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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/30/2026 has been entered.
Status of the Claims
Claims 7-18 and 35-40 are pending in this application. Claims 1-6 and 19-34 have been cancelled by applicant.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 7, 13, 16, and 40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gebremeskel et al. (Int. J. Cancer, 2015, 136, 234–240) (“Gebremeskel”).
Regarding claims 7, 16, and 40, Gebremeskel discloses treatment of B16-F10 melanoma (skin cancer) in mice comprising administration of ticagrelor (10 mg/kg), resulting in reductions in metastases (thus treating the cancer, anticipating claim 40) (abstract).
Regarding claim 13, Gebremeskel reports no coronary syndrome or CAD in treated mice.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 14-15 and 17-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gebremeskel et al. (Int. J. Cancer, 2015, 136, 234–240) (“Gebremeskel”); as applied o claims 7, 13, 16, and 40; in view of Benson et al. (Current Drug Delivery, 2019, 16, 444-460) (“Benson”).
The teachings of Gebremeskel are disclosed in the 102-section above and incorporated herein.
While Gebremeskel does not teach a topical and transdermal formulation (claims 14-15, 17-18); the teachings of Benson are relied upon for these disclosures.
Benson teaches drugs have been successfully developed for transdermal delivery using various topical dosage forms such as patches, gels and ointments and cutaneous solutions (page 445, col. 1, para. 2) – “Continued development for topical and transdermal delivery is providing new technologies for controlled dosing, targeted site-specific delivery, and/or enhanced skin penetration, thereby extending the range of therapeutic compounds that can be applied via the skin”. Benson discloses the skin is a key site for local and systemic drug delivery with the unique qualities of being easily accessible yet relatively impermeable, allowing products from a wide range of formulations to be applied to the skin and then removed as required. (conclusion).
Therefore, regarding claims 14-15 and 17-18, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Gebremeskel’s ticagrelor treatment as a topical or transdermal formulation, as taught by Benson. One of ordinary skill would have been motivated to do so because Gebremeskel discloses their ticagrelor treatment administered via intraperitoneal injections (see page 235, col. 1, para. 1), which is a painful and invasive method of administration; and further because Benson discloses state of the art for topical and transdermal formulations, including patches, gels and ointments, etc., which allow local and systemic drug delivery and controlled dosing with enhanced bioavailabilities. Thus, one of ordinary skill would have been motivated to, with a reasonable expectation of success, prepare a topical or transdermal formulation in the form of a painless patch, gel or ointment of ticagrelor for the treatment of metastatic melanoma in order to avoid painful infections for systemic or localized administration.
Claims 35-37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gebremeskel et al. (Int. J. Cancer, 2015, 136, 234–240) (“Gebremeskel”); as applied o claims 7, 13, 16, and 40; in view of Bhatia et al. (Oncology, 29, 2015, 18 pages) (“Bhatia”).
The teachings of Gebremeskel are disclosed in the 102-section above and incorporated herein.
While Gebremeskel does not teach administration of an additional chemotherapeutic agent, such as a corticosteroid (claims 35-37); the teachings of Bhatia are relied upon for these disclosures.
Bhatia teaches metastatic melanoma has low survival rates (page 2, para. 1), and discloses certain monotherapies may result in immune-related adverse effects (irAEs), which benefited from administration of immunosuppressive treatments like glucocorticoids (a type of corticosteroid) (page 3, CTLA-4 Blockade section) – reading on administration of an additional chemotherapeutic agent (corticosteroid). Bhatia teaches combination blockade of CTLA-4 + PD-1 may be synergistic (page 4, last para.). Bhatia disclose common irAEs associated with blockade of CTLA-4 + PD-1 (page 5, para. 3), which may be treated with immunosuppressive treatments, like glucocorticoids.
Therefore, regarding claims 35-37, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Gebremeskel’s ticagrelor therapy for metastatic cancer, in combination with therapies capable of blocking CTLA-4 + PD-1, further comprising a glucocorticoid, as taught by Bhatia. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Gebremeskel discloses their ticagrelor treatment for metastatic melanoma; and Bhatia teaches low survival rates for metastatic melanoma and that blockade of CTLA-4 + PD-1 might be beneficial but causes side effects, which can be ameliorated by administration of glucocorticoids. Therefore, one of ordinary skill would have been motivated to administer Gebremeskel’s ticagrelor in combination with Bhatia’s CTLA-4 + PD-1 blocking-therapy, further in combination with glucocorticoid.
