Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment to the claims filed after non-final office action on June 23, 2025 is acknowledged. Claims 12-13 were amended, claims 7-11, 16 were canceled and claims 1-6, 12-15, 17-20 are pending in the instant application.
The restriction requirement is deemed proper and made FINAL in this office action. Claims 1-6, and 17-20 remain withdrawn as being from further consideration as being drawn to a nonelected invention/species. Claims 12-15 are examined on the merits of this office action.
Withdrawn Rejections
The objection to the specification is withdrawn in view of amendment of the specification filed June 23, 2025.
The objection of claims 7-8 and 13 are withdrawn in view of amendment of the claims filed June 23, 2025.
The rejection of claims 7-9, 11-16 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claims filed June 23, 2025. However, a new rejection under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph follows due to amendment of the claims.
The rejection of claim(s) 7-9 and 11 under 35 U.S.C. 102(a)(1) as being anticipated by Dupuis (US20150098924 A1) is withdrawn in view of amendment of the claims filed June 23, 2025.
Maintained/Revised Rejections
Claim Rejections – 35 USC § 112, first paragraph
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 12-15 are/remain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Scope of the claims
Claim 12 is a “A fusion protein comprising a calmodulin-like skin protein (CLSP) or a CLSP derivative and a polypeptide, wherein the CLSP derivative comprises an endogenous humanin-homogenous region (EHR), and does not comprise a region to which an inhibitor of the CLSP activity binds; wherein the EHR consists of an amino acid sequence (I):TGKNLSEAQLRKLISEVDS(or "G")DGD, shown by residues 40-61 of SEQ ID NO: 1;wherein the polypeptide consists of an amino acid sequence selected from:(1) an amino acid sequence of the collagen-homologous region of adiponectin (ADNCol) shown by SEQ ID NO:2;(2) an amino acid sequence of ADN as shown by SEQ ID NO:3, or an amino acid sequence derived from SEQ ID NO:3 which includes the ADNCol, wherein one to five amino acids are deleted, substituted or inserted in the amino acid sequence other than the ADNCol; or (3) an amino acid sequence derived from SEQ ID NO:3, which includes the ADNCol, wherein an amino acid sequence other than the ADNCol has an identity of 90% or more to an amino acid sequence other than the ADNCol in SEQ ID NO:3; and wherein the CLSP derivative is a polypeptide consisting of an amino acid sequence selected from:(4) an amino acid sequence consisting of amino acids 1-61 of CLSP;(5) an amino acid sequence derived from (4), wherein one to five amino acids are deleted, substituted or inserted in the amino acid sequence of (4) other than the EHR included in (4); or (6) an amino acid sequence derived from (4), which has an identity of 90% or more to the amino acid sequence of (4) other than EHR included in (4).”
Thus, claim 12 is drawn to a fusion protein comprising CLSP derivative that comprises HER; the HER is consisting of 40-61 of SEQ ID NO:1 (which is CLSP), a second fusion partner selected from SEQ ID NO:2 (ADNCol); SEQ ID NO:3 (full length) or derivatives of SEQ ID NO:3 that include ADNCol and permit up to 5 substitutions, deletions, insertions outside the ADNCol, or variants having at least 90% sequence identity. Thus, the scope of the claim extends beyond the single EHR fragment to a genus of potential CLSP derivatives and multiple adiponectin based fusion partners including broad sequence variants.
In addition, “suppression” and “inhibition” on Alzheimer’s disease-related neuronal cell dysfunction or neuronal cell death have the same meaning about such CLSP activity. Furthermore, “protect,” “keep” and "retain" have the same meaning about the activity of the potentiator or protector of the present invention. However, specific guidance is not provided as to which sequence amino acids should be excluded for the CLSP peptides. Furthermore, Applicants do not sufficiently described peptides having at least 90% sequence identity to SEQ ID NO:3 that would retain the desired properties of suppressing Alzheimer’s disease related neuronal dysfunction or a potentiator/protector of the CLSP activity by CLSP.
