. provide HPβCD specific evidence of biological activity in MDA-MB-231 breast cancer cells, the same TNBC cell line evaluated by Badana et al. Accordingly, the present rejection does not rely merely upon the premise that HPβCD and MβCD affect the same cellular target, but upon additional HPβCD specific evidence supporting the effects relied upon in the present rejection.
Applicant argues that Badana et al. employ MβCD rather than HPβCD and that Alawin et al. merely use HPβCD as a tool for lipid-raft disruption in the context of γ-tocotrienol signaling. Applicant asserts that Alawin et al. do not report the antiproliferative or apoptotic results reported by Badana et al. and therefore do not provide a sufficient bridge for concluding that HPβCD would produce the same TNBC growth inhibition and apoptosis observed with MβCD. However, the argument has been considered but is not persuasive because the present rejection does not rely upon Alawin et al. alone to establish that bridge. Alawin et al. is relied upon for the specific teaching that HPβCD is capable of disrupting lipid raft integrity, thereby establishing that HPβCD acts upon the cellular feature identified by Badana et al. as important to TNBC survival. More significantly, Yokoo et al. independently demonstrate that HPβCD reduces intracellular cholesterol and causes significant cancer cell growth inhibition, G2/M cell-cycle arrest, and apoptosis. Accordingly, the combination does not infer the claimed downstream effects merely from a common lipid raft target. Instead, Yokoo et al. provide experimental evidence that HPβCD produces the same types of relevant downstream anticancer effects relied upon from Badana et al. Wittkowski et al. further demonstrate biological activity of HPβCD in MDA-MB-231 breast cancer cells, providing additional support for use of HPβCD in breast cancer cellular context.
Applicant argues that MβCD and HPβCD differ in cholesterol-complexing affinity, binding kinetics, clearance, solubility, and cellular uptake and that substitution of one cyclodextrin for another would therefore constitute a fundamental pharmacokinetic change whose therapeutic outcome would not have been predictable. Applicant contends that interaction with the same cellular target does not establish equivalent therapeutic efficacy. However, the argument is not persuasive because the present rejection does not depend upon an assumption that HPβCD and MβCD are therapeutically interchangeable merely because both interact with cholesterol or lipid rafts. Nor does the rejection require that HPβCD and MβCD exhibit identical binding constants, clearance rates, or potency. Instead, the reasonable expectation is supported by experimental teachings concerning HPβCD. Yokoo et al. demonstrate that HPβCD reduces intracellular cholesterol and produces growth inhibition, G2/M arrest, and apoptosis in cancer cells, while Wittkowski et al. demonstrate biological activity of HPβCD in MDA-MB-231 breast cancer cells. These teachings are considered together with the demonstration of Badana et al. that cholesterol depletion and disruption of lipid raft integrity produce the relevant growth inhibitory and apoptotic effects in TNBC cells and the teaching of Alawin et al. that HPβCD disrupts lipid raft integrity. Thus, the rejection does not depend upon an assumption that all cyclodextrins are therapeutically interchangeable, but rather upon experimental evidence that the specifically claimed HPβCD possesses the relevant cholesterol depleting and anticancer activities and exhibits biological activity in the same MDA-MB-231 breast cancer cellular context relied upon by Badana et al.
Applicant further argues that Yamaguchi et al. teach that β-cyclodextrin derivatives may not remain in the circulation at an effective concentration for a sufficient time, employing a multidrug combination protocol, and show HPβCD alone tracking the untreated control in tumor volume studies. Applicant therefore contends that Yamaguchi et al. teach away from use of HPβCD and negate a reasonable expectation of success for HPβCD monotherapy. Applicant additionally argues that Yamaguchi et al. report negative side effects associated with β-cyclodextrin-containing treatment and that such disclosure would have caused one of ordinary skill in the art to avoid HPβCD, particularly in view of the claimed requirement that the administered amount be non-toxic. Applicant’s argument has been considered but is not persuasive when the prior art is considered as a whole. Although Yamaguchi et al. disclose limitations associated with the particular treatment conditions evaluated therein, Yamaguchi et al. is not the only relevant teachings that would have been available to one of ordinary skill in the art. In particular, Yokoo et al. independently demonstrate that single use of HPβCD inhibits growth of cancer cells through cholesterol depletion, G2/M cell-cycle arrest, and apoptosis, and further demonstrate that systemic administration of HPβCD alone suppresses leukemia progression and improves survival in murine leukemia models. Thus, Yokoo et al. provide affirmative experimental evidence that HPβCD possesses anticancer activity without requiring an additional active pharmaceutical ingredient. When the teachings of the prior art are considered as a whole, the particular limitations reported by Yamaguchi et al. do not negate the reasonable expectation of success supported by the combined teachings relied upon in the present rejection. Moreover, the claim does not require HPβCD to be incapable of producing toxicity at every dose or under every administration condition. Instead, the claims require administration of an amount that is not toxic to the subject. Yokoo et al. provide experimental evidence of both anticancer efficacy and tolerability of HPβCD. Yokoo et al. report IC50 values of 3.86 – 10.09 mM for the tested leukemia cell lines, whereas HPβCD did not significantly interfere with growth of normal human primary hepatocytes at concentration up to 15 mM. Yokoo et al. further administer HPβCD at 50 mM (695.5 mg/kg) and 150 mM (2086.5 mg/kg) in murine leukemia models and demonstrate improved survival, while reporting no gross lesions, hemolysis, anemia, or obvious changes in lung histology in the treated animals. Thus, Yokoo et al. provide evidence that HPβCD may be administered at an anticancer effective amount that is also tolerated by the treated subject. The disclosure of toxicity or adverse effects under other treatment conditions does not negate the teaching that an effective, tolerated amount of HPβCD may be selected.
