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 .
Summary
Receipt of Applicants Remarks and Restriction/Elections filed on 01/27/2026 is acknowledged. Claims 1-28 are pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/24/2023 are in compliance with the provisions of 37 CFR 1.98. Accordingly, the information disclosure statements has been considered by the examiner. Signed copies have been attached to this office action.
Election/Restrictions
Applicant’s election of Group II, claims 11-18, drawn to a topical composition comprising erlotinib or salt thereof in the reply filed on January 27, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). The requirement is still deemed proper and is therefore made FINAL.
Group I, claims 1-10 and 19-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 11-18 are pending and under examination in this application.
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.
Claim(s) 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over Seykora (WO 2012/099968 A1) in view of Epidermal growth factor receptor activation and inhibition in 3D in vitro models of normal skin and human cutaneous squamous cell carcinoma (hereinafter the reference is referred as Commandeur), Blackman (US Patent 4,883,660) and further in view of Cutaneous Adverse Effects With HER1/EGFR-Targeted Agents: Is There a Silver Lining? (hereinafter the reference is referred as Perez-Soler).
Seykora teaches compositions and methods for treating skin cancer-associated diseases by topically administering tyrosine kinase inhibitors (abstract).
Regarding claims 11, 16, 17, and 18, Seykora explicitly teaches topical compositions comprising EGFR inhibitors including erlotinib or derivatives thereof, analogs thereof, and combinations thereof (¶ 0033) in pharmaceutically acceptable carriers (¶ 0045 and ¶ 0094) for treating cutaneous Squamous Cell Carcinoma (sSCC), with the express purpose of concentrating drug at the tumor site while reducing systemic adverse effects (¶ 0028-¶ 0034). An example of pharmaceutically acceptable carriers is ethanol or DMSO and in certain embodiments, and the pharmaceutical composition is a gel or ointment having the topical formulation comprising tyrosine kinase inhibitor (s) and related compounds in amount of 0.5-1.5%, DMSO 7-9%, propylene glycol 17-19%, hydroxy propyl methyl cellulose 1-2% and water 70-73% (Table 1 of ¶ 0046 and ¶ 0094). Examples of tyrosine kinase inhibitors and related compounds suitable for use in methods of embodiments are dasatinib, erlotinib, and gefitinib, derivatives thereof, analogs thereof, and combinations thereof (¶ 0033). It is noted that Specification (¶ 0002) expressly names Epidermal Growth Factor Receptor (EGFR) inhibitor drugs erlotinib, gefitinib target the EGFR (a known oncogene) and are used for the systemic treatment of some forms of cancer and that erlotinib and gefitinib as suitable tyrosine kinase inhibitors for the claimed topical compositions. The specification describes EGFR inhibitors as a class of kinase inhibitors encompassed by the invention (¶ 0017). Regarding limitation of erlotinib or a pharmaceutically acceptable salt thereof in a concentration of about 0.5%-7.5% w/w, Seykora discloses tyrosine kinase inhibitors at 0.5-1.5 % (table 1) and notes that topical 5-FU, the standard-of-care comparator, is used at "0.5%, 2.5%, or 5.0% formulations" against the same skin lesion types (¶ 0005). Concentrations up to 7.5% w/w represent a routine upward optimization of a known range. Moreover, Seykora discloses one millimolar PP2 in DMSO (25 µL) was topically applied (¶ 0020-¶ 0022) and in Example 4, topical dasatinib, a tyrosine kinase inhibitor in topical of 1% ointment formulation in DMSO 8% (page 25, line 6-7, and Table 2) and further discloses that the compositions deliver erlotinib topically, specifically to avoid systemic adverse effects and distinguishes topical from oral/systemic administration to reduce systemic toxicity and that topical localization avoids systemic EGFR inhibition, which is the source of the acneiform rash and other cutaneous toxicities well-documented for systemic erlotinib. This functional characteristic directly follows from the topical formulation (¶ 0002-¶ 0013, and ¶ 0057-¶ 0062) corresponding to the limitations of reduced cutaneous side-effects vs. systemic administration and reduced cutaneous toxicity. Thus, the limitation of “erlotinib or pharmaceutically acceptable salt thereof is dissolved within the composition” is expressly taught.
