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 .
Response to Amendment
The Amendment filed 08/11/2025 in which claims 26, 33-36, 38, 41 were amended, new claims 48-58 were added, and claims 27-29, 42-43, 45-47 were canceled, has been entered. Claims 1-25 were previously canceled.
Newly submitted claims 49-54 are directed to inventions that are independent or distinct from the invention originally elected in the response to the Restriction Requirement filed on 10/11/2021 for the following reasons:
Claims 49, 50 are directed to a method of producing antibodies (Group C, in the Restriction Requirement mailed on 08/12/2021)
Claims 51-54 are directed to a method of inhibiting a-Syn aggregation or reducing the amount of a-Syn aggregates in a subject (Group D, in the Restriction Requirement mailed on 08/12/2021)
Further, newly submitted claims 55-58, directed to a method of treating a synucleinopathy, are also independent or distinct from the invention originally elected in the response to the Restriction Requirement filed on 10/11/2021, i.e., an alpha-synuclein peptide, for the same reasons set forth in the Restriction Requirement mailed on 08/12/2021. The elected invention, i.e., an alpha-synuclein peptide, has already been examined on the merits.
Accordingly, claims 49-58 are withdrawn from consideration as being directed to non-elected inventions.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 26, 30-41, 44, and 48 are under examination on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 08/11/2025 after the mailing date of the nonfinal rejection on 02/11/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
(Previous objection, withdrawn) Applicant’s amendments to the Drawings submitted on 08/11/2025 have overcome the objection previously set forth in the Non-Final Office Action mailed 02/11/2025.
Specification
(Previous objection, withdrawn) Applicant’s amendments to the Specification submitted on 08/11/2025 have overcome the objection previously set forth in the Non-Final Office Action mailed on 02/11/2025.
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 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.
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.
(Previous rejection, withdrawn as to claims 27-29 and 46, maintained and modified as necessitated by amendment as to claims 26, 30-34, 39-41) Claims 26, 30-34, 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Wang, in view of Ugen, and further in view Wang & Walfield (prior art of record).
The previous rejections of claims 27-29 and 46 are moot in view of Applicant’s cancelation of these claims.
See claims 26, 30-34, 39-41 as submitted on 08/11/2025.
Regarding claim 26, it is noted that amended claim 26 reads the new recitations of “of SEQ ID NO: 15” on line 3, and “of SEQ ID NO: 83” on line 5. However, as previously explained, those limitations are already taught by the cited prior art of record. Specifically, Wang teaches a construct design or platform in which an Aβ peptide immunogen comprising the N-terminus of the Aβ peptide acts as the B cell epitope and it is covalently linked through spacer residues to a heterologous T helper cell (Th) epitope derived from pathogen proteins that act together to stimulate the generation of highly specific antibodies directed against the N-terminus of the Aβ peptide offering protective immune responses to patients at risk for, or with, Alzheimer's Disease (Abstract).
The construct design or platform taught by Wang incorporates three components into one construct for the benefit of generating a synthetic peptide-based immunotherapeutic and/or vaccine. The three components as taught by Wang are:
a target epitope which acts as a B cell epitope comprising the amino acid sequence of a targeted molecule defined by epitope mapping for functional antigenicity (Abstract; col 5, ¶ 4).
a T helper cell epitope comprising of the amino acid sequence derived from pathogen proteins that act together to stimulate the generation of highly specific antibodies (Abstract; col 12, ¶ 1). Th cell epitopes include Measles Virus Fusion (MVF) protein and HBsAg3 (col 4, ¶ 1). Note that Wang & Walfield refer to the T helper cell epitope as UBITh®. One example of a Th cell epitope taught by Wang is set forth in SEQ ID NO:46 which shared 100% sequence identity to instant SEQ ID NO: 83 (col 62, Table 2) (see alignment of record).
a heterologous spacer comprising a linker chosen from the group: Lys-, Gly-, Lys-Lys-Lys-, (α, ε-N)Lys, or ε-N-Lys-Lys-Lys-Lys (Abstract; 17, ¶ 2), wherein the heterologous spacer covalently links the B cell epitope to the T helper cell epitope (Abstract; col 12, ¶ 1). It is noted that instant SEQ ID NO: 148 (KKKK) shares 100% sequence identify with SEQ ID NO: 32 (KKKK) in Wang’s teachings (col 59, Table 1).
