DETAILED ACTION
Examiner acknowledges receipt of the reply filed 1/30/2026, in response to the restriction requirement mailed 7/30/2025.
Claims 1-12, 14, 18 and 19 are pending. Claims 8, 10-12, 14, 18 and 19 are withdrawn from further consideration for the reasons set forth below.
Claims 1-4 and 6-9 are being examined on the merits in this office action.
In response to this office action, the status identifier of the withdrawn claims should be appropriately revised to reflect withdrawn status.
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 .
Election/Restrictions
Applicant’s election of Group 1 (claims 1-9) without traverse in the reply filed on 1/30/2026 is acknowledged.
Claims 10-12, 14, 18 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1/30/2026.
Applicant’s election of the following species without traverse in the reply filed on 1/30/2026 is acknowledged:
AchE sequence: SEQ ID NO:1
Skin disease: eczema
Claims 1-4 and 6-9 read on the elected species. Claims 8 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/30/2026.
Upon searching the elected species, an additional species was found e.g. melanoma . Accordingly, for purposes of compact prosecution, the election of species is modified only to the extent of examining this additional species. Otherwise the election of species requirement is still retained.
Priority
The application claims the following priority per the filing receipt dated 3/11/2025:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings are objected to because Figure 2 is too pixelated and has faint shading on the lines. It is difficult to clearly decipher the font or distinguish between the different data points. Please enlarge and darken the overall image. Additionally, the x-axis indicates time, but no unit of measurement, e.g., days, hrs, min, etc. Please amend to indicate the unit of measurement.
The figure legend of Fig 1B should also be amended to reflect the SEQ ID NO of the peptide, SEQ ID NO:3.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
USPTO Sequence Interpretation/Claim Interpretation
The Office interprets claims comprising SEQ ID NOs: in the following manner: “comprising an amino acid sequence of SEQ ID NO: 1” requires only a dipeptide or more within SEQ ID NO: 1, “comprising the amino acid sequence of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 with or without additional amino acids at any N-/C-terminal ends or additional nucleotides at 5' /3' ends, “consisting of an amino acid sequence of SEQ ID NO: 1” would encompass any sequence of two or more consecutive amino acids (dipeptide or more) fully contained within SEQ ID NO: 1, and “consisting of the amino acid sequence of SEQ ID NO: 1” would be limited to the sequence of the amino acids as specified by SEQ ID NO: 1, and nothing more or less; "an amino acid selected from the group consisting of SEQ ID NOs: 1, 2 and 3” is any sequence of two or more consecutive amino acids (dipeptide or more) fully contained within SEQ ID NO: 1, 2 or 3; and “the amino acid selected from the group consisting of SEQ ID NOs: 1, 2, and 3” requires the full-length sequence with 100% identity to SEQ ID NOs: 1, 2, or 3 and the same length as SEQ ID NOs: 1, 2, or 3.
See, e, g., claim 4, comprising an amino acid sequence.
Claim Objections
Claims 1, 3, 4, and 6-9 are objected to because of the following informalities:
Claim 1 should be amended to recite “the method comprising[[,]] administering to a subject in need thereof
Claim 3 should be amended to recite “group consisting of[[:]] eczema”.
Claim 4 should be amended to recite “SEQ ID NO:1, , or a fragment thereof”.
Claim 6 should be amended to recite ““SEQ ID NO:2, or a functional fragment thereof”.
Claim 7 should be amended to recite ““SEQ ID NO:3, or a functional fragment thereof”.
Claim 8 should be amended to recite ““SEQ ID NO:4, or a functional fragment thereof”.
Claim 9 should be amended to recite “the cyclic polypeptide, derivative or analogue thereof”.
Appropriate correction is required.
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 6-9 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.
The term “skin condition associated with abnormal keratinocyte proliferation” in claim 2 is a relative term which renders the claim indefinite. The term “skin condition associated with abnormal keratinocyte proliferation” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The skilled artisan is not apprised of skin conditions that fall within the instant claim scope and those that are excluded from the instant claim scope.
