DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims 1-6, 8-9, 11, 14, 16-23, 26 and 30 filed July 07, 2026 are currently pending.
Response to Amendment
Applicant’s arguments, filed 07/07/2026 have been fully considered. Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103-Rejections Maintained
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.
Claim(s) 1-6, 8-9, 16-23, 30 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Chen (U.S. Patent 7,923,555 published 04/12/2011), Leducq (European Journal of Dermatology Vol. 29 pages 82-83 published 2019) and Du (Laboratory Investigation Vol. 93 pages 1115-1127 published 2013).
Chen (U.S. Patent 7,923,555 published 04/12/2011) teaches compounds of Formula (I) as potent inhibitors of mTORC1 and mTORC2 (abstract, col.3 lines 1-30). Embraced within Formula (I) is example 258 (col. 321). As evidenced by paragraph [0034]-[0036] of the specification, example 258 of Chen reads on the presently claimed trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid.
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Regarding claim 8, formulation of said mTOR inhibitor as a tromethamine salt is embodied within the teachings of Chen (col. 40 lines 35-60).
Chen additionally teaches that the compound is administered in doses of 0.01-150 mg/kg per day to human patients and that the specific dose for any particular patient can be adjusted due to a variety of factors including age, route of administration and severity of the disease (col. 43 lines 45-65). As evidenced by Reagan-Shaw (FASEBJ Vol. 22 pages 659-661 published 2007), the average weight of an adult human is 60 kg and the average weight of a pediatric patient is 20 kg (table 1). Thus, the therapeutic regimen of Chen embodies administering 0.6 mg to 9000 mg per day to an adult human patient and 0.2 mg to 3000 mg per day to the pediatric patient. Said dosage of the mTOR inhibitor overlaps with the amount embraced within the present claims. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
The difference between the present claims and that of Chen is that Chen does not specifically teach treating a human patient comprising a complex lymphatic malformation comprising administering the art-recognized mTOR inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid.
Leducq (European Journal of Dermatology Vol. 29 pages 82-83 published 2019) teaches the method of treating a pediatric patient comprising a cutaneous microcystic lymphatic malformation comprising administering the mTOR inhibitor sirolimus (abstract, pages 82-83). Regarding claims 18-19, Leducq teaches that said lymphatic malformation was classified as moderate wherein said microcystic lymphatic malformation yielded the complication of chronic pain and discomfort, with daily oozing and bleeding. Leducq teaches that said patient and had undergone scleropathy and retinoid therapy with unsatisfactory results and resulted in 4-5 bacterial flare-ups per year with cutaneous bacterial infections (page 82). Leducq teaches that topical administration of the mTOR inhibitor sirolimus in a 0.1% or 0.25% cream, applied once a day for at least 3 months was very effective against the cutaneous microcystic lymphatic malformation, wherein said daily regimen resulted in 30% reduction of vesicles, a reduction in oozing, a reduction in bleeding and an improved quality of life without any serious side effects (page 83).
Du (Laboratory Investigation Vol. 93 pages 1115-1127 published 2013) teaches the mTOR inhibitor sirolimus of Leducq above is also art-recognized at inhibiting both mTORC1 and mTORC2 receptors in a dose dependent manner (abstract, page 1121 and Figures 3a-b).
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that daily administration of the art-recognized mTORC1 and mTORC2 inhibitor sirolimus was efficacious at treating cutaneous microcystic lymphatic malformations in a human pediatric patient as taught by Leducq and Du above, said skilled artisan would have found it prima facie obvious to substitute the mTORC1 and mTORC2 inhibitor sirolimus in the regimen of Leducq, for an alternative mTORC1 and mTOR C2 inhibitor, such as Example 258 of Chen, arriving at the presently claimed.
MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, considering it was known in the art that daily administration of the art-recognized mTORC1 and mTORC2 inhibitor sirolimus was efficacious at treating cutaneous microcystic lymphatic malformations in a human pediatric patient as taught by Leducq and Du above, said artisan would have readily predicted substitution of the mTORC1 and mTORC2 inhibitor sirolimus, for another, such as Example 258 of Chen, said resulting mTORC1 and mTORC2 inhibitory regimen would have readily treated the lymphatic malformation in the afflicted subject.
Regarding the limitation directed to administration of said mTOR inhibitor in a dose of 1 or 2 mg/day, wherein said dose is administered either in two 0.5 mg doses twice per day separated by about 12 hours, or alternatively wherein said dose is administered either in two 1 mg doses twice per day separated by about 12 hours (claims 1-6), the optimum dose, dosing cycle and frequency of administration of the mTOR inhibitor to the microcystic lymphatic malformation patient would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as activity, efficacy, pharmacokinetics and toxicology profiles of the combined regimen, as well as the age, weight, sex, diet and severity of the medical condition of the patient as recited by Chen above (col. 43 lines 45-65). Thus, the dose, dosing cycle and frequency of administration regimen that would have been employed would have varied widely and, in the absence of evidence to the contrary, the current claimed specific administration regimen is not seen to be inconsistent with one that would have been determined by the skilled artisan. Furthermore, absent and evidence demonstrating a patentable difference between the compositions administered and the criticality of the claimed dose, frequency and dosing cycles, the determination of the optimum or workable dose and frequency of administration given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(”[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the workable ranges by routine experimentation.”).
Regarding claim 23 directed to the limitation wherein the subject is not administered sirolimus at the same time as being administered trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid,, said skilled artisan would have found it prima facie obvious to exclude an additional art-recognized mTORC1 and mTORC2 inhibitor such as sirolimus from the therapeutic regimen as said mTORC1 and mTORC2 receptors are already being inhibited with the administration of trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid.
Lastly, regarding the limitation wherein the administered mTORC1 and mTORC2 inhibitory regimen of Chen, Leducq and Du exhibits a reduction in pain assessed by a visual analog scale, or an improvement in a quality of life based on 36 item short health form or Karnofsky Performance status, as recited above, the combination of Chen, Leducq and Du disclose that administration of an mTORC1 and mTORC2 inhibitory regimen to a patient with a microcystic lymphatic malformation results in an improved quality of life (Leducq page 83). Applicant is reminded that properties, such as a reduction in pain or an improvement in the quality of life based on either a 36-item short health survey or Karnofsky Performance Status are considered characteristic features of the claimed therapeutic regimen.
It is noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case the burden is shifted to Applicant to prove that the administered mTORC1 and mTORC2 inhibitor to the patient with the microcystic lymphatic malformation as taught by Chen, Leducq and Du above does not reduce pain as assessed by a visual analog scale, nor improve quality of life based upon on either a 36-item short health survey or Karnofsky Performance Status.
Applicant traverses. Applicant asserts that Chen does not teach nor suggest treating complex lymphatic malformations in a subject with the claimed compound nor the dosing schedules of 1 mg/day or 2 mg/day as recited in claim 1 and it would impose an undue experimental burden to determine whether any of the broadly disclosed dosages in Chen are effective. Next, Applicant argues that the claimed trans-4-[4-Amino-5-(7- methoxyl-1H-indol-2-yl)-imidazo[5,1-f][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid inhibits both mTORC1 and mTORC2 while the mTOR inhibitor in the methodology of Leducq (sirolimus/rapamycin) only inhibits mTORC1. Applicant contends that it is improper to substitute sirolimus for the dual mTOR C1 and mTORC2 inhibitor of the present claims with a reasonable expectation of success.
Response to Arguments
Applicant’s arguments, filed 07/07/2026 are acknowledged and have been carefully considered. In response to Applicant' s arguments, the Examiner acknowledges and does not dispute Applicants contention that Chen does not teach nor suggest treating complex lymphatic malformations in a subject in need as claimed. However, the Examiner recognizes that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208, USPQ 871 (CCPA 1981) and MPEP 2145.