Applicant is advised that, with respect to a mixture of the two claimed reagents, the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” See MPEP2144.06. It is therefore obvious to provide a mixture of the two agents.
Claims 35-36 and 38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gebremeskel et al. (Int. J. Cancer, 2015, 136, 234–240) (“Gebremeskel”); as applied o claims 7, 13, 16, and 40; in view of Melnikova et al. (Expert Rev. Dermatol., 2009, 4, 431-433) (“Melnikova”).
The teachings of Gebremeskel are disclosed in the 102-section above and incorporated herein.
While Gebremeskel does not teach administration of an additional chemotherapeutic agent, such as a NSAID (claims 35-36 and 38); the teachings of Melnikova are relied upon for these disclosures.
Melnikova teaches the link between cancer and inflammation is widely accepted in the scientific community and that continuous low-dose NSAIDs (ibuprofen or aspirin) were associated with reduced incidence of cutaneous melanoma in women (page 432, col. 1).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer NSAIDs, such as aspirin, in combination with Gebremeskel’s ticagrelor treatment, in view of Melnikova. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Gebremeskel teaches their ticagrelor treatment of metastatic melanoma; and Melnikova teaches NSAIDs lower the risk of incidence of cutaneous melanoma in women.
Applicant is reminded that, with respect to a mixture of the two claimed reagents, the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two agents.
Claim 39 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gebremeskel et al. (Int. J. Cancer, 2015, 136, 234–240) (“Gebremeskel”); in view of Benson et al. (Current Drug Delivery, 2019, 16, 444-460) (“Benson”); as applied o claims 14-15 and 17-18; further in view of Bhatia et al. (Oncology, 29, 2015, 18 pages) (“Bhatia”).
The teachings of Gebremeskel and Benson are disclosed above and incorporated herein.
While Gebremeskel in view of Benson does not teach administration of an additional chemotherapeutic agent, such as a corticosteroid (claims 39); the teachings of Bhatia are relied upon for these disclosures.
Bhatia teaches metastatic melanoma has low survival rates (page 2, para. 1), and discloses certain monotherapies may result in immune-related adverse effects (irAEs), which benefited from administration of immunosuppressive treatments like glucocorticoids (a type of corticosteroid) (page 3, CTLA-4 Blockade section) – reading on administration of an additional chemotherapeutic agent (corticosteroid). Bhatia teaches combination blockade of CTLA-4 + PD-1 may be synergistic (page 4, last para.). Bhatia disclose common irAEs associated with blockade of CTLA-4 + PD-1 (page 5, para. 3), which may be treated with immunosuppressive treatments, like glucocorticoids.
Therefore, regarding claims 39, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer a topical or transdermal pharmaceutical composition comprising Gebremeskel’s ticagrelor therapy for metastatic cancer and a glucocorticoid, in view of Benson and Bhatia. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Gebremeskel discloses their ticagrelor treatment for metastatic melanoma; Benson discloses state of the art for topical and transdermal formulations, including patches, gels and ointments, etc., which allow local and systemic drug delivery and controlled dosing with enhanced bioavailabilities; and Bhatia teaches low survival rates for metastatic melanoma and that blockade of CTLA-4 + PD-1 might be beneficial, but causes side effects which can be ameliorated by administration of glucocorticoids. Therefore, one of ordinary skill would have been motivated to administer Gebremeskel’s in view of Benson’s topical or transdermal ticagrelor treatment further comprising a glucocorticoid, as taught by Bhatia.
Applicant is reminded that, with respect to a mixture of the two claimed reagents, the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two agents.
Claims 7-12, 16, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Stegemann et al. (ARTHRITIS & RHEUMATISM, 65, 2013, 792–804) (“Stegemann”); in view of Morrisroe et al. (Arthritis Care & Research, 72, 11, 2020, 1625–1635 – First Pub. Sep. 20th, 2019) (“Morrisroe”).