Claims 2 and 3 recite the limitation "the skin condition”. There is insufficient antecedent basis for this limitation in the claim. Independent claim 1 recites a skin disease, not a skin condition.
The metes and bounds of claim 4 are deemed to be indefinite. Claim 4 recites Claim 4 recites two consecutive "or" statements; “SEQ ID No: 1 or a variant or fragment”. This leads to alternative claim interpretation. Under the first interpretation, the fragment is construed as a fragment of SEQ ID NO:1. Under the second interpretation, the fragment is construed as i) a fragment of SEQ ID NO:1, OR ii) a fragment of a variant of SEQ ID NO:1. Applicant should amend claim 4 to clarify the claim scope.
To overcome this rejection, claim 4 should be amended to recite “SEQ ID NO:1, [[or]] a variant, or a fragment thereof”.
Claims 6-8 are similarly rejected as claim 4 for recitation of two consecutive "or" statements. Examiner recommends that claims 6-8, respectively, be amended as set forth above.
Claim 9 recites the limitation "the polypeptide, derivative”. There is insufficient antecedent basis for this limitation in the claim. To overcome this rejection, claim 9 should be amended to recite “the cyclic polypeptide, derivative”.
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.
Claims 1-4 and 6-9 are 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.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient” (MPEP § 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure (MPEP § 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and (d) representative number of samples.
In the instant case, the claims recite a method of treating, preventing or ameliorating a skin disease, the method comprising, administering to a subject in need of such treatment, a therapeutically effective amount of a cyclic polypeptide, derivative or analogue thereof comprising an amino acid sequence derived from the C-terminus of acetylcholinesterase (AChE), or a truncation thereof.
The term “skin disease” is not expressly defined in the specification. The specification states at p. 3, ll. 9-12: “The skin condition which is treated is preferably a skin condition associated with abnormal keratinocyte proliferation. Preferably, the skin condition, which is treated, may be selected from a group consisting of: eczema, psoriasis, melanoma, dermatitis, and acne”. A “subject” may be a vertebrate, mammal, or domestic animal (specification at p. 23, ll. 19).
The C-terminus of acetylcholinesterase is not expressly defined in the specification. The specification states:
The term “derived from” can mean an amino acid sequence, which is a derivative or a modification of an amino acid sequence that is present in, or forms, the C-terminus of AChE, and portion thereof.
The term “truncation thereof” can mean the cyclic polypeptide derived from AChE is reduced in size by the removal of amino acids. The reduction of amino acids may be achieved by removal of residues from the C- or N-terminal of the peptide prior to cyclisation into the cyclic polypeptide of the invention, or may be achieved by deletion of one or more amino acids from within the core of the peptide prior to cyclisation.
Specification at p. 4, ll. 9-17.
The term “derivative or analogue thereof” can mean a polypeptide within which amino acid residues are replaced by residues (whether natural amino acids, non-natural amino acids or amino acid mimics) with similar side chains or peptide backbone properties (specification at p. 3, ll. 23-26).
The terms “substantially the amino acid/nucleotide/peptide sequence”, “functional variant” and “functional fragment”, can be a sequence that has at least 40% sequence identity with the amino acid/nucleotide/peptide sequences of any one of the sequences referred to herein, for example 40% identity with the sequence identified as SEQ ID No:1-4, and so on (specification at p. 26, ll. 12-16).
The issue at question is whether a person of ordinary skilled in the art would be able to determine what structural feature/amino acid sequence is required for the instant claimed cyclic polypeptide derived from the C-terminus of AChE to be considered a derivative, an analogue, or truncation thereof, respectively, and to have the functional utility in treating and/or preventing a skin disease in any vertebrate, including but not limited to mammals.