Wang does not explicitly teach the alpha-synuclein protein as the B cell epitope comprising the amino acid sequence of SEQ ID NO: 15.
However, as previously explained, Ugen teaches human α-synuclein (α-Syn) 3 peptides synthesized based upon predicted B cell epitopes within the full length α-Syn protein sequence for the purpose of developing a vaccine against Parkinson’s disease (PD) (Abstract). Ugen further teaches peptide fragments comprising amino acids 111-139 of the α-Syn 3 protein as the target sequences or epitopes (page 923). One such peptide termed “Peptide Fragment C” (MPVDPDNEAYEMPSEEGYQDY) comprises a sequence that shares 100% sequence identity with instant SEQ ID NO: 15 (see alignment of record - Peptide Fragment C with instant SEQ ID NO: 15). Further Ugen teaches an effective humoral immune response upon stimulation with Peptide Fragment B and Peptide Fragment C (page 923-924).
It would have been prima facie obvious to a person of ordinary skill in the art, at the time of filing, to have included the teachings of Ugen on the α-Syn 3 peptides to act as the B cell epitopes in the construct design or platform taught by Wang for the benefit of generating a synthetic peptide-based immunotherapeutic and/or vaccine against PD given that Ugen demonstrated effective antibody response against such α-Syn 3 peptides and Wang & Walfield teach that the construct design or platform taught by Wang, which is also described by Wang & Walfield, can be applied to the development of therapeutic and protective vaccines for multiple conditions including chronic and infectious diseases (Wang & Walfield, Abstract, page 1, 7).
One of ordinary skill in the art would have had a reasonable expectation of success for introducing the α-Syn peptides into the construct comprising a Th cell epitope and a heterologous spacer sequence as taught by Wang given that the methods of vector cloning and peptide expression are known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Regarding claims 30 and 31, it is noted that no amendments were introduced to claims 30 and 31 in the amendment filed on 08/11/2025. As previously explained, Wang already teaches a ε-N-Lys spacer sequence as well as an ε-N-Lys-Lys-Lys-Lys spacer sequence (Abstract; 17, ¶ 2), SEQ ID NO: 32 (KKKK) in Wang’s teachings (col 59, Table 1) has 100% sequence identity to instant SEQ ID NO: 148 (KKKK).
Regarding claim 32, it is noted that no amendments were introduced to claim 32 in the amendment filed on 08/11/2025. As previously explained, Wang teaches wherein the heterologous spacer covalently links the B cell epitope to the T helper cell epitope (Abstract; col 12, ¶ 1).
Regarding claim 33, it is noted that based on the amendments filed on 08/11/2025, claim 33 now reads as an independent claim and it no longer depends on claim 26. However, all of the limitations of claim 33 are already taught by the cited prior art. As previously explained, Wang and Ugen teach all three components of the construct as recited in claim 26: a) the α-Syn as the B cell epitope, b) the Th cell epitope, and c) a spacer which covalently links the B cell epitope to the Th cell epitope. Therefore, the construct of Wang in view of Ugen comprises one or both formulas as recited in claim 33. Further, Wang recites the same formula on col. 17, ¶ 1 ((peptide)-(A)0 -(Th)-X) for a different target peptide. Further, the T helper epitope of SEQ ID NO: 83 is already taught by Wang (see alignment of record). Further, it is noted that Wang also teaches the heterologous spacer of SEQ ID NO: 148 (see above) and Ugen teaches the α-Syn epitope of SEQ ID NO: 15 (see alignment of record). Further, Wang already teaches wherein the heterologous spacer covalently links the B cell epitope to the T helper cell epitope (Abstract; col 12, ¶ 1). Accordingly, the teachings of Wang, Ugen, and Wang & Walfield combined meet the limitations of claim 33.