Regarding claims 7, 16, and 40, Stegemann teaches tropisetron as a 5-HT3/4 receptor modulator and capable of reducing collagen synthesis in human dermal fibroblasts (HDF). Stegemann discloses the antifibrogenic and antifibrotic effects of this agent observed in a mouse model of bleomycin-induced scleroderma indicate the future potential of tropisetron in the treatment of fibrotic diseases such as scleroderma (abstract, conclusion). Stegemann suggests investigation of the cutaneous cholinergic system in systemic sclerosis (SSc) but also the exploitation of tropisetron and other α7nAChR agonists as a future treatment option for
fibrotic diseases (page 802, col. 2, last para.).
Regarding claims 8-10, Stegemann teaches SSc as a chronic inflammatory connective tissue disease that affects the skin and internal organs (reading on organ fibrosis and skin fibrosis) (page 792, col. 2, last para.).
Regarding claim 11, Stegemann used a murine model of bleomycin-induced scleroderma to assess the effects of tropisetron (abstract, methods).
Regarding claims 12, Stegemann reports no nausea in treated mice.
While Stegemann does not teach tropisetron for treating or reducing the risk of developing cancer in a subject, the teachings of Morrisroe are relied upon for these disclosures.
Morrisroe teaches SSc carries an increased risk of developing cancer, including melanoma, and a higher mortality (abstract, conclusions).
Therefore, regarding claims 7 and 16, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer tropisetron to a subject suffering from SSc, as taught by Stegemann, to reduce the risk of melanoma in a subject, in view of Morrisroe. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Stegemann teaches tropisetron reduces collagen synthesis in dermal fibroblasts and suggests exploitation of tropisetron as a future treatment option for fibrotic diseases, such as SSc; further because Morrisroe teaches SSc as a risk factor for developing cancer, including melanoma. Thus, by treating SSc with tropisetron, one would expect reduced risk of melanoma in a subject with a fibrotic disease, such as scleroderma or SSc.
Regarding claim 40, Morrisroe teaches patients with SSc have a >2 fold increased risk of all-cause mortality compared to non-cancer patients – thus, in order to reduce this risk of death in patients with cancer and SSc, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer tropisetron as part of a method of treating cancer in this population also suffering from SSc. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings above.
Claims 35-38 are rejected under 35 U.S.C. 103 as being unpatentable over Stegemann et al. (ARTHRITIS & RHEUMATISM, 65, 2013, 792–804) (“Stegemann”); in view of Morrisroe et al. (Arthritis Care & Research, 72, 11, 2020, 1625–1635 – First Pub. Sep. 20th, 2019) (“Morrisroe”); as applied to claims 7-12, 16, and 40; further in view of Vitiello et al. (J. Clin. Aesthet. Dermatol., 2012, 5, 33–43) (“Vitiello”).
The teachings of Stegemann and Morrisroe are disclosed above and incorporated herein.
While Stegemann in view of Morrisroe do not teach their method further comprising a chemotherapy agent or radiotherapy (claim 35); the teachings of Vitiello are relied upon for these disclosures.
Vitiello teaches most specialists recommend corticosteroid use, despite potential renal impacts, for the treatment of complications associated with SSc (page 36, col. 2, para. 1). Vitiello discloses topical tocoretinate has been used for the treatment of SSc, and that retinoids have been used in combination with other therapeutic agents, such as systemic corticosteroids, immunosuppressants, D-penicillamine, and ultraviolet light A (UVA) irradiation, etc. (page 37, col. 2, para. 4). Vitiello teaches that non-steroidal anti-inflammatory drugs (NSAIDs) are typically prescribed, though they should be avoided in favor of acetaminophen and opiates due to risk of renal toxicity (page 34, col. 2, 2nd to last para.); and that statins provided significant improvement in SSc due to anti-inflammatory properties (reading on NSAID) (page 35, col. 2, last para.).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer (Stegemann and Morrisroe)’s tropisetron SSc treatment to reduce the risk or treat a skin cancer in a subject in combination with an additional chemotherapy agent or radiotherapy, such as topical tocoretinate, corticosteroids, or ultraviolet light A (UVA) irradiation, in view of Vitiello. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because (Stegemann and Morrisroe) disclose their tropisetron SSc treatment, which would reduce the risk and treat the symptoms associated with skin cancer, such as melanoma; further because Vitiello teaches topical tocoretinate, corticosteroids, or ultraviolet light A (UVA) irradiation have been used for the treatment of SSc.