(a) actual reduction to practice and (b) disclosure of drawings or structural chemical formulas:
The specification indicates that human acetylcholinesterase (AChE) correlates with SEQ ID NO:1. Example 1 discloses synthesis of cyclic T14 (also referred to as NBP-14; SEQ ID NO:3; amino acid positions 586-599 of SEQ ID NO:1). Example 1 discloses linear peptide SEQ ID NO:2 (T15, the last 15 amino acids of instant SEQ ID NO:1), and linear peptide SEQ ID NO:3 (T30; amino acid positions 586-599 of SEQ ID NO:1). Example 2 discloses that T30 induced an increase in intracellular calcium in the keratinocyte cell line HaCaT. T15 did not induce a raise of intracellular calcium. NBP-14 inhibited the effects of T30. Example 3 assess the effect of AChE Drive peptides on proliferation of the keratinocyte cell line HaCaT. T30 induced cell proliferation whereas T15 did not alter cell proliferation (Fig 3B). NBP14, T15, and T30 did not show induced significant cytotoxic effects in the cell line (Fig 3A). NBP-14 was not assessed for cell proliferation.
The only cyclic polypeptide of the C-terminus of AChE reduced to practice in the specification was instant SEQ ID NO:3 (referred to as T14 or NBP-14 in the specification).
There are no examples of treatment or prevention of any skin diseases in the specification.
Taken all these together, the instant specification does not describe a general correlation between structure and function for the claimed genus of cyclic polypeptides derived from the C-terminus of AChE, derivatives, analogues, variants, or fragments thereof, and further having functional utility in treating, preventing, or preventing a skin disease in a vertebrate.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure:
As discussed above, in the instant case, based on the disclosure of instant specification, other than the limited examples, a person of ordinary skilled in the art would not be able to determine what structural feature is required for the claimed cyclic polypeptides derived from C-terminus of AChE and having functional activity in treating, preventing, or ameliorating a skin disease.
Furthermore, the present application is attempting to patent what has not yet been invented and the fact that one of skill in the art can test for the effect used to determine the compounds does not necessarily confer sufficient written description. The claimed cyclic polypeptides would entail testing limitless potential peptides and proteins, and one of skill in the art could afterwards still be faced with no hits with the desired functionality.
In addition, it is well known in the peptide/protein art that even single amino acid changes or differences in the amino acid sequence of a protein can have dramatic effects on the protein’s function. As an example of the unpredictable effects of mutations on protein function, Drumm et al (Annu. Rev. Pathol. Mech. Dis., 2012, 7, pages 267-282) teach cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, for example, page 268, Section “CYSTIC FIBROSIS”. Drumm et al further teach several mutations can cause cystic fibrosis, including two mutations G551D and G551S; and clinical consequences are quite different for these two changes, as the G551D variant has virtually no detectable activity, and consequently a classic, severe phenotype is associated; G551S, however, has reduced but clearly detectable function and is associated with a much milder presentation of CF, for example page 269, left column, the last paragraph. Drumm et al also teach that in the most common cystic fibrosis mutation ΔF508 (the absence of amino acid 508 of the normally 1,480-amino acid protein) gives rise to the cystic fibrosis phenotype, for example, page 268, right column, the 2nd paragraph. Thus, even the substitution or deletion of a single amino acid can have dramatic and unpredictable effects on the function of the protein. The unpredictability of the effect of amino acid substitution on the function and/or property of peptide/protein is further confirmed and discussed in Yampolsky et al (Genetics, 2005, 170, pages 1459-1472). Yampolsky et al teach even conservative substitution can significantly affect the function of the protein/peptide, for example, page 1465, Table 3. Although the disclosures of Drumm et al and Yampolsky et al are directed to proteins/peptides other than the claimed cyclic polypeptides, they illustrate the inherent unpredictability with respect to the biological activity of a given protein/peptide after even minor changes to the primary amino acid sequence.
Therefore, based on the state of art, a person of ordinary skilled in the art would not be able to determine what structural feature is required for the claimed cyclic polypeptides of C-terminus AChE based on limited data from full-length sequence of SEQ ID NO:3 (reduced to functional practice in the examples).
(d) representative number of samples:
And, as discussed in (a) and (b) above, the instant specification discloses sequences of SEQ ID NOs 1-4, with only SEQ ID NO:3 being a cyclic polypeptide of the instant claim scope.
