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 .
Current Status of 17/755,182
This Office Action is responsive to the amended claims and Applicant remarks of 12/05/2025. Claims 1, 2, 12-15, and 24-29 are pending in this application and have been considered on the merits.
Priority
The instant application is a national stage entry of PCT/CN2021/124587, international filing date, 10/19/2021, which claims priority to CN 202011381947.8, filed 11/19/2020, and CN 20211074555.0, filed 01/20/2021.
The claims are given the effective filing date of 01/20/2021.
Information Disclosure Statement
No information disclosure statements were submitted for consideration at the time of examination.
Response to Arguments
In the prior Office Actions, the examiner cited CN 106163557 A, identified herein as Andersen. In the present Office Action, the examiner cites the corresponding U.S. Application, which identifies Laberge as the first-named inventor. The U.S. application is the English-language equivalent of the previously cited CN application.
The arguments presented by Applicant in the remarks filed 12/05/2025 have been fully considered. Applicant's characterization of Andersen as merely teaching that ABT-737 kills human primary fibroblasts does not accurately reflect the disclosure. While the reference includes experimental data demonstrating senolytic activity in fibroblasts, the reference as a whole expressly teaches the administering ABT-737 as a senolytic agent to treat dermatological diseases, including psoriasis, and contemplates topical administration, including gels.
Applicant's arguments about the multifunctionality of IL-6 and the lack of a definitive IL-6 pathogenic mechanism in psoriasis are not persuasive. The rejection is not based on IL-6 being a sole or primary therapeutic target. Rather, the reference expressly teaches treating psoriasis by administering the BCL-2 inhibitor ABT-737. The reference's disclosure of IL-6 reflects a biomarker or downstream inflammatory correlate of disease activity, not a required mechanistic premise for therapeutic use. The reference expressly teaches the use of the BCL-2 inhibitor ABT-737 in treating psoriasis.
Applicant’s arguments of II, regarding the motivation for selecting a gel formulation with the recited excipients is persuasive. Andersen does not explicitly provide a motivation for the selection of the gel from the other topical application methods listed.
Applicant’s assertion that there is no reasonable expectation of success due to the lack of specific gel components incorrectly assumes that a reasonable expectation of success requires the disclosure of specific excipients and their corresponding ratios. However, topical gel formulations rely on a known and finite set of functional excipient classes such as solvents or co-solvents, gelling agents, penetration enhancers, and stabilizers or preservatives. Andersen does not suggest that ABT-737 present any formulation challenges that would render standard gel formulation unpredictable or infeasible. Andersen does not disclose the instability or incompatibility of ABT-737 within topical vehicles, and absent any such disclosure, it is reasonable to expect that ABT-737 could be incorporated into a gel using conventional formulation principles within the ordinary skill of the artisan.
The previous rejections are withdrawn based on the lack of motivation provide by the references to select a topical gel for the method of treatment.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: A method of treating cellular senescence-related diseases using B-cell lymphoma (BCL-2) inhibitors and pharmaceutical compositions thereof.
The suggested title aligns the claimed invention with the appropriate statutory class.
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.
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.
Claims 1, 2, 12- 15, and 24-29 are rejected under 35 U.S.C. 103 as being unpatentable over Laberge (US 9,993,472 B2) as evidenced by the Encyclopedia Britannica ("Psoriasis." Britannica Academic, Encyclopedia Britannica, 7 Mar. 2018. academic.eb.com/levels/collegiate/article/psoriasis/61711. Accessed 3 Apr. 2025.) in view of Carrara (US 2009/0069364 A1) and Torsekar (Torsekar, R, and Manjyot M Gautam. “Topical Therapies in Psoriasis.” Indian dermatology online journal vol. 8,4 (2017): 235-245. doi:10.4103/2229-5178.209622).
The Examiner notes that claim 13 further recites that psoriasis is in a progressive, stationary, or regressive phase. This limitation does not meaningfully narrow the scope of the claim, as any such disease necessarily exists in one of these phases. Accordingly, claim 13 is coextensive in scope with claim 1.
Laberge teaches a method of treating psoriasis comprising administering to a subject in need thereof a BCL-2 inhibitor, specifically ABT-737 as part of a topical (external) preparation (Col 1, lines 54-55, Col 1 line 66-Col 2 line 3, Col 2 lines 13-16, Col 2, lines 36-44, Col 4 lines 45-47, Col 5, lines 3-5, Col 97 lines 50-54, Col 99 line 53-Col 100 line 4). The reference teaches gels as one such topically administered composition (Col 99 line 53-Col 100 line 4). Laberge also teaches preservatives as excipients for the senolytic agent formulations, suitable preservatives include ethyl paraben, sodium benzoate, and chlorobutanol (Col 99 line 64-Col 100 line 4). The reference teaches that the treatment can reduce the likelihood of cellular senescence-related diseases; delay onset or progression of cellular senescence-related diseases; or inhibit, delay, slow or retard the progression or severity of cellular senescence-related diseases (Col 14 lines 24-52). The reference further discloses embodiments comprising multiple senolytic agents for use in the treatment regimen, which amounts to the use of additional active ingredients or drugs in treating psoriasis (Col 36 lines 15-37).