Applicant previously argued in the Remarks of October 28, 2024 that Yokoo et al. do not teach the use of HPβCD for treatment of breast cancer or triple negative breast cancer and further relied upon that statement of Yokoo et al. that conflicting results have been reported regarding the efficacy against cancers, including leukemia to contend that one of ordinary skill in the art would not have had a reasonable expectation of success in using HPβCD to treat TNBC. Applicant’s argument have been considered but is not persuasive. The cited statement concerning conflicting results appears in the discussion of statins of Yokoo et al. and concerns conflicting results reported regarding the anticancer efficacy of statins rather than conflicting results concerning the anticancer efficacy of HPβCD. In contrast, the experimental results of Yokoo et al. directly demonstrate that HPβCD reduces intracellular cholesterol and produces significant cancer cell growth inhibition through G2/M cell-cycle arrest and apoptosis. Moreover, the present rejection does not rely upon Yokoo et al. alone to establish treatment of TNBC. Badana et al. directly demonstrate that cholesterol depletion and disruption of lipid raft integrity produce reduced cell survival, G2/M cell-cycle arrest, and apoptosis in TNBC cells; Alawin et al. teach that HPβCD disrupts lipid raft integrity; and Wittkowski et al. demonstrate biological activity of HPβCD in MDA-MB-231 breast cancer cells, the same triple negative breast cancer cell line evaluated by Badana et al. Thus, the reasonable expectation of success does not arise from extrapolating the leukemia results of Yokoo et al. alone to TNBC, but from the combined experimental teachings connecting HPβCD to the relevant cholesterol/lipid-raft mechanism and downstream anticancer effects and demonstrating biological activity of HPβCD in the MDA-MB-231 breast cancer cellular context.
Applicant previously argued that Guerra et al. consider only invasion and migration of cancer cells and that the reported correlation between membrane cholesterol signaling and breast tumor cell migration does not establish that HPβCD would inhibit growth of TNBC cells, cause apoptosis of TNBC cells, or provide the claimed therapeutic effect. Applicant further relied on the Declaration of Mandeep Kaur for the proposition that inhibition of migration or invasion does not necessarily establish antiproliferative activity or a therapeutic effect (page 7 – 10 of Applicant’s Remarks on January 6, 2026). These arguments have been considered but are not persuasive with respect to the present rejection. The examiner does not determine that inhibition of migration necessarily results in growth inhibition or apoptosis, nor is Guerra et al. relied upon to establish such a relationship. Instead, the teachings concerning breast cancer cell migration provide breast-cancer-specific evidence concerning the biological consequences of cyclodextrin-mediated lipid depletion. Separate experimental evidence establishes the relevant growth inhibitory and apoptotic effects. In particular, Badana et al. directly demonstrate that cholesterol depletion and disruption of lipid raft integrity by MβCD in TNBC cells results in reduced TNBC cell survival, G2/M cell-cycle arrest, and apoptosis. Alawin et al. teach that HPβCD disrupts lipid raft integrity. Yokoo et al. directly demonstrate that HPβCD reduces intracellular cholesterol and produces growth inhibition, G2/M cell-cycle arrest, and apoptosis in cancer cells. Wittkowski et al. additionally demonstrate biological activity of HPβCD in MDA-MB-231 breast cancer cells, the same triple negative breast cancer cell line evaluated by Badana et al. Thus, Guerra et al. is not relied upon to establish that inhibition of migration necessarily results in growth inhibition or apoptosis. Instead, the migration teachings provide breast cancer-specific evidence concerning cyclodextrin-mediated lipid depletion, while the separate experimental teachings of Badana et al. and Yokoo et al. establish the relevant growth inhibitory and apoptotic effects, and Wittkowski et al. provide HPβCD-specific biological activity in MDA-MB-231 breast cancer cells. Applicant finally relies on the Declaration of Mandeep Kaur, asserting that cancer treatment is a multi-pronged problem and that the presence of a particular mechanistic pathway for one compound does not establish that another compound would reasonably be expected to produce a therapeutic effect. Applicant therefore contends that the prior art fails to establish a reasonable expectation of success for HPβCD as the sole active pharmaceutical ingredient. However, the argument is not persuasive. The present rejection does not depend solely on the general proposition that two compounds affecting lipid rafts must necessarily produce the same therapeutic effect. As discussed above, the prior art provides specific experimental evidence connecting HPβCD to the relevant downstream anticancer effects and to the breast cancer context. In particular, Yokoo et al. directly demonstrate that HPβCD reduce intracellular cholesterol and produces growth inhibition, G2/M cell-cycle arrest, and apoptosis in cancer cells, while Wittkowski et al. demonstrate biological activity of HPβCD in MDA-MB-231 breast cancer cells. These teachings are considered together with the demonstration of Badana et al. that cholesterol depletion and disruption of lipid raft integrity produce the claimed types of anticancer effects in TNBC cells and the teachings of Alawin et al. that HPβCD disrupts lipid raft integrity. Thus, the prior art as a whole provides specific experimental evidence connecting HPβCD to the relevant cholesterol/lipid-raft mechanism, the claimed downstream anticancer effects, and biological activity in the same MDA-MB-231 breast cancer cell line relied upon by Badana et al. Accordingly, when the teachings of references are considered together, one of ordinary skill in the art would have had a reasonable expectation of success in using HPβCD to obtain the claimed growth inhibition and apoptosis in TNBC cells.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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