SEQ ID NO:1 is 614 amino acids in length. A polypeptide that has 40% identity “substantially” allows for 368 amino acid changes- substitutions, deletions, additions, or a combination thereof. This equates to 36820 or 2.07x1051 changes for 20 naturally occurring amino acids. The number is much higher when one considers the inclusion of non-naturally occurring amino acids. These numbers are limited to full-length SEQ ID NO:1.
The actual number of cyclic polypeptides of SEQ ID NO:1 is significantly higher when derivatives, analogues, variants, fragments, or truncations – or sequences of the C-terminus [of undefined length] of AChE thereof and 40% identity thereto are taken into consideration.
SEQ ID NO:2 is 30 amino acids in length. A polypeptide that has 40% identity “substantially” allows for 18 amino acid changes- substitutions, deletions, additions, or a combination thereof. This equates to 1820 or 1.27x1025 changes for 20 naturally occurring amino acids. The number is much higher when one considers the inclusion of non-naturally occurring amino acids. Further yet, the actual number of cyclic peptides is significantly higher when derivatives, analogues, variants, fragments, or truncations of SEQ ID NO:2 are considered.
SEQ ID NO:3 is 14 amino acids in length. A polypeptide that has 40% identity “substantially” allows for 8 amino acid changes- substitutions, deletions, additions, or a combination thereof. This equates to 820 or 1.15x1018 changes for 20 naturally occurring amino acids. The number is much higher when one considers the inclusion of non-naturally occurring amino acids. Further yet, the actual number of cyclic peptides is significantly higher when derivatives, analogues, variants, fragments, or truncations of SEQ ID NO:3 are considered.
SEQ ID NO:4 is 15 amino acids in length. A polypeptide that has 40% identity “substantially” allows for 9 amino acid changes- substitutions, deletions, additions, or a combination thereof. This equates to 920 or 1.21x1019 changes for 20 naturally occurring amino acids. The number is much higher when one considers the inclusion of non-naturally occurring amino acids. Further yet, the actual number of cyclic peptides is significantly higher when derivatives, analogues, variants, fragments, or truncations of SEQ ID NO:4 are considered.
Considering the scope of the genus of instant claimed cyclic polypeptides of the C-terminus of AChE, derivatives, analogues, variants, fragments, or truncations thereof, the instant specification fails to provide sufficient examples to describe the entire genus of cyclic polypeptides of the C-terminus of AChE claimed based on limited data.
Taken all these together, considering the state of the art and the disclosure in instant specification, it is deemed that the instant specification fails to provide adequate written description for the claimed genus of cyclic polypeptides; and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claims 1-4 and 6-9 are 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 treating or ameliorating eczema, psoriasis, melanoma, dermatitis, or acne with SEQ ID NO:3, does not reasonably provide enablement for treating other skin diseases, much less preventing any skin disease with other cyclic polypeptides of the C terminus of AChE. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(1) Breadth of claims.
The claims are drawn to a method of treating, preventing or ameliorating a skin disease, the method comprising, administering to a subject in need of such treatment, a therapeutically effective amount of a cyclic polypeptide, derivative or analogue thereof comprising an amino acid sequence derived from the C-terminus of acetylcholinesterase (AChE), or a truncation thereof.
The term “skin disease” is not expressly defined in the specification. The specification states at p. 3, ll. 9-12: “The skin condition which is treated is preferably a skin condition associated with abnormal keratinocyte proliferation. Preferably, the skin condition, which is treated, may be selected from a group consisting of: eczema, psoriasis, melanoma, dermatitis, and acne”. A “subject” may be a vertebrate, mammal, or domestic animal (specification at p. 23, ll. 19).
The specification discloses SEQ ID NO:1 (human AChE), SEQ ID NOs:2 and 4 (linear peptides), and SEQ ID NO:3 (cyclic peptide; referred to as T14 or NBP-14). The boundaries of what Applicant intends as the “C-terminus” of AchE are not expressly defined in the specification. For instance, the specification does not disclose the C-terminus is amino acid positions X-Y of human AChE as taught in SEQ ID NO:1. The specification generally sets forth derivatives, analogues, variants, fragments, and truncations of the C-terminus of AChE. See above written description rejection for details relating to cyclic polypeptides that fall within the instant claim scope.
