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 .
DETAILED ACTION
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/12/2025 has been entered.
Review of Claim Status
Claims 1-6, 8-11 and 13-21 were rejected in the prior Office Action.
Upon amendment entry, Claims 2-3, 6-8 and 12 are cancelled.
Upon amendment entry, Claims 22 and 23 are added.
Claims 1, 4-5, 9-11 and 13-23 are pending investigation.
Review of Priority
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Applicant claims priority to the foreign document; therefore the effective filing date is 03/29/2019.
Information Disclosure Statements
Examiner acknowledged previous IDS(s) submission in prior Office Action.
Drawings
Examiner acknowledged submission date of drawings in previous Office Action.
Examiner Responses to Amendments/Arguments
The issues raised in the Office Action are addressed below:
I. Claim Amendments –
In view of the Applicant’s amendment, the additional limitation of independent Claim 1, “A phosphoinositide-3-kinase (PI3K) inhibitor for use in the treatment of keloid, hypertrophic and/or burn scars in a subject in need thereof, wherein the PI3K inhibitor is selected from the group consisting of BYL719 (alpelisib), and wherein the PI3K inhibitor is formulated for oral, cutaneous or topical administration” is acknowledged.
Similar limitation amendments are acknowledged for Independent Claims 4, 10, and 14-15.
II. Response to Claim Rejections -
Applicant' s arguments, filed 08/12/2025, with respect to claims have been fully considered but they are not persuasive for the following reason:
35 USC § 102 Rejections
Claims 1-6, 8-11, and 14-15 rejected under 35 U.S.C. 102 as being anticipated by Syed et al. (Am J Pathol. 2012; 181(5):1642-58).
In view of Applicant’s amendment to Claim 1, “A phosphoinositide-3-kinase (PI3K) inhibitor for use in the treatment of keloid, hypertrophic and/or burn scars in a subject in need thereof, wherein the PI3K inhibitor is selected from the group consisting of BYL719 (alpelisib), and wherein the PI3K inhibitor is formulated for oral, cutaneous or topical administration””, the 35 USC § 102 rejection is withdrawn.
35 USC § 103 Rejections
Claims 1-6, 8-11, and 14-15 rejected under 35 U.S.C. 103 as being unpatentable over Syed et al. (Am JPathol. 2012; 181(5):1642-58).
Claims 1-6, 8-11 and 13-21 were rejected under 35 U.S.C. 103 as being unpatentable over Syed et al. (Am Jpathol. 2012; 181(5):1642-58) in view of Janku et al. (“Targeting the PI3K pathway in cancer: are we making headway?”) as evidenced by Wikipedia (rapamycin aka sirolimus)
Claims 1-6, 8-11 and 13-21 were rejected under 35 U.S.C. 103 as being unpatentable over Syed et al. (Am J Pathol. 2012; 181(5):1642-58) in view of Kangas et al. (Basic Clin Pharmacol Toxicol. 123:6-19) as evidenced by Wikipedia (rapamycin aka sirolimus)
In view of Applicant’s amendment to Claim 1, as well as similar limitation additions to Claims 4, 10, and 14-15 seen as: “A phosphoinositide-3-kinase (PI3K) inhibitor for use in the treatment of keloid, hypertrophic and/or burn scars in a subject in need thereof, wherein the PI3K inhibitor is selected from the group consisting of BYL719 (alpelisib), and wherein the PI3K inhibitor is formulated for oral, cutaneous or topical administration”, the 35 USC § 103 rejections are withdrawn.
III. New Rejections –
The 35 USC § 102 and 103 rejections are withdrawn because Applicant amended independent Claim 1 (as well as Claims 4, 10, and 14-15), with a further limitation.
This necessitated a new rejection.
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.
Joint Inventors
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4-5, 9-11 and 13-23 are rejected under 35 U.S.C. 103 as being unpatentable over F. Janku, et. al in “Targeting the PI3K pathway in cancer: are we making headway?” (pub’d 05/2018; hereinafter “Janku”) in view of J. Kangas, et. al titled “Development of Molecular Therapies for Venous Malformations” (Basic Clin Pharmacol Toxicol, 123: 6-19; hereinafter “Kangas”).
