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 .
Priority
This application, filed 5 March, 2024, claims the benefit of a prior-filed application PRO 63/450,556, filed 3 March, 2023. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
Three information disclosure statements (IDS), all submitted on 25 October, 2024 are acknowledged and have been considered.
Election/Restrictions
Applicant’s election without traverse of Group I – Method of Treating in the reply filed on 12 May, 2026 is acknowledged.
Applicant’s amendment adds Claims 21-23, which depend from Claim 5 and recite embodiments wherein the administration comprises topical administration of a topical formulation. Claims 21-23 are considered to remain within the scope of the elected Group I method invention because they are directed to limitations on the administration step of the elected method claims. Accordingly, Claims 21-23 will be examined with the elected invention.
Status of the Application
Receipt is acknowledged of Applicant's claimed invention, filed 12 May, 2026, in the matter of Application N° 18/596,363. Said documents have been entered on the record.
Claims 13-15 have been canceled. Claims 21-23 are new. No new matter was introduced.
Claims 11-12 and 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 May, 2026.
Thus, Claims 1-10 and 21-23 represent all claims currently under consideration.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 4 and 8-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites that “the skin fragility disease is a skin blistering disease; and/or wherein the skin fragility disease is associated with dysregulation of at least one of…” The phrase “and/or” renders the scope of the claim unclear because it encompasses multiple alternative claim constructions, including embodiments requiring both recited conditions, embodiments requiring only the first condition, and embodiments requiring only the second condition. As a result, one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the claimed invention.
Claim 4 recites “the skin fragility disease is associated with administration of a B-RAF inhibitor.” The phrase “associated with” is unclear in the context of the claim because it does not reasonably inform one of ordinary skill in the art of the relationship between the recited skin fragility disease and the administration of the B-RAF inhibitor. For example, it is unclear whether the disease is caused by, exacerbated by, correlated with, identified by, treated with, or otherwise related to administration of the B-RAF inhibitor. Accordingly, the scope of the claim cannot be determined with reasonable certainty.
Claim 8 recites “based on the administering, determining that a level of ERK activity or phosphorylation in the subject has decreased.” However, the claim fails to set forth the reference point from which the decrease is measured. For example, it is unclear whether the recited decrease is relative to a pretreatment level, a control value, a reference population, or another comparison standard. As a result, one of ordinary skill in the art would not be reasonably apprised of the scope of the claim determining step.
Claim 9 further recites “predicting that the subject has the skin fragility disease.” However, the claim does not recite any act or acts by which the prediction is performed. The claim therefore recites a result to be achieved without reasonably informing one of ordinary skill in the art of the scope of the claimed predicting step. Accordingly, the metes and bounds of the claim cannot be determined with reasonable certainty.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 3 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for Darier disease and Grover disease, does not reasonably provide enablement for the full list of diseases cited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 3 depends from Claim 1 and recites that the skin fragility disease is “Darier disease, Grover disease, Hailey-Hailey disease, pemphigus, epidermolytic ichthyosis, epidermolysis bullosa simplex, keratoderma, palmoplantar keratoderma, or pachyonychia congenita.” The specification provides substantial working disclosure directed to Darier disease and Grover disease, including disclosure that Darier disease is caused by mutation of ATP2A2/SERCA2 and manifests as recurrent skin blisters, erosions, and infections (Pg 1, Para 0006); that Grover disease lesions may exhibit acquired ATP2A2 mutation and pathologic features indistinguishable from Darier disease (Pg 2, Para 0007); and that Grover disease biopsies exhibit ERK hyperactivation and desmosomal disruption (Pg 9, Para 0024, Fig 16A-16D.) The specification further reports experimental models involving SERCA2-deficient keratinocytes, thapsigargin-induced SERCA2 inhibition, B-RAF inhibitor-induced Darier/Grover-like pathology, ERK hyperactivation, and rescue by MEK inhibitors (Pg 22-56, Experimental Examples.)