(2) The nature of the invention and predictability in the art: It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Given this fact, historically the development of new drugs has been difficult and time-consuming. Adding to the unpredictability is that many treatment options may show promise in animal models, but may fail to show therapeutic improvement in clinical trials. There is no absolute predictability, even in view of the high level of skill in the art.
(3) Direction or Guidance: The guidance provided is limited. The specification fails to provide guidance on how a claimed cyclic polypeptide derived from the C- terminus of AChE that can be used to treat/prevent all skin diseases. There are no examples of treatment or prevention of any skin diseases.
The skilled artisan does not have sufficient guidance to extrapolate the limited teachings comprising a single cyclic polypeptide (SEQ ID NO:3), to all iterations of cyclic polypeptides of the C-terminus of AChE and treatment/prevention of all diseases that affect the skin. Additionally, there is no guidance in the specification as to dosage amounts, or dosing schedule that can be used to treat/prevent all skin diseases.
(4) State of the Prior Art:
The following is a selection of references that discussing skin disorders that fall within the instant claim scope.
Melanoma (Merck Manuals melanoma accessed 1/13/2021 at URL merckmanuals.com/professional/ dermatologic-disorders/cancers-of-the-skin) teach that melanoma arises from melanocytes in a pigmented area (e.g., skin, mucous membranes, eyes, or central nervous system). Metastasis is correlated with depth of dermal invasion. With spread, prognosis is poor. Diagnosis is by biopsy. Wide surgical excision is the rule for operable tumors. Metastatic disease requires systemic therapy but is difficult to cure. Melanomas occur mainly on the skin but also on the mucosa of the oral, genital, and rectal regions and conjunctiva. Melanomas may also develop in the choroid layer of the eye, in the leptomeninges (pia or arachnoid mater), and in the nail beds. Melanomas vary in size, shape, and color (usually pigmented) and in their propensity to invade and metastasize. Metastasis occurs via lymphatics and blood vessels. Local metastasis results in the formation of nearby satellite papules or nodules that may or may not be pigmented. Metastasis to skin or internal organs may occur, and, occasionally, metastatic nodules or enlarged lymph nodes are discovered before the primary lesion is identified.
Hypersensitivity and reactive skin disorders (Merck Manual, overview of hypersensitivity and reactive skin disorders, accessed 6/25/2023 at URL merckmanuals.com/home/skin-disorders/hypersensitivity-and-reactive-skin-disorders/overview) teach that the immune system plays a vital role in maintaining the health of all the tissues of the body. Some hypersensitivity reactions are called allergies, especially when they occur after exposure to substances that are usually harmless to most people. Hypersensitivity reactions can involve the skin and cause disorders such as the following: drug rashes, erythema multiforme, erythema nodosum, granuloma annulare, keratosis pilaris, Stevens Johnson syndrome, and toxic epidermal necrolysis. Treatment depends on the cause of the disease/disorder.
Psoriasis and scaling diseases (Merck Manual, introduction to psoriasis and scaling diseases, accessed 6/25/2023 at URL merckmanuals.com/home/skin-disorders/psoriasis-and-scaling-disorders) teach that psoriasis, parapsoriasis, pityriasis rosea, pityriasis rubra pilaris, lichen planus, and lichen sclerosus are different skin disorders that have been grouped together because the bumps, rashes, scales, and skin discoloration they cause have similar characteristics. That is, the rashes and bumps have well-defined borders, and the scales usually do not crust, crack, or weep with fluid.
The claimed skin diseases further encompass genetic skin disorders including but not limited to epidermolysis bullosa, ichthyosis, neurofibromatosis, albinism, epidermal dysplasia thus, tuberous sclerosis, xeroderma pigmentosum, Ehlers-Danos, Marfan syndrome, vitiligo, etc.