As set forth above, the combination of Leducq and Du teach that compounds that inhibit mTORC1/mTORC2 (sirolimus) are efficacious at treating complex lymphatic malformations in a subject in need, coupled with the knowledge that trans-4-[4-Amino-5-(7- methoxyl-1H-indol-2-yl)-imidazo[5,1-f][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid of Chen is an art-recognized inhibitor of mTORC1 and mTORC2. Regarding Applicant’s assertion that an undue experimental burden would have been imposed to find the claimed dose of 1 mg/day or 2 mg/day in the therapeutically effective range embodied within Chen to arrive at the presently claimed, this argument is unpersuasive. An undue experimental burden would not have been imposed as one of ordinary skill in the art knows how to make the art-recognized mTOR inhibitor trans-4-[4-Amino-5-(7- methoxyl-1H-indol-2-yl)-imidazo[5,1-f][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid and knows how to administer said mTOR inhibitor and knows that overlapping doses in the range of 0.6 mg to 9000 mg per day are therapeutically effective in a pediatric patient (0.01-150 mg/kg taught in col. 43 lines 45-65; pediatric patient weighs 20 kg as evidenced by Reagan-Shaw FASEBJ Vol. 22 pages 659-661. Published 2007). The guidance provided in MPEP §2121.01[R-3] states that, “A reference contains an ‘enabling disclosure' if the public was in possession of the claimed invention before the date of invention. “Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531,226 USPQ 619 (Fed. Cir. 1985)." Once again, note that, per the MPEP, a reference does not have to prove efficacy to constitute an enabled disclosure. Rather, so long as the reference provides a clear description of the invention, which, when coupled with the skilled artisan' s own knowledge, is sufficient to describe how to make and use the invention as described, the reference provides an enabled disclosure.
Applicant is also reminded that it is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985).” In the instant case, Chen teaches that doses of the claimed mTORC1/C2 inhibitor in the range of 0.6 mg to 9000 mg per day are therapeutically effective and thus, selection of a dose within the therapeutically effective range, including 1 mg/day or 2 mg/day will be efficacious to treat the disclosed disorder. Furthermore, Applicant has not demonstrated that there is unpredictability in treating complex lymphatic malformations with the claimed mTOR inhibitor trans-4-[4-Amino-5-(7- methoxyl-1H-indol-2-yl)-imidazo[5,1-f][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid and that doses outside of 1 mg/day or 2 mg/day as embodied within the range of Chen, Leducq and Du would not be effective.
Next, regarding Applicant’s contention that the claimed trans-4-[4-Amino-5-(7- methoxyl-1H-indol-2-yl)-imidazo[5,1-f][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid inhibits both mTORC1 and mTORC2 while the mTOR inhibitor in the methodology of Leducq (sirolimus/rapamycin) only inhibits mTORC1 and thus, it is improper to substitute sirolimus for the dual mTOR C1 and mTORC2 inhibitor of the present claims with a reasonable expectation of success, this argument is also unpersuasive. The preponderance of evidence of Du shows that sirolimus targets both mTOR C1 and mTOR C2 (Figures 3a, 3b, 4a, abstract, page 1121-1124 left col.). While the compound of Chen may be more potent at blocking both mTOR C1 and mTOR C2 than sirolimus of Leducq, both compounds are art-recognized as dual mTORC1 and mTOR C2 inhibitors.