Regarding claims 12 and 13, the claims recites wherein the topical composition has a systemic absorption of less than 100 ng/ml of erlotinib or less than 10 ng/ml of erlotinib metabolite and wherein systemic absorption of less than 1% or less than 0.5% by weight of erlotinib or pharmaceutically acceptable salt thereof. At the concentrations described in Seykora (erlotinib at 1%–10% w/w in a topical carrier) i.e., “The data show that these small molecule kinase inhibitors can be more potent than existing agents which are used as 0.5% to 5% formulations” (page 24, lines 5-6), the low systemic absorption is a natural consequence of topical application, particularly with a near-anhydrous or penetration-limited vehicle. A PHOSITA would understand that systemic absorption from topical erlotinib compositions would be a small fraction of the 150 mg/day oral dose that produces peak plasma concentrations of approximately 1,600–3,000 ng/mL (typical Cmax). The claimed % absorption thresholds of less than 1 % follow necessarily from the disclosed topical compositions and represent nothing more than a predictable property of the disclosed formulations with a carrier applied to a localized skin area. Systemic absorption from a well-designed topical formulation is routinely below 1% by weight of the applied dose. This is not an inventive achievement but a standard feature of topical dosage forms, well within the skill of a PHOSITA formulating a topical kinase inhibitor composition.
Regarding claims 14, Seykora teaches preparations for topical administration include aqueous or non-aqueous solutions, suspensions, emulsions, and gel and examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate (¶ 0049, lines 12-15), and the experimental DMSO-based solutions (Figs. 7-13 contain no added water, and Tyrosine kinase inhibitor(s) and related compounds in DMSO (table 1) and topical 1 % dasatinib ointment in DMSO (table 1 and 2) and PP2 in DMSO (¶ 0020-¶ 0023). It is noted that Dimethyl sulfoxide (DSMO) is of low water content and commonly used in gel and ointment topical pharmaceutical formulations. However, Seykora do disclose high water content (70-73%) in the dasatinib formulation of (table 1-2) which is directly opposite of claimed limitation of water content of (0%-4%), but Seykora expressly discloses the alternative non-aqueous (anhydrous) solutions in preparation are also suggested and taught. A PHOSITA would have been motivated to use an anhydrous or near-anhydrous vehicle for erlotinib given the known sensitivity of erlotinib to acidic pH and oxidation in aqueous systems and minimizing water content to 0%- 4% w/w to preserve drug stability is a routine and expected formulation optimization.
Regarding claim 15, Seykora teaches the carrier system may also comprise, when desired, a suitable gelling agent including, but not limited to, cellulose esters such as hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, carboxy vinyl polymer and the like that may be provided in any amount necessary to thicken the composition to a desired gel consistency, and when formulated as a gel, the base composition exhibits favorable spreadability characteristics, and in addition, it remains visible on the skin surface longer, thereby instilling in the user the impression that the vehicle is more completely delivering its active ingredient(s) (¶ 0055). Therefore, the limitation of “gelling agent in an amount of about 0.1 % w/w to about 6 % w/w” is suggested and expressly taught.
Commandeur teaches transmembrane tyrosine kinase epidermal growth factor receptor (EGFR) is considered a key player in the development of cutaneous squamous cell carcinoma (SCC), and inhibition of EGFR with the small molecule tyrosine kinase inhibitor erlotinib is currently under clinical investigation in cutaneous SCC patients. the effects of EGFR activation and inhibition on normal and malignant in vitro human skin equivalents (HSEs). In healthy HSEs, increasing EGF concentrations ranging from 5 to 50 ng/mL resulted in a dramatic decrease in epidermal proliferation as immunohistochemically assessed by Ki67 and increased epidermal stress as assessed by K17 after 2 weeks of air-exposed culture. Also, higher concentrations of
EGF induced remarkable epidermal disorganization with loss of proper stratification. Similar effects were observed in HSEs generated with cutaneous SCC cell lines SCC-12B2 and SCC-13. Treatment of both healthy and SCC-HSEs with 10 µM erlotinib resulted in efficient reduction of epidermal thickness from 10 to 3 viable cell layers and counteracted EGF-induced epidermal stress. Remarkably, erlotinib treatment caused severe desquamation in healthy HSEs, reminiscent of xerosis as a known side-effect in
patients treated with erlotinib. The presented three-dimensional organotypic SCC models appear suitable for further investigations on the morphological and functional impacts of modifying EGFR signaling in cutaneous SCC, without burdening patients or
mice. The effective inhibition of epidermal growth by erlotinib in our HSEs confirms the therapeutic potential of this tyrosine kinase inhibitor for cutaneous SCC patients (abstract).