It would have been prima facie obvious to a person of ordinary skill in the art, at the time of filing, to have included the teachings of Ugen on the α-Syn 3 peptides to act as the B cell epitopes in the construct design or platform taught by Wang for the benefit of generating a synthetic peptide-based immunotherapeutic and/or vaccine against PD given that Ugen demonstrated effective antibody response against such α-Syn 3 peptides and Wang & Walfield teach that the construct design or platform taught by Wang, which is also described by Wang & Walfield, can be applied to the development of therapeutic and protective vaccines for multiple conditions including chronic and infectious diseases (Wang & Walfield, Abstract, page 1, 7).
One of ordinary skill in the art would have had a reasonable expectation of success for introducing the α-Syn peptides into the construct comprising a Th cell epitope and a heterologous spacer sequence as taught by Wang given that the methods of vector cloning and peptide expression are known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Regarding claim 34, as indicated above the α-Syn epitope of SEQ ID NO: 15 was taught by Ugen and all other components of the construct which are formulated as indicated by the formulas of claim 33 are taught by Wang. It is noted that Wang also teaches the heterologous spacer of SEQ ID NO: 148 (see above). Therefore, the limitations of claim 34 are met by the teachings of Wang, Ugen, and Wang & Walfield.
Regarding claim 39, it is noted that no amendments were introduced to claim 39 in the amendment filed on 08/11/2025. As previously explained, Wang further teaches a pharmaceutical composition comprising the construct as recited in claim 26 and further comprising a pharmaceutically acceptable delivery vehicle and/or adjuvant (Abstract; claims 3, 4; col 18, ¶ 5).
Regarding claim 40, it is noted that no amendments were introduced to claim 40 in the amendment filed on 08/11/2025. As previously explained, Wang further teaches a pharmaceutical composition comprising an CpG oligodeoxynucleotide (ODN) to form a stabilized immunostimulatory complex (col 21, ¶ 4).
Regarding claims 41, it is noted that amended claim 41 reads the new recitations of “the pharmaceutically acceptable delivery vehicle and/or adjuvant…”. However, as previously explained, that limitation is already taught by the cited prior art. Specifically, Wang teaches a pharmaceutical composition wherein the adjuvant is ADJUPHOS® or Aluminum phosphate (AlPO4) (col 22, ¶ 2).
The rejection is maintained for reasons of record.
(Previous rejection, withdrawn as to claims 42 and 47, maintained and modified as necessitated by amendment as to claims 35-37 and 44, expanded as necessitated by amendment as to claims 38 and 48) Claims 35-38, 44, 48 are rejected under 35 U.S.C. 103 as being unpatentable over Wang, in view of Ugen, and Wang & Walfield, as applied to claims 26, 30-34, 39-41 above, and further in view of Ingelsson (prior art of record).
The previous rejections of claims 42 and 47 are moot in view of Applicant’s cancelation of these claims.
See claims 35-38, 44 and 48 as submitted on 12/30/2024.
Regarding claims 35 and 36, it is noted that the amendments to claim 35 and 36 introduced in the amendment filed on 08/11/2025 recite “SEQ ID NOs: 112 and 118” and “comprising the amino acid sequence of SEQ ID NO: 112”, respectively. However, these limitations are already taught by the cited prior art. As previously explained and indicated above, SEQ ID NO: 112 comprises the following sequences: SEQ ID NO: 83 - SEQ ID NO: 148 - SEQ ID NO: 15. Wang, Ugen, and Wang & Walfield teach a construct with the following features:
a Th cell epitope of the sequence set forth in SEQ ID NO: 83 (ISITEIKGVIVHRIETILF); Wang, SEQ ID NO:46 (col 62, Table 2). See alignment above.
the spacer sequence of SEQ ID NO: 148 (KKKK). See SEQ ID NO: 32 (KKKK) in Wang’s teachings (col 59, Table 1) has 100% sequence identity to instant SEQ ID NO: 148 (KKKK).
an α-Syn epitope comprising the sequence of SEQ ID NO: 15 EMPSEEGYQD; Ugen, Peptide Fragment C, (page 923). See alignment above.