Sunlight can also be a causative agent of skin damage leading to sunburn, but also wrinkling and other changes associated with aging, photoaging, actinic keratoses, skin cancers, and even allergic reactions and worsening of some skin diseases (Merck Manual, overview of sunlight and skin damage, accessed 6/25/2022 at URLmerckmanuals.com/home/skin-disorders/sunlight-and-skin-damage).
Hair loss, also called alopecia, can occur on any part of the body. Hair loss that occurs on the scalp is generally called baldness. Hair loss is often of great concern to people for cosmetic reasons, but I can also be a sign of a systemic disorder. Common causes of parallels are alopecia areata, chemotherapy, fungal infections, physical or psychological stress, injury, burns and radiation. Alopecia can also have a genetic component (Merck Manual, alopecia, accessed 6/25/2022 at URL merckmanuals.com/home/skin-disorders/hair-disorders).
Atopic dermatitis (Eczema) is a chronic relapsing inflammatory skin disorder with a complex pathogenesis involving genetic susceptibility, immunologic and epidermal barrier dysfunction, and environmental factors. Pruritus is a primary symptom; skin lesions range from mild erythema to severe lichenification to erythroderma (Merck Manual, Atopic Dermatitis (Eczema), accessed 3/7/2026 at URL merckmanuals.com/professional/dermatologic-disorders/dermatitis/atopic-dermatitis-eczema). Genetic factors, epidermal barrier dysfunction, immunologic mechanisms, and environmental triggers contribute to the development of atopic dermatitis. Genes implicated in atopic dermatitis are those encoding epidermal and immunologic proteins.
(5) Working Examples: Example 1 discloses synthesis of cyclic T14 (also referred to as NBP-14; SEQ ID NO:3). Example 1 discloses linear peptide SEQ ID NO:2 (T15, the last 15 amino acids of instant SEQ ID NO:1), and linear peptide SEQ ID NO:3 (T30).
The specification states at p 30, ll. 19-23: The AChE C-terminal peptide “T14” has been identified as being the salient part of the AChE molecule responsible for its range of non-hydrolytic actions. The synthetic 14 amino acids peptide analogue (i.e. “T14”), and subsequently the larger, more stable, and more potent amino acid sequence in which it is embedded (i.e. “T30”) display actions comparable to those reported for ‘non-cholinergic’ AChE.
Example 2 discloses that T30 induced an increase in intracellular calcium in the keratinocyte cell line HaCaT. T15 did not induce a raise of intracellular calcium. NBP-14 inhibited the effects of T30.
Example 3 assessed the effect of AChE Drive peptides on proliferation of the keratinocyte cell line HaCaT. T30 induced cell proliferation whereas T15 did not alter cell proliferation (Fig 3B). NBP14, T15, and T30 did not show induced significant cytotoxic effects in the cell line (Fig 3A). NBP-14 was not assessed for cell proliferation.
There are no examples of treatment or prevention of any skin diseases in the specification. The only cyclic polypeptide of the C-terminus of AChE reduced to practice in the specification was instant SEQ ID NO:3 (referred to as T14 or NBP-14 in the specification).
(6) Skill of those in the art: MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(7) The quantity of experimentation needed: Owing to the factors listed above, the amount of experimentation needed will be extensive in view of the lack of guidance by the inventor. MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
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.
Claim(s) 1, 3, 4 and 6-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Greenfield et al (U.S. 2017/0368151), and further in view of Paluncic et al (Biochim Biophys Acta 1863:770-784 (2016)).
Greenfield et al teach cyclic polypeptides derived from the C-terminus of acetylcholinesterase for use in treating or preventing cancer or metastatic disease (e.g., abstract, paras. [0004]-[0005], [0027]-[0029], [0033]- [0046]; claims 1, 5-8, 10-14, and 16). Greenfield et al teach administering a therapeutically effective amount a cyclic polypeptide, derivative or analogue thereof that comprises or consists of an amino acid sequence derived from the C-terminus of acetylcholinesterase (AChE), or a truncation thereof (e.g., paras. [0006], [0013]-[0028]; claims 1, 6, 14). A “therapeutically effective amount” of cyclic polypeptide is any amount which, when administered to a subject, is the amount of active agent that is needed to treat the cancer or metastasis, or produce the desired effect (para. [0041]). Greenfield et al teach cancer and malignant tumours form a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body (para. [0002]).