With respect to the Instant Claims, the prior arts speak to the scope of the claims through keloids and hypertrophic scars as forms of fibrosis, which is excessive and unregulated connective tissue (collagen) buildup from a wound healing process gone awry, leading to thick, fibrous tissue. Fibrosis occurs when the key repair processes become deregulated, stressed, which lead to excessive extracellular matrix (ECM) accumulation, which result in the formation of scars or keloids. Growth factors, such as TGF-β, plays a role in excessive collagen production. This with features of abnormalities in regulation and commonly associated with genetic mutations affect connective tissues and their components. Keloids have excessive vascularization and noticeable blood vessels as a core component of their pathology, and so the prior art also reads on this functional language.
With respect to Claim 1, Janku teaches the PI3K–AKT–mTOR signalling pathway is one of the most frequently dysregulated pathways. This pathway controls key cellular processes, such as metabolism, growth, and proliferation, that support the survival, expansion and distribution of malignant cells, forming a malignant tumor or neoplasm; the pathway can be abnormally activated through multiple mechanisms, including changes involving PIK3CA, PIK3R1, PTEN, AKT, MTOR, and other oncogenes/tumor suppressor genes (FIG. 1). These changes are noticed in a range of tumor types targeting of the PI3K–AKT–mTOR pathway, including alpelisib (Table 2, pg. 278).
Janku further teaches Claims 4-5, 9-11, 13-15:
Janku continues (pg. 275, Figure 1) teaching oral PI3Kα‑specific inhibitors, for example, in a study of alpelisib patients with advanced-stage solid tumors harboring PIK3CA alterations were treated using once-daily and twice daily schedules (pg. 283, col. 2, paras. 3-4). This reads on the scope of the claims for formulation of use in the treatment of keloid, hypertrophic and/or burn scars.
Figure 1 of Janku teaches how the PI3K/AKT pathway drives fibrosis by promoting the activation, proliferation, survival, and migration of fibroblasts and their excessive production of extracellular matrix (ECM) proteins (collagen), leading to scarring. Fibroblasts are the key cells that create keloids, so their similarities lie in their common role in producing the excessive collagen and extracellular matrix (ECM) that define keloid scars. After injury, growth factors activate PI3K, which generates PIP3, leading to AKT activation. Activated AKT promotes fibroblast increase and enhances their survival by blocking pro-apoptotic proteins, allowing them to persist and accumulate.
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Janku teaches targeting the PI3K pathway, specifically since PI3K–AKT–mTOR signalling pathway (pg. 279, Fig. 2) controls multiple cellular processes and is one of the most frequently dysregulated pathways (pg. 274, Key Point 1, and reads on Claim 9). Janku continues teaching “more than 40 inhibitors of the PI3K–AKT–mTOR signalling pathway — temsirolimus (Table 2, pg. 278, also as mTOR inhibitor claimed in Claims 16, 18-19, and 21), and everolimus (as seen in Claims 16, 18-19, and 21)-.” (pg. 274, Key Point 2).
Janku finishes teaching to the selected PI3K–AKT–mTOR inhibitors for use as seen in the examples of Taselisib, Alpelisib, Miransertib in Table 2. Since PI3Kα inhibitors inhibit the class I PI3K catalytic subunit α isoform, which is often activated owing to molecular alterations in PIK3CA, the gene encoding this protein (FIG. 5, below left). However, molecular alterations in other downstream components of the PI3K pathway can negate the requirement for PI3K activity (FIG. 1, above) and lead to the emergence of resistance to these inhibitors.
Janku further teaches Dactolisib (pg. 282, col. 2, full para. 3) reads on the functional language of Claims 15-16, 19, 22-23.
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Janku fails to teach the rest of Claim 1, wherein the PI3K inhibitor is BYL719 - Alpelisib and pharmaceutical formulation is a paste, an ointment, a suspension, a solution, a cream, a gel or a spray (pg. 14, col. 1, hang para. 3; which reads on oral, cutaneous or topical administration).
Kangas teaches the rest of Claim 1 (Fig. 1), wherein the PI3K inhibitor is BYL719-Alpelisib (pg. 8, Fig. 1, sirolimus and alpelisib are indicated).