While, Ugen’s Peptide Fragment C comprises the sequence of SEQ ID NO: 15, neither Wang, nor Ugen, nor Wang & Walfield explicitly teach an α-Syn epitope including amino acids 126-135 (EMPSEEGYQD) of the α-Syn protein as set forth in SEQ ID NO: 15.
However, Igelsson teaches a fragment of the α-Syn protein consisting of amino acids 126-135 (EMPSEEGYQD) as identified by immunohistochemistry studies of Lewy bodies present in brain stem and neocortex sections of patients with Parkinson’s disease (PD) (page 1, Figure 1).
It would have been prima facie obvious to a person of ordinary skill in the art, at the time of filing, to have included the teachings of Ingelsson on the α-Syn peptide (amino acids 126-135) to act as the B cell epitope in the construct design or platform taught by Wang for the benefit of generating a synthetic peptide-based immunotherapeutic and/or vaccine against PD given that Ingelsson demonstrated the presence of this fragment in PD pathology and Wang & Walfield teach that the construct design or platform taught by Wang can be applied to the development of therapeutic and protective vaccines for multiple conditions including chronic and infectious diseases.
One of ordinary skill in the art would have had a reasonable expectation of success for introducing the α-Syn fragment (amino acids 126-135) into the construct comprising a Th cell epitope and a heterologous spacer sequence as taught by Wang given that the methods of vector cloning and peptide expression are known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Accordingly, the sequence taught by Wang, Ugen, Wang & Walfield, and Ingelsson combined shares 100% sequence identity with instant SEQ ID NO: 112 which is 33 amino acid long, as outlined below:
a Th cell epitope of the sequence set forth in SEQ ID NO: 83 (amino acids 1-19 of SEQ ID NO: 112) (ISITEIKGVIVHRIETILF); taught by Wang, SEQ ID NO:46 (col 62, Table 2). See alignment above.
a spacer sequence of SEQ ID NO: 148 (KKKK) (amino acids 20-23 of SEQ ID NO: 112). Taught by Wang’s SEQ ID NO: 32 (KKKK) (col 59, Table 1) which has 100% sequence identity to instant SEQ ID NO: 148 (KKKK).
an α-Syn epitope comprising amino acids 126-135 (EMPSEEGYQD) of the α-Syn protein of SEQ ID NO: 15 (amino acids 24-33 of SEQ ID NO: 112), taught by Ingelsson (page 1, Figure 1).
Therefore, the teachings of Wang, Ugen, Wang & Walfield, and Ingelsson combined meet the limitations of claims 35 and 36.
Regarding claim 37, it is noted that instant Specification does not provide a clear indication of what the basic and novel characteristics actually are as to SEQ ID NO:112, therefore, “consisting essentially of” will be construed as equivalent to “comprising.” See MPEP 2111.03. For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, “consisting essentially of” will be construed as equivalent to “comprising.” See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 (“PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention.”)
Accordingly, as indicated above, the construct taught by Wang in view of Ugen, Wang and Walfield, and Ingelsson comprises the sequences outlined above and therefore shares 100% sequence identity with SEQ ID NO: 112.
Regarding claim 38, as indicated above, the sequence taught by Wang, Ugen, Wang & Walfield, and Ingelsson combined shares 100% sequence identity with instant SEQ ID NO: 112 which is 33 amino acid long, as outlined above. It is noted that the combination of the sequences taught by Wang and Ingleson as outlined above consist of the sequence of SEQ ID NO: 112. It is further noted that the sequences taught by Wang and Ingleson consists of the exact regions as outlined above. Accordingly, the construct taught by Wang in view of Ugen, Wang and Walfield, and Ingelsson consists of the sequences outlined above which shares 100% sequence identity with SEQ ID NO: 112.
Regarding claim 44, Wang further teaches a pharmaceutical composition of claim 41 comprising the construct of claim 26 and set forth in SEQ ID NO: 112 which, as explained above, was rendered obvious by the teachings of Wang, Ugen, Wang & Walfield, and Ingelsson.