Greenfield et al do not expressly teach that the cancer is melanoma.
Paluncic et al teach that melanoma is responsible for 80% of skin cancer-related deaths worldwide (p. 770). Melanoma originates from neural-crest-derived melanocytes, which are pigment-producing cells located in various anatomic sites, such as the base layer (stratum basale) of the skin's epidermis, the uvea of the eyes, the inner ear, meninges, bones, and heart. Id. The transformation of melanocytes into melanoma cells is a multistep process that begins with the horizontal or radial growth phase, which then progresses toward the invasive phenotype. The development of melanoma from melanocytes occurs via a stepwise mechanism involving clonal succession and acquisition of deleterious genomic alterations. Following the vertical growth phase, the tumor cells invade deeply into the dermis/hypodermis, and eventually penetrate the endothelium of capillaries and enter the blood stream, allowing them to form distant metastases (p. 771). Cancer results from abnormal cellular growth and proliferation, which is uncoordinated with that of the normal tissues around it and is caused by a combination of genetic and epigenetic modifications that lead to neoplastic transformation (p. 772).
It would have been obvious to one of ordinary skill in the art to administer a cyclic polypeptide derived from the C-terminus of AchE to patient with melanoma [reads on skin disease] in order to treat the melanoma. The skilled artisan would have known from Greenfield et al that AChE derived polypeptides can be used to treat cancers and metastatic tumors. Paluncic et al taught that melanoma was a form of skin cancer. The skilled artisan would have recognized that patients with melanoma [skin cancer] were the patient population that Greenfield et al specifically sought to treat. The skilled artisan would have had a reasonable expectation of success in treating such patient given that Greenfield et al disclosed therapeutic amounts and routes of administering a cyclic polypeptide derived from the C-terminus of AchE for treatment of cancer and metastatic tumors (e.g., paras. [0029]-[0045], claim 14).
Accordingly, claims 1 and 3 are rendered obvious.
Regarding claims 4 and 6-8, SEQ ID NOs:1-4 of Greenfield et al have 100% identity with instant SEQ ID NOs:1-4 (e.g., paras. [0013]-[0029], claims 6, 7, 12, 13). Regarding claim 9, Greenfield et al teach that peptides can be prepared using stepwise linear peptide synthesis combined with MALDI-TOF MS (reads on de novo peptide synthesis) (paras [0025], [0081]-[0083]).
Accordingly, claims 1, 3, 4 and 6-9 are rendered obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 4 and 6-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10053677 (hereinafter referred to “the ‘677 patent”) in view of Greenfield et al (U.S. 2017/0368151), and Paluncic et al (Biochim Biophys Acta 1863:770-784 (2016)).
Claim 1 of the ‘677 patent is drawn to a cyclic polypeptide consisting of SEQ ID NO:4. Claim 4 of the ‘677 patent is drawn to pharmaceutical composition comprising the cyclic polypeptide according to claim 1, and a pharmaceutical acceptable vehicle. SEQ ID NO:4 of the ‘677 patent has 100% identity with instant SEQ ID NO:3.
The claims of the ‘677 patent do not teach or suggest a method of treating, preventing or ameliorating a skin disease.
Greenfield et al teach cyclic polypeptides derived from the C-terminus of acetylcholinesterase for use in treating or preventing cancer or metastatic disease (e.g., abstract, paras. [0004]-[0005], [0027]-[0029], [0033]- [0046]; claims 1, 5-8, 10-14, and 16). Greenfield et al teach administering a therapeutically effective amount a cyclic polypeptide, derivative or analogue thereof that comprises or consists of an amino acid sequence derived from the C-terminus of acetylcholinesterase (AChE), or a truncation thereof (e.g., paras. [0006], [0013]-[0028]; claims 1, 6, 14). A “therapeutically effective amount” of cyclic polypeptide is any amount which, when administered to a subject, is the amount of active agent that is needed to treat the cancer or metastasis, or produce the desired effect (para. [0041]). Greenfield et al teach cancer and malignant tumours form a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body (para. [0002]).