However, the specification does not provide commensurate guidance or working examples for the remaining diseases recited in Claim 3. Although the specification broadly lists these conditions as examples of “skin fragility diseases,” the disclosure does not provide representative data showing the MEK inhibition treats each of these diseases, nor does it provide sufficient explanation establishing that the same SERCA2/ATP2A2-MAPK/ERK mechanism demonstrated for Darier disease and Grover disease applies across the full scope of the recited diseases genus.
The breadth of claim 3 is therefore not commensurate with the scope of enablement provided by the specification. The specification enables, at most, treatment of diseases reasonably supported by the disclosed SERCA/ATP2A2 deficiency, ERK hyperactivation, and desmosomal disruption rationale, particularly Darier disease and Grover disease. Undue experimentation would be required to determine whether administration of a MEK inhibitor would successfully treat the other recited skin fragility diseases, which are not shown by the specification to share the same operative disease mechanism or therapeutic response. Accordingly, Claim 3 is not enabled across its full scope.
Claim 21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 21 depends from Claim 5 and recites that the topical administration comprises administration of a topical formulation, wherein the topical formulation may comprise, inter alia, “an inhalant.” However, the specification does not describe an inhalant as a topical formulation for application to the skin, nor does it describe administration by inhalation as a topical administration route for treating a skin fragility disease. Accordingly, the specification fails to provide adequate written description support for the claimed inhalant embodiment.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 10 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental process (abstract idea) that is based upon a natural relationship (natural phenomenon) without significantly more.
The claim recites obtaining a sample from a subject, determining a level or activity of one or more biomarkers in the sample, comparing the determined level or activity to a reference level, and based on the comparison, predicting that the subject has a skin fragility disease. The claim therefore recites a mental process because the claim requires evaluating biomarker information and making a diagnostic determination regarding the presence of a disease. The claimed prediction is based upon the relationship between biomarker levels or activities and disease status, which is a naturally occurring biological relationship. This judicial exception is not integrated into a practical application because the additional elements of obtaining a sample, determining biomarker levels or activities, and comparing those levels to a reference level merely gather and analyze data for purposes of making the recited prediction. The claim does not recite treatment of the subject, modification of a therapeutic regimen, administration of a therapeutic agent, improvement of a laboratory technique, improvement of a computer or other technology, or any other practical application beyond determining information and reaching a diagnostic conclusion.
The specification describes these activities as routine clinical and laboratory practices. For example, the specification teaches obtaining a biopsy or other sample from a subject, analyzing the sample to determine biomarker levels or activities, comparing the determined values to reference values, and using the resulting information for diagnosis and/or prognosis of skin fragility disease (Pg 13-14, Para 0034-0036.) The specification further describes determining ERK activity and biomarker levels using conventional analytical techniques (Pg 61, Para 0180.) Thus, the additional elements merely apply routine and conventional data-gathering and analysis activities to observes the relationship between biomarker information and disease status.
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the obtaining, determining, and comparing steps are well-understood, routine, and conventional activities in the field of disease diagnosis and biomarker analysis.
Accordingly, Claim 10 amounts to no more than collecting biological information, analyzing that information, and using the resulting information to predict the presence of a skin fragility disease.
Claim Rejections - 35 USC § 102
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 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.
Claim 1-3, 5, 7 and 21-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (US 2021/0060018 Al, cited in IDS), hereinafter Zhang.
Regarding Claims 1, 3, 5 and 7, Zhang teaches a method of treating a subject having Grover’s disease through topical administration of a therapeutically effective amount of a MEK inhibitor (e.g., trametinib, cobimetinib, binimetinib, selumetinib, and tetrathiomolybtate) (‘018, Pg. 1, Para 0009 and 0010, Pg. 5, Para 0052 and 0054). Grover’s disease is expressly identified by Applicant as one example of a “skin fragility disease” (instant Specification, Pg 12, Para 0029.) Therefore, Zhang teaches the claimed method of treating a subject having a skin fragility disease.