Regarding claims 11-13, as noted above, Commandeur teaches (1) the limitations of Erlotinib dissolved and applied to cutaneous SCC models ("treatment of both healthy and SCC-HSEs with 10 μM erlotinib resulted in efficient reduction of epidermal thickness from 10 to 3 viable cell layers", wherein erlotinib is dissolved in the treatment medium and directly applied to the skin equivalent surface, constituting topical administration of dissolved erlotinib to a cutaneous SCC model, (2) Erlotinib as therapeutic agent for cutaneous SCC, "Inhibition of EGFR with the small molecule tyrosine kinase inhibitor erlotinib is currently under clinical investigation in cutaneous SCC patients." This confirms that erlotinib was a recognized therapeutic agent being investigated specifically for cutaneous SCC, motivating topical formulation development, (3) skin toxicity of erlotinib and motivation to reduce cutaneous side effects (that erlotinib treatment caused "severe desquamation in healthy HSEs, reminiscent of xerosis as a known side-effect in patients treated with erlotinib," directly documenting the cutaneous toxicity that claims 11–13 seek to avoid by topical (as opposed to systemic) delivery.
Blackman teaches pharmaceutical compositions suitable for topical, transmucosal and oral administration may be prepared utilizing the novel gel bases. Methods of administration of topically, systemically and orally active pharmaceutical agents utilizing the novel gel bases (abstract).
Regarding claims 14 and 15, Blackman expressly teaches anhydrous composition "a pharmaceutical composition comprising a gel base ... the base being anhydrous." (claim 1), and Examples 1–18 disclose compositions consisting exclusively of glycol solvent (propylene glycol or PEG 400) and ethoxylated fatty alcohol surfactant, thus no water is present (0% w/w water), which falls squarely within the claimed 0%–4% w/w range. Moreover, Blackman expressly teaches gel base is formed by adding ethoxylated fatty alcohol surfactants (gelling agents) at concentrations of 0.5–10% w/w to glycol solvents (column 4, lines 20-22), and claim 1 recites gel bases comprising from about 0.5% to about 10% by weight ethoxylated behenyl alcohol (or C16-C21 ethoxylated alcohol at 2.5%–10%) in a glycol solvent, and in Examples 1–18 demonstrate specific anhydrous gel compositions with gelling agent concentrations of 0.5%, 1%, 2.5%, 5%, and 10% w/w, thus the ranges are all within or overlapping the claimed 0.1%–6% range of instant claim 15. Moreover, Blackman expressly teaches
vehicles as suitable for topical application to the skin and mucosa, and which provide rapid penetration of any compatible pharmaceutical agent, dissolved or suspended therein (column 2, lines 55-58) and a pharmaceutical composition with an active "pharmaceutical agent dissolved therein or admixed therewith." (claim 1) and in (Example 19, Table 1) demonstrate dissolution of active agents (corticosteroids, propranolol HCl, ibuprofen) in the anhydrous glycol gel base. Additionally, Blackman discloses anhydrous vehicle for moisture-sensitive active ingredients and expressly teaches that anhydrous gel bases are preferred for "active ingredients which are water-decomposable or water-insoluble" (column 1, line 6 to column 2, line 38) and that such bases "do not adversely affect moisture-degradable or water-insoluble ingredients" (column 2, line 42 to column 3, line 2). A PHOSITA would directly be motivated to selecting an anhydrous vehicle for erlotinib because erlotinib is known to be sensitive to oxidation and acidic pH in aqueous environments. Lastly, Blackman teaches superior skin penetration and topical efficacy and demonstrates in a vasoconstriction assay (Example 21) that the anhydrous glycol gel formulations were superior to commercial KENALOG® cream and ointment in delivering a topical corticosteroid, thus, providing direct motivation to use anhydrous gel vehicles to improve topical drug delivery efficacy.
Perez-Soler teaches The human epidermal growth factor receptor (HER1/EGFR) is dysregulated in many solid tumors, making it an attractive target for anticancer therapy. A number of agents that target this receptor are in use or in development. A specific adverse effect common to this class of agent is a papulopustular rash, usually on the face and upper torso, which generally occurs in a dose-dependent manner. Little is known about the etiology of this rash, and there are no clear evidence-based management recommendations. Histologic data indicate that rash may be caused by HER1/EGFR inhibition in skin, although this has not been confirmed. Findings suggest that there is a relationship between the development of rash and response and/or survival, making rash a potential surrogate marker of activity. Data from multiple studies
with cetuximab and erlotinib show a consistent relationship between rash and response, as well as between rash and survival. The relationship between rash and clinical outcome is currently less consistent for gefitinib. Some studies report a correlation, whereas others do not. The cause of the possible relationship between rash and clinical benefit remains unclear at this time, and additional studies are needed to determine the clinical utility of this observation (abstract).