With respect to a mixture of the two claimed reagents, the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” See MPEP2144.06. It is therefore obvious to provide a mixture of the two agents.
Regarding claim 36-37, Vitiello teaches administration of corticosteroids for the treatment of skin sclerosis (page 37, col. 2, para. 4) and that most specialists recommend corticosteroid use, despite potential renal impacts, for the treatment of complications associated with SSc (page 36, col. 2, para. 1).
Regarding claim 36 and 38, Vitiello teaches non-steroidal anti-inflammatory drugs (NSAIDs) are typically prescribed, though they should be avoided in favor of acetaminophen and opiates due to risk of renal toxicity (page 34, col. 2, 2nd to last para.); and that statins provided significant improvement in SSc due to anti-inflammatory properties (reading on NSAID) (page 35, col. 2, last para.).
Claims 14-15, 17-18, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Stegemann et al. (ARTHRITIS & RHEUMATISM, 65, 2013, 792–804) (“Stegemann”); in view of Morrisroe et al. (Arthritis Care & Research, 72, 11, 2020, 1625–1635 – First Pub. Sep. 20th, 2019) (“Morrisroe”); as applied to claims 7-12, 16, and 40; further in view of Dutz et al. (STL, 2000, 5, 7 pages) (“Dutz”); and Benson et al. (Current Drug Delivery, 2019, 16, 444-460) (“Benson”).
The teachings of Stegemann and Morrisroe are disclosed above and incorporated herein.
While Stegemann in view of Morrisroe do not teach: (i) a topical and transdermal formulation (claims 14-15, 17-18, and 39); the teachings of Dutz and Benson are relied upon for these disclosures.
Dutz teaches the use of topical corticosteroids have been used for the treatment of localized sclerosis (LS) (page 2, para. 1). Dutz teaches treatment with topical modalities such as super-potent corticosteroids or calcipotriol is prudent (last para. Page 4).
Benson teaches drugs have been successfully developed for transdermal delivery using various topical dosage forms such as patches, gels and ointments and cutaneous solutions (page 445, col. 1, para. 2) – “Continued development for topical and transdermal delivery is providing new technologies for controlled dosing, targeted site-specific delivery, and/or enhanced skin penetration, thereby extending the range of therapeutic compounds that can be applied via the skin”. Benson discloses the skin is a key site for local and systemic drug delivery with the unique qualities of being easily accessible yet relatively impermeable, allowing products from a wide range of formulations to be applied to the skin and then removed as required. (conclusion).
Therefore, regarding claims 14-15 and 17, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer (Stegemann and Morrisroe)’s tropisetron SSc treatment in the form of a topical or transdermal formulation, in view of Dutz and Benson. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because (Stegemann and Morrisroe) teach their tropisetron therapy for SSc to reduce the risk of, and treat, skin cancers such as melanoma; further because Dutz teaches topical corticosteroids have been used in the past for LS, and that topical modalities have shown some success for the treatment of these skin conditions. One would have further had a reasonable expectation of success because Benson discloses the state of the art for topical and transdermal formulations, including patches, gels and ointments, etc., which allow local and systemic drug delivery and controlled dosing with enhanced bioavailabilities.
Regarding claims 18 and 39, Dutz teaches topical corticosteroids and Benson teaches topical dosage forms include patches, gels and ointments, etc. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a topical formulation of tropisetron alone or comprising an anti-inflammatory such as a corticosteroid. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings disclosed herein.
Response to Arguments
Claims
Claim amendments are acknowledged and have been entered. No new matter has been introduced.
Claim Rejections - 35 USC § 112(b)
In view of claim amendments, 35 USC § 112(b) rejections have been withdrawn.
Claim Rejections - 35 USC § 102
In view of claim amendments, 35 USC § 102 rejections have been withdrawn.
Claim Rejections - 35 USC § 103
Applicant’s arguments with respect to 103 rejections of instant claims (see pages 9-14) have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. See new grounds of 35 USC § 103 rejections set forth above.
Conclusion
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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