The claims of the ‘677 patent and Greenfield et al do not expressly teach melanoma.
Paluncic et al teach that melanoma is one of the most aggressive and treat-resistant human cancers with an overall mortality rate of around 20%. It is responsible for the 80% of skin cancer-related deaths worldwide (p. 770). Melanoma originates from neural-crest-derived melanocytes, which are pigment-producing cells located in various anatomic sites, such as the base layer (stratum basale) of the skin's epidermis, the uvea of the eyes, the inner ear, meninges, bones, and heart. Id. The transformation of melanocytes into melanoma cells is a multistep process that begins with the horizontal or radial growth phase, which then progresses toward the invasive phenotype. The development of melanoma from melanocytes occurs via a stepwise mechanism involving clonal succession and acquisition of deleterious genomic alterations. Following the vertical growth phase, the tumor cells invade deeply into the dermis/hypodermis, and eventually penetrate the endothelium of capillaries and enter the blood stream, allowing them to form distant metastases (p. 771). Cancer results from abnormal cellular growth and proliferation, which is uncoordinated with that of the normal tissues around it and is caused by a combination of genetic and epigenetic modifications that lead to neoplastic transformation (p. 772).
It would have been obvious to one of ordinary skill in the art to administer a cyclic polypeptide derived from the C-terminus of AchE, e.g., cyclic polypeptide of SEQ ID NO:4 of the ‘677 patent to patient with melanoma [reads on skin disease] in order to treat the melanoma. The skilled artisan would have known from Greenfield et al that AChE derived polypeptides can be used to treat cancers and metastatic tumors. Paluncic et al taught that melanoma was a form of skin cancer. SEQ ID NO:4 of the ‘677 patent has 100% identity with SEQ ID NO:3 of Greenfield et al [100% identity with instant SEQ ID NO:3]. The skilled artisan would have recognized that patients with melanoma [skin cancer] were the patient population that Greenfield et al specifically sought to treat. The skilled artisan would have had a reasonable expectation of success in treating such patient given that Greenfield et al disclosed therapeutic amounts and routes of administering a cyclic polypeptide derived from the C-terminus of AchE for treatment of cancer and metastatic tumors (e.g., paras. [0029]-[0045], claim 14).
Accordingly, claims 1 and 3 are rendered obvious.
Regarding claims 4, 6, and 8, SEQ ID NOs:1, 2, 4 of Greenfield et al have 100% identity with instant SEQ ID NOs:1, 2, and 4 (e.g., paras. [0013]-[0029], claims 6, 7, 12, 13).
Regarding claim 9, Greenfield et al teach that peptides can be prepared using stepwise linear peptide synthesis combined with MALDI-TOF MS (reads on de novo peptide synthesis) (paras [0025], [0081]-[0083]).
Accordingly, claims 1, 3, 4 and 6-9 are rendered obvious.
Relevant Art Not Relied Upon
Tao et al (U.S 200/90263370, U.S. equivalent of CN101283956- cited in IDS filed 9/06/2022) teach a method for treating a skin disorder in a mammal by administering cholinesterase or a pharmaceutical composition of cholinesterase (abstract). Cholinesterase is selected from the group consisting of acetylcholinesterase, butyrylcholinesterase, acetylcholinesterase or butyrylcholinesterase isozymes (para [0027]). The composition can be used to treat the skin disorder caused by a microbial infection (claims 14-15).
Tao et al do not expressly teach or suggest an amino acid sequence derived from the C-terminus of acetylcholinesterase (Ache), much less a cyclic polypeptide.
Conclusion
No claims are allowed.
Claims 1-12, 14, 18 and 19 are pending. Claims 8, 10-12, 14, 18 and 19 are withdrawn.
Claims 1-4 and 6-9 are rejected.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654