Even assuming Applicant’s argument is valid and that sirolimus of Leducq only inhibits mTORC1, which the examiner does not concede, based on this rationale, Leducq demonstrates that the inhibition of only mTORC1 pathway is an efficacious strategy to treat complex lymphatic malformations in a subject in need. As such, said skilled artisan would have readily predicted that pathogenesis of complex lymphatic malformations is mediated by the mTORC1 pathway and that substitution of sirolimus in the methodology of Leducq for any alternative compound that inhibits the mTORC1 pathway would be efficacious at treating complex lymphatic malformations in a subject in need, including the art-recognized mTORC1 and mTORC2 inhibitor trans-4-[4-Amino-5-(7- methoxyl-1H-indol-2-yl)-imidazo[5,1-f][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid of Chen. Applicant has not demonstrated that there is unpredictability in the field of treating complex lymphatic malformations with the alternative inhibitors that target mTOR C1 and/or mTORC2 and that any compound that inhibits the mTORC1 pathway does not treat complex lymphatic malformations in a subject in need. Therefore, the rejection is maintained.
Claim(s) 26 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Chen (U.S. Patent 7,923,555 published 04/12/2011), Leducq (European Journal of Dermatology Vol. 29 pages 82-83 published 2019) and Du (Laboratory Investigation Vol. 93 pages 1115-1127 published 2013) as applied to claims 1-6, 8-9, 16-23 and 30 above, in view of Ghaffarpour (Lymphatic malformation: Final approved patient pathway by Vascular Anomalies Working Group: Published 04/29/2020).
As disclosed above, the combination of Chen, Leducq and Du render obvious the administration of the art-recognized mTORC1 and mTORC2 inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid to a patient with a microcystic lymphatic malformation as it was known in the art that administration of an inhibitor of mTORC1 and mTORC2 resulted in 30% reduction of vesicles, a reduction in oozing, a reduction in bleeding and an improved quality of life without any serious side effects in said microcystic lymphatic malformation patient.
The difference between the present claims and that of the combined teachings of Chen, Leducq and Du is that neither Chen, nor Leducq nor Du teach administering a topical steroid with the mTOR inhibitor.
Ghaffarpour (Lymphatic malformation: Final approved patient pathway by Vascular Anomalies Working Group: Published 04/29/2020) teaches that topical corticosteroids, along with antibiotics due to recurrent infections are utilized as specialty treatments for microcystic lymphatic malformations (page 4).
Therefore, said skilled artisan would have found it prima facie obvious to administer a topical steroid in combination with the art-recognized mTOR inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid regimen to the patient comprising a microcystic lymphatic malformation, in view of Ghaffarpour, arriving at the presently claimed methodology.
Motivation to administer a topical corticosteroid with the mTOR inhibitor regimen logically flows from the fact that Ghaffarpour teaches that topical corticosteroids are utilized as specialty treatments for microcystic lymphatic malformations. Motivation to administer the compositions together flows logically from the very fact each agent or combination of agents was known in the prior art to have the same therapeutic utility of treating microcystic lymphatic malformations and, in turn, raises the reasonable expectation of success, that when combined, a composition comprising the art-recognized mTOR inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid and a topical corticosteroid would be efficacious at treating microcystic lymphatic malformations. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose (MPEP 2144.06).
Applicant traverses. Applicant argues that the combination of Chen, Leducq and Du does not teach the presently claimed methodology and the combination of Ghaffarpour fails to cure the deficiencies of Chen, Leducq and Du.