Therefore, to meet the written description requirement of 35 U.S.C. § 112, first paragraph, the specification must disclose a representative number of species that meet both the structural and functional limitations of the genus or the specification and/or the prior art must identify the structural elements that correlate to the claimed function in a manner that demonstrates to one of ordinary skill in the art that Applicant was in possession of the claimed genus at the time the application was filed. In the instant case, the specification must establish which peptides having at least 90% sequence identity to SEQ ID NO:3 and CLSP derivatives encompassed by the claims satisfy the structural limitations of the claim and are also able to treat Alzheimer’s disease related neuronal cell dysfunction, diseases accompanied by Alzheimer’s disease related memory impairment and neurodegeneration.
Actual Reduction to Practice
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses that ADNCol can bind to the N-terminal region of CLSP (amino acids 1-61)(paragraph 0087, figure 4C). Applicants present data showing potentiation of CLSP activity by adiponectin and suggest that CLSP1-61/ADNCol fusion protein has CLSP activity and crosses the BBB (see paragraphs 0093-0095). However, no actual construct is disclosed or shown to have been expressed, purified or functionally tested. There is no working example of a fusion protein comprising only HER, no construct with full adiponectin (SEQ ID NO:3) and no construct with the claimed SEQ ID NO:3 variants. At best, the disclosure amounts to prophetic description of one possible construct (CLSP1-61 fused to ADNCol). One of ordinary skill in the art would not view this as representative of the claimed genus.
Applicants specification states “The “activity to suppress Alzheimer's disease-related neuronal cell dysfunction or cell death” in the present invention indicates the suppression or antagonization of at least one of neuronal cell dysfunction or cell death regardless of their causes or causal relationships. The suppression of neuronal cell death may be not full suppression but rather significant suppression. The neuronal cell death-suppressing activity can be evaluated in accordance with methods described in Examples below or methods described in other documents (¢.g., see International Patent Number WO00/14204)}. The CLSP activity can be measured, for example, as the V6421-APP-induced neuronal cell death-suppressing activity using various neuronal cell death assays” (See paragraph 0031). Applicants found that CLSP bound to ADNCol (See Figure 4C, paragraph 0093). Applicants disclose a fusion peptide consisting of CLSP1-61 and ADNCol (see paragraph 0094, referred to as CLSPCOL), it passes through blood brain barrier and have CLSP activity (see paragraph 0094-0095).
Applicant’s conclude “As described by the present invention, however, if adiponectin potentiates the CLSP activity and protects CLASP from CLSP inhibitors in a dominant fashion by binding to the endogenous humanin-homogeneous region (EHR) of CLSP (Figs. 5 to 7), the in vivo CLSP activity is guaranteed even in the presence of higher concentrations of the CLSP inhibiting substances. Even in the presence of much higher concentrations of CLSP inhibitors, 0.2-0.25 nM adiponectin can completely keep the CLSP Go nM) activity (Figs. 5 and 7). In the case of non-AD, the concentration of adiponectin in the CSF is 6.96 + 0.19 nM (Fig. 10 and Table 1), and consequently the CLSP activity is likely kept” (See paragraph 0100).
One of ordinary skill in the art would not consider reduction to practice of only ADNCol and CLSP1-61 sufficient without any guidance with respect to variants that could be made to be representative of the full scope of the claimed genus of peptides.
Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
Sufficient relevant identifying characteristic
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination thereof.
Applicants identify the EHR region as amino acids 40-61 of SEQ ID NO:1. Regarding CLSP derivative, the derivative is left open ended. There is no disclosure of which additional residues beyond EHR are necessary or sufficient for activity. It is therefore unclear what sequences qualify as “derivative”. Regarding Adiponectin partner, SEQ ID Nos:2-3 are disclosed, but the claims include SEQ ID NO:3 variants with substitutions deletions or insertions. The application provides not representative examples or structural rules that would allow one to predict which of these variants retain activity. The disclosure of a single fragment (CLSP1-61) plus ADNCol is insufficient to represent the full breadth of the CLSP derivatives fused to adiponectin or its numerous possible variants.