Kangas further teaches Claims 4-5, 9-11, 13-15:
Claim 4: wherein the PI3K inhibitor is selected from the group consisting of BYL719 (alpelisib).
Claim 10: wherein the PI3K inhibitor is BYL719-Alpelisib (pg. 6, abstract; pg. g. 14, col. 1, hang para. 3, “alpelisib was also efficient in treating cutaneous VMs in mouse allo-transplantation model when administered topically as a cream,” which reads on the claim).
Claim 13: wherein the pharmaceutical formulation is a paste, an ointment, a suspension, a solution, a cream, a gel or a spray (pg. 14, col. 1, hang para. 3 which reads on the claim);
Claims 14-15: a method for treating keloid, hypertrophic, burn scars and/or hyperpigmentation disorders in a subject in need thereof comprising a step of administering to the subject with a therapeutically effective amount of a PI3K inhibitor (pg. 6, abstract: current treatment is based on surgical resection and sclerotherapy; pg. 7, col. 1, full para. 2).
pg. 14, col. 1, hang para. 3: “One potent drug for repurposing is alpelisib, a highly specific PIK3CA inhibitor currently in Phase I–III clinical trials for the treatment of various types of cancer as combination therapy. Alpelisib was able to efficiently inhibit Akt phosphorylation and normalize the phenotype of both TIE2-VM- and PIK3CA-VM-transduced HUVECs... Importantly, alpelisib was also efficient in treating cutaneous VMs in mouse allotransplantation model when administered topically as a cream.”
This reads on the claims and scope because TIE2-VM- is linked to the formation of keloids through an imbalance in TIE2 ligands, which can lead to increased TIE2 activity. This and PIK3CA mutations activate the PI3K-AKT-mTOR signaling pathway, which is involved in the pathogenesis of VMs and keloids. These roles of TIE2 and PIK3CA in keloid formation lead to fundamental activation of endothelial signaling pathways, primarily PI3K–AKT–mTOR, which pushes endothelial proliferation, abnormal vascular morphogenesis, and altered smooth muscle coverage.
Claim 16 & 19: wherein the mTOR inhibitor is rapamycin (pg. 8, Fig. 1), a rapalog (pg. 8, Fig. 1), sirolimus (pg. 8, Fig. 1 and as evidenced by Wikipedia).
Claim 17 & 20: wherein the mTOR inhibitor is rapamycin (pg. 8, Fig. 1).
With respect to the subject matter of venous malformations (VMs), hypertrophic scars, and keloids as discussed, these conditions share several overlapping features associated with abnormal vascular or extracellular tissue restoration. The core lies in dysregulated tissue growth, whether via vascular networks (VMs) or extracellular matrix accumulation (scars/keloids). Both involve abnormal signaling responses to either developmental or reparative cues, are clinically visible as raised lesions. Keloids represent the extreme end of fibro-collagenous overgrowth, while hypertrophic scars are intermediate, and VMs represent vascular overgrowth—the common thread is failure of normal homeostatic regulation during repair or development.
Thus it establishes the prima facie through applying KSR prong A which discloses the Instant Claims as already known in the prior art. All the inhibitors discussed are known PI3K inhibitors since they act through the same mechanism of action. With respect to formulation excipients, it would have been prima facie obvious to one having ordinary skill in the art to substitute or combine known excipients in order to for example have an alternative topical composition.
In combining the teachings and embodiments as provided by Janku and Kangas, it is reasonable to expect success due to the prior art being known for the same purpose of treatment via similar pathways. Since one would be motivated with the success of Janku and Kangas in the results of keloid diseases, one would expect combined compositions based on Janku and Kangas’ work to also have these properties. MPEP 2144.05 (incorporated by reference herein).
Alternatively, apply prong (B) of KSR one could substitute one inhibitor in the primary reference for the one taught in the secondary reference both know to inhibit the same enzyme/pathway. Thus, one would predict success on the substitution.
Conclusion
Claims 1, 4-5, 9-11 and 13-23 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Josmalen M. Ramos-Lewis whose telephone number is (571)272-0084. The examiner can normally be reached M-F 9:00-5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached on (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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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621