Regarding claims 48, Wang further teaches a pharmaceutical composition of claim 40 as indicated above which comprises the construct of claim 26 and set forth in SEQ ID NO: 112 which, as explained above, was rendered obvious by the teachings of Wang, Ugen, Wang & Walfield, and Ingelsson. Wang teaches a pharmaceutical composition wherein the adjuvant is ADJUPHOS® or Aluminum phosphate (AlPO4) (col 22, ¶ 2).
The rejection is maintained for reasons of record.
(Previous rejection, withdrawn as to claims 35, 36, 38, 42, 43, 45 and 47) Claims 35, 36, 38, 42, 43, 45 and 47 were rejected under 35 U.S.C. 103 as being unpatentable over Wang, in view of Ugen, Wang & Walfield, and Ingelsson as applied to claims 26-34, 39-42, 44, 46, 47 above, and further in view of Gentile A et al. (prior art of record).
See claim 35, 36, 38, 42, 43, 45 and 47 as submitted on 08/11/2025.
The previous rejections of claims 42, 43, 45 and 47 are moot in view of Applicant’s cancelation of these claims.
Applicant’s amendment to claims 35, 36, and 38 have overcome previous rejection to these claims.
Response to Arguments
Applicant's arguments filed 08/11/2025 have been fully considered but they are not persuasive.
Applicant contends on page 11 of the Remarks submitted on 08/11/2025: First, we address the rejection over the combination of Wang, Wang & Walfield and Ugen. As discussed in the response filed December 30, 2024 and as acknowledged in the Office Action, Wang does not teach, suggest or mention any alpha-synuclein peptide immunogen constructs or any alpha-synuclein B cell epitopes. Wang certainly does not teach or suggest the alpha-synuclein B cell epitope of SEQ ID NO: 15 or inform the selection of alpha-synuclein B cell epitope of SEQ ID NO: 15. Wang & Walfield has the same deficiencies as Wang, and thus cannot rectify the deficiencies of Wang. Further, Ugen discloses a cell-based vaccination approach, which is very different from the peptide-based vaccination approach of Applicant's claims. Ugen discloses use of its peptide fragments, including the above-referenced Peptide Fragment C, to sensitize mouse bone- marrow-derived dendritic cells ex vivo, followed by the administration of such sensitized dendritic cell-based vaccines (and not any peptides) to subjects (see, e.g., Ugen at para. spanning p. 927, righ col. and p. 928, left column). Contrary to the statement in the Office Action, Ugen certainly does not teach or suggest, or show effective antibody response upon administration of its alpha-synuclein peptides to subjects, much less fusing its alpha-synuclein peptides to any T helper cell epitopes to arrive at the constructs of the amended claims. On top of that, as acknowledged by the Office, even Peptide Fragment C of alpha-synuclein, used in Ugen for sensitization of dendritic cells ex vivo, comprises but is not identical to the B cell epitope of SEQ ID NO: 15. Importantly, due to different mechanisms of action, the selection of peptides for use in ex vivo sensitization of cell-based vaccines of Ugen does not inform the selection of B cell epitopes for designing peptide-based vaccines of Applicant's claims, as, in particular, the two approaches may require different alpha- synuclein peptide fragments. That is, it is not known based on the disclosure of alpha-synuclein peptides in Ugen, in combination with the disclosure of general construct design (such Th epitopes and spacers) in Wang and Wang & Walfield, whether effective immunity against alpha-synuclein can actually be achieved using the claimed peptide immunogen constructs (having the B cell epitope of SEQ ID NO: 15 and the T helper cell epitope of SEQ ID NO: 83), much less with a reasonable expectation of success.