Physical and/or chemical properties:
The data presented in the specification do not suggest the physical basis for the claimed activity (CLSP activity for treating Alzheimer’s disease related dysfunction) and therefore do not describe which substitutions, deletions or additions could be made while preserving function of SEQ ID NO:3 and CLSP. Understanding the physical basis for the claimed activity is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
Applicants assert that the fusion protein has “CLSP activity” and can cross the BBB (see paragraph 0094), but no experimental characterization of the physical or chemical properties of the claimed fusions is provided. There is not data on stability, solubility, folding, half-life, or binding affinity that would distinguish the claimed constructs or demonstrate possession of the full genus as claimed.
Functional characteristics when coupled with a known or disclosed correlation between function and structure:
The specification does not describe a general correlation between structure and function for the claimed genus. The role of the specific amino acids of SEQ ID NO:3 and CLSP on CLSP activity for treating Alzheimer’s disease related dysfunction is not sufficiently described.
As a result, it is impossible to predict, based on the specification or the prior art, how changing any amino acid position will affect the ability of the instant peptides encompassed by the claims to promote CLSP activity and treating Alzheimer’s disease related dysfunctions.
The application states that the fusion proteins are expected to potentiate CLSP activity and suppress neuronal cell death (see paragraphs 0031, 0087-0100). However, these statements are intended functional properties without supporting data. No assays or results are presented for the EHR alone or for full length adiponectin fusions. There is no data showing that derivatives of SEQ ID NO:3 with mutations retain the desired activity. Applicants do not establish a reliable structure-function relationship across the scope of the claim. Possession of the genus cannot be inferred from one untested construct and speculative assertions of activity.
Method of Making
Applicants disclose ADNCol (SEQ ID NO:2, 60mer) and CLSP (amino acids 1-61 of CLSP).
Where the specification fails to provide description is in the structure of the peptides having 90% sequence identity to SEQ ID Nos:3 and CLSP derivatives. For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless proteins that meet the structural requirements of the claims would also be able to promote CLSP activity and treating Alzheimer’s disease related dysfunctions. Thus, it is not possible for one of ordinary skill in the art to distinguish based on sequence alone which sequences having at least 90% sequence identity to SEQ ID NOs:3 and CLSP derivatives encompassed by the claim will have the required functional properties as claimed.
Conclusion
In conclusion, only ADNCol (SEQ ID NO:2) and CLSP1-61 satisfies the written description requirements of 35 U.S.C. 112, first paragraph. Claim 12 encompasses a broad genus of fusion proteins that include open-ended CLSP derivatives, narrowly defined EHR fragments, full length adiponectin, and adiponectin variants. Applicants have not provided sufficient representative species, structural characterization, or functional data to demonstrate possession of this genus.
Response to Applicant’s Arguments
Applicants argue that amended claim 12 recites CLSP derivative lacking the C-terminal region (amino acids 62-146 of SEQ ID NO:1) but including the EHR (amino acids 40-61). They assert this construct is supported by the specification since ADNCol is bound to the N-terminal CLSP fragment and therefor ethe claimed invention is properly described.
Applicants arguments have been fully described but not found persuasive. While the specification discloses binding between adiponectin and CLSP1-61, Applicants do not provide support for the broader genus encompassed by amended claim 12. The disclosure identifies only one putative construct-CLPS61 fused to ADNCol. The claim, however, covers any CLSP derivative containing the EHR, which could encompass sequences outside of 1-61 and variants beyond those expressly disclosed. The absence of representative examples or structural descriptions beyond CLSP1-61 fails to demonstrate possession of the entire clamed genus of CLSP derivatives.
Applicants argue that the ADN derivatives in claim 12 encompass full length adiponectin sequence (SEQ ID NO:3) or variants thereof, and that the “variations in the ADN derivatives are in non-essential portions”, i.e. outside of the ADNCol, such that the function is maintained.