Response to Arguments
Applicant’s arguments, filed 07/07/2026 are acknowledged and have been carefully considered. Arguments pertaining to combination of Chen, Leducq and Du and the rejection of claims 1-6, 8-9, 16-23 and 30 have been addressed above. Regarding Applicant’s contention that Ghaffarpour fails to cure the deficiencies of the combination of Chen, Leducq and Du, this argument is unavailing. Applicant is reminded that “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references” In re Merck and Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
In the present case, while neither Chen, nor Leducq, nor Du specifically administering a topical steroid with the mTOR inhibitor inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid to treat complex lymphatic malformations in a subject in need, Ghaffarpour (Lymphatic malformation: Final approved patient pathway by Vascular Anomalies Working Group: Published 04/29/2020) teaches that topical corticosteroids, along with antibiotics due to recurrent infections are utilized as specialty treatments for microcystic lymphatic malformations (page 4). Consistent with this reasoning, it would have been obvious to have selected the administration of a topical steroid to a patient with complex lymphatic malformations from within the prior art of Ghaffarpour above and apply it to the complex lymphatic malformation treating regimen comprising the mTOR inhibitor inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid of Chen, Leducq and Du above, arriving at the claimed methodology yielding no more than one would expect from such an arrangement. Motivation to administer a topical corticosteroid with the mTOR inhibitor regimen logically flows from the fact that Ghaffarpour teaches that topical corticosteroids are utilized as specialty treatments for microcystic lymphatic malformations. Motivation to administer the compositions together flows logically from the very fact each agent or combination of agents was known in the prior art to have the same therapeutic utility of treating microcystic lymphatic malformations and, in turn, raises the reasonable expectation of success, that when combined, a composition comprising the art-recognized mTOR inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid and a topical corticosteroid would be efficacious at treating microcystic lymphatic malformations. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose (MPEP 2144.06).
Claim(s) 11 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Chen (U.S. Patent 7,923,555 published 04/12/2011), Leducq (European Journal of Dermatology Vol. 29 pages 82-83 published 2019) and Du (Laboratory Investigation Vol. 93 pages 1115-1127 published 2013) as applied to claims 1-6, 8-9, 16-23 and 30 above, in view of Deklotz (WO2019/156999 published 08/15/1999).
As disclosed above, the combination of Chen, Leducq and Du render obvious the administration of the art-recognized mTORC1 and mTORC2 inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid to a patient with a microcystic lymphatic malformation as it was known in the art that administration of an inhibitor of mTORC1 and mTORC2 (sirolimus) resulted in 30% reduction of vesicles, a reduction in oozing, a reduction in bleeding and an improved quality of life without any serious side effects in said microcystic lymphatic malformation patient.
The difference between the present claims and that of the combined teachings of Chen, Leducq and Du is that neither Chen, nor Leducq nor Du teach wherein the lymphatic malformation patient comprises at least one localized lesion on the face or limbs, nor does said combination teach wherein the therapeutic regimen yields at least a 20% reduction in the size of the lesion from baseline to the end of treatment using radiologic imaging or achieves no evidence of disease as assessed using radiologic imaging following treatment.
Deklotz (WO2019/156999 published 08/15/1999) teaches treating lymphatic malformations on the face and limbs in pediatric patients comprising administering a therapeutically effective amount of the mTOR inhibitor sirolimus (pages 49-50, claims 1, 3-6, 9-10). Deklotz teaches that said pediatric patients comprised a mixed venolymphatic malformation on the limbs following radiological imaging that yielded oozing and throbbing pain. The mTOR inhibitor sirolimus was administered twice-a-day for 2 months, wherein pain was reduced and quality of life was improved (pages 49-50 example 2). Deklotz additionally teaches that said twice-a-day mTOR inhibitor regimen is efficacious at treating a capillary malformation-arteriovenous malformation on the face and limbs, wherein said malformation lessened in visibility and was without side effects (page 50-51 example 3).
Therefore, said skilled artisan would have found it prima facie obvious to administer the art-recognized mTOR inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid regimen to the patient comprising a lymphatic malformation on the face or limbs, in view of Deklotz, arriving at the presently claimed methodology.
Motivation to administer said mTOR inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid regimen to the patient comprising a lymphatic malformation on the face or limbs logically flows from the fact that Deklotz teaches that twice-a-day administration of an mTOR inhibitor to a patient comprising a lymphatic malformation on the face or limbs treated the malformation, reduced pain in the individual and improved the quality of life. Accordingly, said artisan would have readily predicted that the resulting administration of the art-recognized mTOR inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid regimen to the patient comprising a lymphatic malformation on the face or limbs would have reduced pain in the individual and improved the quality of life, thereby treating the patient.