Regarding Claim 2, Zhang teaches that the skin disorder may comprise Grover’s disease. Zhang further teaches dysregulation of the MEK/ERK signaling pathway underlies a wide range of skin disorders (‘018, Pg. 1, Para 0003). Zhang further demonstrates in Example 1 that phosphorylated MEK was expressed at a markedly increased level in the mutant epidermis compared to wild-type skin (‘018, Pg. 9, Para 0097, Example 1), thereby evidencing dysregulation of MEK signaling associated with the disclosed skin disorder.
Regarding Claims 21-22, Zhang teaches pharmaceutical composition is in a form selected from ointments, gels, creams, lotions, oil-in-water emulsions, water-in-oil emulsions, microemulsions, foams, sprays, mousses, patches, powders, pastes, and medicated plasters (‘018, Pg. 1, Para 0010).
Regarding Claim 23, Zhang teaches the pharmaceutical composition further comprises a penetration enhancer, to include oleic acid, N-alkylpyrrolidone, etc. (‘018, Pg. 2, Para 0018).
As such, Zhang anticipates instant Claims 1-3, 5, 7 and 21-23.
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.
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 6 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2021/0060018 Al, cited in IDS), as applied to Claims 1-3, 5, 7 and 21-23 above.
Regarding Claim 6, Zhang teaches topical administration of a therapeutically effective amount of a MEK inhibitor, such as trametinib, for treating skin disorders, including Grover’s disease, and further teaches administration of an approximately 0.2 mg dose of trametinib (‘018, Pg. 2, Para 0021). Although Zhang does not expressly disclose the dosage in units of mg/kg/day, it would have been prima facie obvious to one of ordinary skill in the art to administer or express the known therapeutically effective dose in weight-normalized units, as such dosing is a routine and well-known method of determining and expressing pharmaceutical dosages for human subjects. Moreover, a 0.2 mg dose administered to a human subject corresponds to a weight-normalized dose well within the claimed range of about 0.1 μg/kg/day (equal to 0.0001 mg/kg/day) to about 2 mg/kg/day for ordinary patient body weights.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2021/0060018 Al, cited in IDS), as applied to Claims 1-3, 5, 7 and 21-23 above, and further in view of Singh et al. (Dermatology Online Journal, Volume 26 Number 2, February 2020, 26(2):9), hereinafter Singh.
The teachings of Zhang are set forth in the above 35 U.S.C. 102 Rejections and are incorporated herein. Zhang teaches topical administration of a therapeutically effective amount of a MEK inhibitor, such as trametinib, for treating skin disorders, including Grover’s disease.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to employ the MEK inhibitor treatment of Zhang in a subject whose skin fragility disease is associated with administration of a B-RAF inhibitor, as taught by Singh. Singh explains that Grover’s disease has increasingly been reported in patients receiving B-RAF inhibitor monotherapy and specifically describes development of Grover’s disease following administration of vemurafenib, a B-RAF inhibitor (Singh, Abstract, Introductions and Case Synopsis).
Singh further teaches that B-RAF inhibitor-induced Grover’s disease is believed to result from paradoxical activation of the MAPK/MEK/ERK signaling pathway, resulting in keratinocyte proliferation (Singh, Abstract and Discussion).
Moreover, Singh teaches that combination therapy with a MEK inhibitor appears to prevent B-RAF-induced Grover’s disease and cites clinical evidence that no patients receiving combined B-RAF inhibitor and trametinib therapy developed Grover’s disease, in contrast to patients receiving B-RAF inhibitor monotherapy (Singh, Discussion). Singh further explains that selective inhibition of B-RAF activates C-RAF and downstream MEK-ERK signaling, and therefore the addition of a MEK inhibitor mitigates that effect (Singh, Pg 3, Para 3).