Applicants arguments have been fully described but not found persuasive. Applicants have not provided written description support for SEQ ID NO:3 derivatives with up to five amino acid insertions, deletions or substitutions outside ADNCol, or for variants with greater than or equal to 90% identity. No representative species are disclosed, nor is there guidance explaining which modification are tolerated without disrupting function. As the possibilities for sequence variation are vast, possession of this scope cannot be inferred from the single untested disclosure of ADNCol binding to CLSP1-61. Mere assertions that changes occur in “non-essential portions” are conclusory and not supported by experimental data or structural analysis.
Applicants argue that the structural features of CLSP and ADN derivatives essential for function are recited in the claims (EHR and ADNCol, respectively) and therefore the claims are supported by the disclosure.
Applicants arguments have been fully described but not found persuasive. The mere recitation of functional features in the claims does not establish written description support. MPEP 2163 requires adequate description of a representative number of species or structural features that demonstrate possession of the genus. Here, the specification identifies only one specific construct (CLSP1-61 fused to ADNCol) with no evidence of broader species, no correlation between structure and function for the claimed variants, and no actual demonstration that EHR alone or SEQ ID NO:3 fusions retain the asserted activity. Accordingly, the disclosure does not reasonably convey possession of the entire genus recited in claim 12.
In conclusion, the specification provides, at most, a single putative sequence. The broad clam language of amended claim 12 extends to CLSP derivatives containing EHR and to full adiponectin or variants thereof. Applicants have not provided sufficient representative species, experimental data, or structure-function correlations to establish possession of this broad genus at the time of filing. Therefore, the 112(a) written description rejection is maintained.
New Rejection
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 12-15 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 12 recites a “CLSP derivative” that comprises an endogenous humanin homologous region (EHR), wherein the EHR consists of residues 40-61 of SEQ ID NO:1. The use of “consists of” in defining the EHR limits the element to a closed set of residues. However, the “CLSP derivative” is recited in open language, which leaves ambiguity as to the actual scope of the claimed construct. It is unclear whether the claimed invention requires only the defined EHR (residues 40-61) or whether broader fragments of CLSP that contain the EHR (examples residues 1-61, or residues 1-146 with the EHR embedded) are encompassed with the scope of the claim. This internal inconsistency is compound by Applicant’s arguments, which assert that the CLSP derivative lacks the C-terminal region (amino acids 62-146 of SEQ ID NO:1) but nevertheless includes resides 1-61. The specification, however does not clearly define “CLSP derivative” in this manner and it is unclear whether claim is limited to residues 40-61, 1-61 or potentially other constructs. Accordingly, the metes and bound of claim 12 cannot be reasonably ascertained. One of ordinary skill in the art would not understand with reasonable certainty whether the claim is limited to the EHR alone, or whether it encompasses larger CLSP derivatives containing additional residues.
Furthermore, claim 12 claims EHR as “residues 40-61 of SEQ ID NO:1” but then recites 58 as “S (OR G)”. SEQ ID NO:1 shows serine at this position and does not disclose glycine as an alternative. The contradictory wording renders it unclear whether the claimed EHR is strictly the sequence of SEQ ID NO:1, or whether Applicants intend to claim an additional sequence variant not present in SEQ ID NO:1. The scope of the claimed sequence therefore cannot be determined with reasonable certainty.
Further, claim 12 recites “…the polypeptide consists of an amino acid sequence selected from….(2) an amino acid sequence of ADN as show in SEQ ID NO:3 or an amino acid sequence derived from SEQ ID NO:3 which includes (means comprising) the ADNCol…..” The limitation begins with a closed transitional phrase “consists of” but later recites the polypeptide may be “Derived from SEQ ID NO:3 which includes/comprises ADNCol”. The use of comprises contradicts the closed nature of “consists of” and creates ambiguity as to the exact scope of the polypeptide. This also seen in “(3)”, the use of closed transitional language followed by open language.
Claims 13-15 are also rejected due to their dependence on claim 12 and not further clarifying these points of confusion.
New Objection
Claim 12 is objected to for the following informality: in the last line of the claim, Applicant should remove the duplicate “more” after “90% or…”.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/ Examiner, Art Unit 1654
/JULIE HA/Primary Examiner, Art Unit 1654