Regarding claims 11-13, as noted above, Perez-Soler teaches that systemic erlotinib causes characteristic cutaneous toxicities by inhibiting EGFR in normal skin keratinocytes, and thus provides direct motivation for topical formulation. Perez-Soler discloses that acneiform/papulopustular rash occurs in 43–75% of patients receiving systemic EGFR inhibitors, including erlotinib (Tarceva), by inhibiting EGFR signaling in the sebaceous gland epithelium and hair follicle. The mechanism is on-target inhibition of EGFR in normal skin, the same pathway exploited therapeutically in cutaneous SCC (page 5238-5240).
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to arrive at the topical composition comprising erlotinib or a pharmaceutically acceptable salt thereof comprising a concentration of about 0.5 % - 7.5% as taught by Seykora. The teachings of Seykora highlight Erlotinib -Tyrosine Kinase Inhibitor (TKI), incorporated (dissolved/dispersed) in the ointment/gel base and DMSO functions as the solubilizing component for the hydrophobic small-molecule TKIs, thus Erlotinib is established as soluble in DMSO and suitable for the same carrier system in Seykora (¶ 0033). The concentration up to 7.5 % w/w represent a routine optimization of a known range, as discussed in the rejections above. The teachings in Commandeur, Blackman and Perez-Soler establishes the motivation to combine. Commandeur teaches that erlotinib was in active clinical investigation, specifically for cutaneous SCC (page 2120), confirming that erlotinib is the clinically relevant EGFR inhibitor target for the same disease treated by Seykora. Perez-Soler teaches that systemic EGFR inhibitor therapy causes dose-limiting cutaneous toxicity in 43 – 75 % of patients, establishing a clear clinical problem that topical delivery is beneficial and directly addresses. Therefore, combining these known teachings, and substituting erlotinib into the expressly disclosed topical TKI composition of Seykora, motivated by Commandeur clinical context and Perez-Soler’s toxicity profile, is reasonable to a PHOSITA to involve only known elements combined with known methods and components in a topical composition to yield predictable results. Prior art Blackman establishes Erlotinib is soluble in the glycol solvents that form the basis of anhydrous gels, primarily of propylene glycol or PEG 400 (90-99.5 % w/w) with small quantities of ethoxylated fatty alcohol gelling agent (Examples 1-18), and Seykora establishes Erlotinib is freely soluble in DMSO and propylene glycol. A PHOSITA would have a well-founded expectation that erlotinib could be dissolved in anhydrous propylene glycol/PEG 400 gel base at the claimed concentrations (0.5-7.5% w/w), particularly since Blackman teaches that active agents soluble in glycols are excellent candidates for its gel bases. Furthermore, Blackman provides a complete, reproducible formulation framework with 21 detailed working examples of anhydrous gel formulations and a validated in vivo performance study (example 21), thus it would have been obvious to a PHOSITA to apply this technology to erlotinib with a reasonable expectation of success. While Seykora expressly states the purpose of gelling agents, to thicken topical composition to a “desired gel consistency” (¶ 0055), a PHOSITA formulating an anhydrous topical erlotinib composition would need to achieve adequate viscosity for skin application, and too thin a composition would not adhere to the lesion site, and adding a gelling agent at 0.1-6 % w/w is the standard pharmaceutical approach to achieving this. Therefore, Seykora (¶ 0055, Table 1) in view of Blackman (Claim 1, Examples 1-18) teach gelling agent concentrations squarely within or encompassing the claimed range. The gelling agents in Seykora (HPMC, hydroxypropyl cellulose, polyvinylpyrrolidone) and Blackman (ethoxylated behenyl/cetyl/stearyl alcohols) are both established, commercially available pharmaceutical excipients with well characterized behavior in topical formulations, and their use of 0.1-1.6 % w/w to achieve gel consistency is propylene glycol or DMSO/PG carrier is fully predictable to a PHOSITA. Moreover, Blackman
demonstrates successful gel formation at concentrations as low as 0.5% w/w (Examples 1–2), confirming that gelling is achievable throughout the claimed range. Thus, predictable chemistry in this combination and it is routine topical formulation practice.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615