Accordingly, one of ordinary skill in the art would have been motivated to employ the MEK inhibitor treatment taught by Zhang in subjects whose Grover disease is associated with administration of a B-RAF inhibitor and would have had a reasonable expectation of success because Singh provides a mechanistic explanation for the disease process and teaches that MEK inhibition mitigates the underlying signaling pathway responsible for the B-RAF inhibitor-associated eruption.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2021/0060018 Al, cited in IDS), as applied to Claims 1-3, 5, 7 and 21-23 above, and further in view of Osum et al. (Neuro-Oncology Advances 3(1), 1–11, 2021. doi:10.1093/noajnl/vdab020), hereinafter Osum.
The teachings of Zhang are set forth in the above 35 U.S.C. 102 Rejections and are incorporated herein. Zhang teaches topical administration of a therapeutically effective amount of a MEK inhibitor, such as trametinib, for treating skin disorders, including Grover’s disease.
Zhang does not expressly teach the further limitation of, based on the administering, determining that a level of ERK activity or phosphorylation in the subject has decreased.
However, Osum teaches that inhibition of ERK phosphorylation is a well-established pharmacodynamic biomarker for MEK inhibition. Specifically, Osum teaches administering the MEK inhibitor selumetinib and determining the extent of ERK phosphorylation inhibition in tissues following administration in order to evaluate pharmacodynamic activity and target engagement (Osum, Abstract and Introduction). Osum further teaches quantifying phosphorylated ERK (pERK) following administration of the MEK inhibitor and using the measured reduction in ERK phosphorylation as an indicator of MEK inhibition (Osum, Pg. 4, Final Paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, at the time of the invention, to modify the method of Zhang by further determining whether ERK activity or phosphorylation had decreased following administration of the MEK inhibitor, as taught by Osum, because ERK phosphorylation was recognized in the art as conventional downstream pharmacodynamic marker of MEK inhibition. One of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Osum demonstrates that determination of ERK phosphorylation following administration of a MEK inhibitor provides confirmation of target engagement and biological activity of the administered inhibitor, thereby permitting evaluation of the effectiveness of the treatment regimen.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2021/0060018 Al, cited in IDS), as applied to Claims 1-3, 5, 7 and 21-23 above, and further in view of Sousou et al. (Cureus 14(4): e24082. DOI 10.7759/cureus.24082), hereinafter Sousou.
The teachings of Zhang are set forth in the above 35 U.S.C. 102 Rejections and are incorporated herein. Zhang teaches topical administration of a therapeutically effective amount of a MEK inhibitor, such as trametinib, for treating skin disorders, including Grover’s disease.
Zhang does not expressly teach the additional limitation of further comprising determining (i.e., predicting) that the subject has the skin fragility disease.
However, Sousou teaches that Grover’s disease may be diagnosed clinically and that the definitive diagnosis is made through a skin biopsy revealing intraepidermal acantholysis (Sousou, Introduction). Sousou further teaches a patient presenting with a characteristic rash who was referred for biopsy, wherein the biopsy confirmed a diagnosis of Grover’s disease prior to initiation of treatment with topical triamcinolone acetonide. Thus, Sousou teaches determining or diagnosing that the subject has Grover disease before administering therapy.
It would have been prima facie obvious to one skilled in the art at the time of invention to modify the method of Zhang by first determining or predicting that the subject has Grover’s disease. One of ordinary skill in the art would have been motivated to do so because accurately diagnosing a patient’s disease before selecting and administering an appropriate therapeutic regimen is a routine and fundamental aspect of medical practice. A person of ordinary skill in the art would have had a reasonable expectation of success because Sousou demonstrates that Grover’s disease can be reliably diagnosed clinically and confirmed by biopsy prior to treatment, thereby facilitating selection of an appropriate therapy.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Donna M. Nestor whose telephone number is (703)756-5316. The examiner can normally be reached generally (w/flex): 5:30a-5p EST M-Th.
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/D.M.N./ Examiner, Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627
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