Regarding the limitation wherein the subject exhibits at least a 20% reduction in the size of the lesion from baseline to the end of treatment using radiologic imaging (claim 11) or achieves no evidence of disease as assessed using radiologic imaging following treatment (claim 14), said properties are considered characteristic features that will naturally flow from the administration of the claimed mTOR inhibitor therapeutic regimen.
It is noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case the burden is shifted to Applicant to prove that the administered mTORC1 and mTORC2 inhibitor to the patient with the microcystic lymphatic malformation as taught by Chen, Leducq and Du above does not result in at least a 20% reduction in the size of the lesion from baseline to the end of treatment using radiologic imaging, nor achieves no evidence of disease using radiologic imaging following treatment.
Applicant traverses. Applicant argues that the combination of Chen, Leducq and Du does not teach the presently claimed methodology and the combination of Deklotz fails to cure the deficiencies of Chen, Leducq and Du.
Response to Arguments
Applicant’s arguments, filed 07/07/2026 are acknowledged and have been carefully considered. Arguments pertaining to combination of Chen, Leducq and Du and the rejection of claims 1-6, 8-9, 16-23 and 30 have been addressed above. Regarding Applicant’s contention that Deklotz fails to cure the deficiencies of the combination of Chen, Leducq and Du, this argument is unavailing. Applicant is reminded that “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references” In re Merck and Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). In the present case, while neither Chen, nor Leducq nor Du teach wherein the lymphatic malformation patient comprises at least one localized lesion on the face or limbs, nor does said combination teach wherein the therapeutic regimen yields at least a 20% reduction in the size of the lesion from baseline to the end of treatment using radiologic imaging or achieves no evidence of disease as assessed using radiologic imaging following treatment, Deklotz (WO2019/156999 published 08/15/1999) teaches treating lymphatic malformations on the face and limbs in pediatric patients comprising administering a therapeutically effective amount of the mTOR inhibitor sirolimus (pages 49-50, claims 1, 3-6, 9-10). Deklotz teaches that said pediatric patients comprised a mixed venolymphatic malformation on the limbs following radiological imaging that yielded oozing and throbbing pain. The mTOR inhibitor sirolimus was administered twice-a-day for 2 months, wherein pain was reduced and quality of life was improved (pages 49-50 example 2). Deklotz additionally teaches that said twice-a-day mTOR inhibitor regimen is efficacious at treating a capillary malformation-arteriovenous malformation on the face and limbs, wherein said malformation lessened in visibility and was without side effects (page 50-51 example 3). As such, said skilled artisan would have motivated to administer said mTOR inhibitor trans-4-[4-Amino-5-(7-methoxyl- 1H-indol-2-yl)-imidazo[5,1-][1,2,4]triazine-7-yl]-cyclohexanecarboxylic acid regimen to the patient comprising a lymphatic malformation on the face or limbs logically flows from the fact that Deklotz teaches that twice-a-day administration of an mTOR inhibitor to a patient comprising a lymphatic malformation on the face or limbs treated the malformation, reduced pain in the individual and improved the quality of life.
Regarding Applicant’s contention that Deklotz teaches sirolimus only inhibits mTORC1 and not mTORC2 and that it is improper to substitute sirolimus of Deklotz for the dual mTOR C1 and mTORC2 inhibitor of the present claims with a reasonable expectation of success, this argument is also unpersuasive. Deklotz merely suggests that sirolimus does not inhibit mTORC2 without any physical evidence. Meanwhile, Du demonstrates with actual physical evidence that sirolimus inhibits mTOR C2 pathway targets including pAKT (s473), and phosphorylation of p4E-BR1 (T37/46). (See Chen Col. 3 lines 1-5 and Du page 1121-1124 illustrating that pAKT (s473) is a mTORC2 target, Du: Figures 3a, 3b, 4a, abstract, pages 1121, 1124 left col.). In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
In view of the rejections set forth above, no claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CLINTON A BROOKS can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GEORGE W KOSTURKO/ Primary Examiner, Art Unit 1621
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