In response: In response to Applicant's arguments against the references individually, for example Applicant’s remark on page 11 that Wang and Wang & Walfield do not teach, suggest or mention any alpha-synuclein peptide immunogen constructs or any alpha-synuclein B cell epitopes and Applicant’s remark on page 12 that Ugen discloses yet another vaccination approach, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Ugen was cited for teaching alpha-synuclein epitopes as indicated above, while Wang was cited for teaching the construct design comprising a B cell epitope, a spacer and T helper cell epitope. Wang & Walfield teach that the construct design or platform taught by Wang, which is also described by Wang & Walfield, can be applied to the development of therapeutic and protective vaccines for multiple conditions including chronic and infectious diseases (Wang & Walfield, Abstract, pages 1, 7).
Further, in response to Applicant’s argument that it is not known whether effective immunity against alpha-synuclein can actually be achieved using the claimed peptide immunogen constructs (having the B cell epitope of SEQ ID NO: 15 and the T helper cell epitope of SEQ ID NO: 83), much less with a reasonable expectation of success, this argument is not persuasive because as indicated previously, Ugen already demonstrated effective humoral immune response (antibody production) upon stimulation with a peptide fragment B and peptide fragment C (instant SEQ ID NO: 15) (“Epitope mapping of the anti-sera generated from the vaccinated animals revealed that
antibodies produced…”, see pages 923-924).
Further, Igelsson teaches a fragment of the α-Syn protein consisting of amino acids 126-135 (EMPSEEGYQD) as identified by immunohistochemistry studies of Lewy bodies present in brain stem and neocortex sections of patients with Parkinson’s disease (PD) (page 1, Figure 1). Therefore, on the contrary, the precise sequence of the α-Syn peptide (amino acids 126-135) was well recognized in the art as a B cell epitope capable of stimulating an antibody response. Hence, the prior art provides clear teachings, suggestions and motivation to combine all elements of the claimed invention into a single construct, as recited in instant claims. Accordingly, the claimed construct represents an obvious embodiment of the teachings of the cited prior art. See MPEP 2144.07. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
Applicant contends on page 12 of the Remarks submitted on 08/11/2025: Second, we address the rejection over the combination of Wang, Wang & Walfield, Ugen and Ingelsson. In addition to the references discussed above, this rejection relies on Ingelsson. Ingelsson is a review article discussing that alpha-synuclein has neurotoxic properties and represents an appropriate molecular target for therapeutic intervention in Parkinson's disease. See, e.g., Abstract. Regarding the disclosure of "a-synuclein amino acids 126-135" in the legend of Figure 1 of Ingelsson, it merely states that the figure shows "Lewy bodies and Lewy neuritis [...] in a substantia nigra from a PD patient, stained with a polyclonal antibody directed against a-synuclein amino acids 126-135." This means that a polyclonal antibody generated against a-synuclein amino acids 126-135 was able to immunologically detect alpha-synuclein in Lewy bodies and Lewy neurites in the brain tissues of a patient with Parkinson's disease. Thus, Ingelsson discloses the use of polyclonal antibodies targeting a-synuclein amino acids 126-135 to detect the presence of alpha- synuclein. The statement in the Office Action that Ingelsson "demonstrated the presence of this fragment in PD pathology" is not clear because, as Ingelsson explains, it is the aggregation of alpha- synuclein, the entire length of the protein and not a short fragment thereof, into oligomeric forms that leads to cellular toxicity and PD pathology (see, e.g., Ingelsson at pages 2-4). This disclosure does not suggest that the peptide of amino acids 126-135 of alpha-synuclein is suitable for use as part of a therapy much less its use in a peptide immunogen construct designed as claimed. Thus, the disclosure of Ingelsson fails to rectify the deficiencies of Wang, Wang & Walfield, and Ugen.