The term psoriasis is defined by the Encyclopedia Britannica as a chronic recurrent inflammatory skin disorder where the most common type is psoriasis vulgaris. Other types of psoriasis include guttate, pustular, inverse (or flexular), and erythrodermic. Complications from psoriasis can cause psoriatic arthritis. This definition establishes that psoriasis is an umbrella term encompassing multiple clinical subtypes, and the use of the term psoriasis in the disclosure would reasonably be understood by the artisan to encompasses psoriasis generally, rather than a single subtype.
Laberge does not expressly disclose the specific components of the gel compositions recited in the instant claims. However, such gel compositions are well known to those of ordinary skill in the art.
Carrara (US 2009/0069364 A1) discloses one such transdermal gel for the delivery of 5-alpha-reductase inhibitors (Abstract, claim 1). The gels are comprised of their active ingredient (5-alpha-reductase inhibitor), gelling agents; permeation enhancers, preservatives, anti-oxidants, buffers, humectants, sequestering agents, moisturizers, surfactants, emollients, film-forming agents, solubilizers, flavors, fragrances, stabilizers, and solubilizers (Claims 1, 12, and 13). [0097] of Carrara teaches gelling agents of the formulations and expressly lists cellulose derivatives such as hydroxypropyl methylcellulose, carboxymethyl cellulose, carbomer, chitosan, polyvinyl alcohols, and alginates. The reference teaches that the gelling agent or thickener is present from about 0.2-30%w/w depending on the type of polymer, as known by one of skill in the art [0097].
[0098] of Carrara teaches penetration enhancers of the formulations and specifically identifies DMSO, DMA, DMF, polyethylene glycol, and oleic acid as exemplary penetration enhancers. The reference teaches that the penetration enhancer is present from about 0.1-30% w/w depending on the compound.
[0100] of Carrara teaches buffering agents as part of the formulations. Exemplary buffers include carbonate buffers, acetate buffers, borate buffers, and citrate buffers. The reference teaches that the amount of buffer present is determinable by one of ordinary skill in the art. The reference also discloses that the The composition typically comprises a primary vehicle comprising a mixture of water, at least one short-chain alcohol, a monoalkylether of diethylene glycol, and a glycol [0094].
[0101] of Carrara teaches that the formulations may further include preservatives such as benzalkonium chloride and derivatives, benzoic acid, benzyl alcohol and derivatives, bronopol, parabens, centrimide, chlorhexidine, cresol and derivatives, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric salts, thimerosal, sorbic acid and derivatives. The reference additionally teaches that the preservative is present from about 0.01-about 10% w/w depending on the compound, as known by one skilled in the art.
[0102], [0107-0108], and claims 12 and 13 disclose that the formulations may also include humectants.
Torsekar teaches that topical therapies are the backbone of management of psoriasis, and that they are safe and well tolerated by patients (Conclusion pg. 242, left col.). The reference also teaches that new vehicle formulations such as gels have been developed to improve the aesthetics and thereby patient compliance with application which is of utmost importance for optimum treatment results.
The artisan would have a background in pharmaceutical sciences, organic chemistry, chemical engineering, or a related field and would have experience in the formulation and development of topical and transdermal drug delivery systems. The artisan would be familiar with gel-based formulations for dermatological applications including the selection and optimization of excipients, penetration enhancers, preservatives, and solvent systems. The artisan would understand the challenges of transdermal delivery of small molecule APIs and would be knowledgeable about topical treatment approaches for psoriasis.
The artisan would have been motivated to use the BCL-2 inhibitor ABT-737 in a topical formulation for the treatment of psoriasis based on the disclosure of Laberge, which expressly contemplates therapeutic uses and identifies topical dosage forms, including gels. The artisan would have been motivated to select gel formulations because these formulations improve patient compliance with application, thereby improving treatment outcomes (see Torsekar). The selection of the specific gel components would have been within the routine skill of the artisan, as such components are determinable through routine formulation optimization. Carrara teaches that the excipients recited in the instant claims are both well-known and commonly used in topical gel formulations. Laberge teaches the use of the API for treating psoriasis and identifies topical gel formulations. Torsekar provides motivation to select a gel vehicle due to improved patient compliance. Carrara demonstrates that the claimed gel components represent routine formulation choices. For these reasons, the instant claims represent the substitution of a known active pharmaceutical ingredient into a known delivery vehicle for a known indication, and the artisan would have had a reasonable expectation of treating psoriasis using ABT-737 in a gel formulation.
Conclusion
No claims are allowed.
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/C.K.E./ Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625