In response: As indicated above, Ingelsson was cited for teaching a fragment of the α-Syn protein consisting of amino acids 126-135 (EMPSEEGYQD) as identified by immunohistochemistry studies of Lewy bodies present in brain stem and neocortex sections of patients with Parkinson’s disease (PD) (page 1, Figure 1). The binding of Ingelsson’s antibody to detect α-Syn in Lewy bodies and Lewy neurites in the brain tissues of a PD patient demonstrated that the fragment of the α-Syn protein consisting of amino acids 126-135 is present in PD pathology, furthermore, it demonstrated that that precise fragment of amino acids 126-135 is at a specific, accessible site on the α-Syn protein's surface such that a binding molecule, like an antibody, can recognize and attach to it. Furthermore, Fig. 1 of Inglesson demonstrated that amino acids 126-135 of the α-Syn protein are mostly accessible for binding by the antibody when the protein is in the aggregated form in Lewy bodies and/or Lewy neurites, and not when the protein is in its native unfolded monomer conformation (Ingelsson, Fig. 1). Therefore, the prior art provides clear teachings, suggestions and motivation to combine all elements of the claimed invention into a single construct, as recited in instant claims. Accordingly, the claimed construct represents an obvious embodiment of the teachings of the cited prior art. See MPEP 2144.07. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
Applicant contends on page 13 of the Remarks submitted on 08/11/2025: It is Applicant's specification, and not the disclosure of the cited references, that provides surprising evidence of the therapeutic relevance of the claimed construct, and a reason to combine its components as claimed. For example, the specification shows that, surprisingly, the claimed alpha-synuclein peptide immunogen construct elicits antibodies that do not bind the natural alpha- helix of alpha-synuclein monomer in its native form, but instead recognize and bind the denatured -sheet of alpha-synuclein, with unexpectedly high specificity for aggregated, -sheet oligomeric/fibrillar alpha-synuclein, which is a unique advantageous characteristic for targeting pathologic forms of alpha-synuclein.
In response: Is it noted that the only difference between the claimed invention and that of Wang’s patent described above is the sequence of the selected B cell epitope. As explained above Wang & Walfield teach the same configuration of sequences as applied to multiple therapeutic areas. As explained in detail above, the selected B cell epitopes of the claimed invention were known in the art (See e.g., Ingelsson and Gentile et al.), and they have been studied to significant length in PD pathology as evidenced the findings of Ingelsson and Gentile et al. The fact that antibodies directed to these specific sequences (α-syn 111-132 and 126-135) were commercially available and used in the cited prior art further demonstrated that these epitopes were known and widely recognized. For example, antibody S3062 available since or prior to 2009 was used in Gentile et al.’s study (page 2) (Sigma-Aldrich S3062 (July 2009), prior art of record). Further, it is noted that therapeutic relevance is not required by instant claims. In reference to Applicant’s argument that “surprisingly, the claimed alpha-synuclein peptide immunogen construct elicits antibodies that do not bind the natural alpha- helix of alpha-synuclein monomer in its native form, but instead recognize and bind the denatured -sheet of alpha-synuclein, with unexpectedly high specificity for aggregated, -sheet oligomeric/fibrillar alpha-synuclein”, this argument is not persuasive because, as indicated above, it was well known in the art that the B cell epitope claimed herein as SEQ ID NO: 15 was present and it was detectable in Lewy bodies specifically (see Ingelsson Fig. 1). It was also known that antibodies raised against α-syn 126-135, such as the antibody used by Ingelsson, can specifically recognize alpha-synuclein in the aggregated conformation (Lewy bodies) without significant binding to the natural alpha-helix of the α-syn monomer in its native form conformation (see Ingelsson Fig. 1). Therefore, the specific binding referenced by Applicant is not a surprising result but instead it is entirely consistent with teachings of the prior art. It is not surprising either that antibodies against the claimed B cell epitope would prevent further aggregation because it was known in the prior art that antibodies targeting the mid region of the protein (for example, amino acids 126-135) can provide protection from the cytoplasmic exposure needed for spontaneous aggregation (see Ingelsson).
With respect to Applicant’s remarks about results observed in a mouse model and more recently in human clinical trials, this argument is not persuasive because neither safety, efficacy nor tolerability results are required by the claimed invention. Further, the results mentioned do not provide evidence to support that the claimed invention is nonobvious.
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 MARLENE V BUCKMASTER whose telephone number is (703)756-5371. The examiner can normally be reached M-F 8-5.
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/MARLENE V BUCKMASTER/Examiner, Art Unit 1671
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1671