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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/05/2025 has been entered.
Claims Status
The remarks filed 11/05/2025 are acknowledged.
Claims 1-2, 4-12, and 20 are pending.
Claims 12 and 20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claims.
Therefore, claims 1-2 and 4-11 are under examination.
Withdrawn
The previous rejections of claims 1-2 and 4-11 under 35 U.S.C. 103 are withdrawn. Applicant’s arguments, see pages 2-3 of the remarks filed 11/05/2025 with respect to the rejections of claims 1-2 and 4-11 under 35 U.S.C. 103, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, new rejections under 35 U.S.C. 103 are made below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/05/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
Claims 1-2 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Ransohoff et al., 2000 (instant PTO-892) in view of Yu et al., 2015 (12/20/2024 PTO-892), Pandini et al., 2016 (instant PTO-892), and Skaper et al., 2011 (instant PTO-892).
Regarding claim 1, Ransohoff teaches NGF treated animals experienced delay in EAE, with five of the six treated animals fared better than any of the controls [page 1627, left column, third paragraph]. Ransohoff also teaches that the results of inflammation and demyelination in both control and NGF-treated marmosets were concordant, suggesting a change in the ability of primed T cells to orchestrate the CNS inflammatory response, with a significant decrease in IFN-y-immunoreactive cells and an increase in IL-10-producing cells, with the cells expressing IL-10 being astrocytes [page 1627, left column, fourth paragraph]. Ransohoff further teaches that the beneficial effect of NGF treatment was mediated by an immunoregulatory response from the neural cells, and that astrocyte IL-10 represents CNS-intrinsic mechanism for suppressing inflammation [page 1627, right column, first paragraph]. Ransohoff additionally teaches that it has been reported that IL-10 enhances NGF production by astrocyte in culture, suggesting an autoregulatory feed-forward circuit [page 1627, right column, third paragraph].
However, Ransohoff does not specifically teach that the NGF (Nsp) protein and IL-10 protein are together in a single (Nsp-IL10) fusion polypeptide, or that the NGF protein consists of SEQ ID NO: 2.
Yu teaches that synthetic fusion proteins can be designed to achieve improved properties and that the fusion of two or more protein domains enhances bioactivities [see Abstract]. Yu also teaches that the simplest method of combining a pair of fusion partners is an end-to-end genetic fusion, however, this strategy reduces the degrees of freedom in protein dynamics and may give rise to undesirable outcomes. Yu further teaches that for this reason, linker peptides are mostly required to connect fusion partners to better maintain their individual structures and functions, and maintain necessary distance to reduce steric hinderance and/or permit favorable domain-domain interaction between two protein moieties [page 156, left column, third paragraph – right column, first paragraph].
Pandini teaches an NGF (1-14) protein with the sequence of SSSHPIFHRGEFSV that is able to activate TrkA signaling pathways essential for neuronal survival, imitating the effects of the whole protein NGF [see Abstract, page 3, see Scheme 1, and page 15, left column, fourth paragraph] and that since the NGF-mimetic peptide can reproduce the signal transduction of the whole protein, it would be a promising drug candidate for clinical studies [see Abstract and page 15, right column, third paragraph].
The sequence of NGF (1-14) taught by Pandini has 100% sequence identity to SEQ ID NO: 2 of the instant application.
Skaper teaches that neurotropic factors (i.e. NGF; Nsp) prevent naturally occurring cell death in the developing nervous system, and that data suggests administration of neurotrophic factors may be effective treatment of peripheral nervous system disease, but that these proteins present problems when used as therapeutic agents because they cannot be given orally, present uncertain pharmacokinetic behavior, and large-scale production is labor and cost intensive [page 1, first paragraph]. Skaper also teaches that neurotropic factor treatment of central nervous system diseases presents an even more complex scenario, since they are not able to cross the blood-brain barrier and must be given intracerebrally, and that small molecule mimetics over [whole] proteins are advantageous as they can be modified to penetrate freely into the brain parenchyma and can be designed for oral administration [page 1, first paragraph]. Skaper further teaches that for therapeutic use in the peripheral nervous system, neurotrophic proteins could be replaced by active peptide fragments with receptor binding properties similar to the full-length protein, but improved pharmacokinetic properties and lower production costs [page 2, first paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the NGF and IL-10 into a single fusion polypeptide. One would have been motivated to have combined the NGF and IL-10 into a single fusion polypeptide because Ransohoff teaches that the beneficial effect of NGF treatment was brought about by an immunoregulatory response from neural cells: astrocytes producing IL-10. One would have further been motivated to have combined the NGF and IL-10 into a single fusion polypeptide because Yu teaches that synthetic fusion proteins can be designed to achieve improved properties and that the fusion of two or more protein domains enhances bioactivities.
It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the whole NGF protein of Ransohoff to be the NGF (1-14) of Pandini. One would have been motivated to make this modification because Pandini teaches that the NGF (1-14) protein is able to activate TrkA signaling pathways essential for neuronal survival, imitating the effects of the whole protein NGF, and that since the NGF-mimetic peptide (i.e. NGF (1-14)) can reproduce the signal transduction of the whole protein, it is a promising drug candidate, and Skaper teaches small molecule mimetics of neurotropic factors are advantageous over the whole protein because they can be modified to penetrate freely into the brain parenchyma, can be designed for oral administration, have improved pharmacokinetic properties, and have lower production costs.
Regarding claims 2, 7, and 8, the instant specification defines “directly linked” to mean the individual polypeptides are connected to one another via one or more intervening amino acids (e.g., linkers) [see page 17, lines 23-27]. Thus, it further would have been obvious to have a linker, as taught by Yu, between the NGF polypeptide and the IL10 polypeptide of the Nsp-IL10 polypeptide, as taught by Ransohoff, Yu, Pandini, and Skaper, thereby directly linking the Nsp polypeptide and the IL10 polypeptide. One would have been motivated to have a linker between the individual polypeptides of the fusion because Yu teaches that linker peptides are mostly required to connect fusion partners to better maintain their individual structures and functions, and maintain necessary distance to reduce steric hinderance and/or permit favorable domain-domain interaction between two protein moieties.
Claims 1-2, 4-8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Ransohoff et al., 2000 (instant PTO-892) in view of Yu et al., 2015 (12/20/2024 PTO-892), Pandini et al., 2016 (instant PTO-892), and Skaper et al., 2011 (instant PTO-892), as applied to claims 1-2 and 7-8 above, and further in view of UniProt, 1991 (12/20/2024 PTO-892).
The teachings of Ransohoff, Yu, Pandini, and Skaper are above.
However, Ransohoff, Yu, Pandini, and Skaper do not specifically teach that the IL10 polypeptide comprises SEQ ID NO: 4
Regarding claims 4-6 and 10, UniProt teaches that residues 1-18 of human IL10 is a signal peptide and residues 19-178 is the mature protein chain segment [see page 5-6]. UniProt further teaches the sequence of the signal peptide [see page 7] and the sequence of the mature segment [see page 8].
Residues 1-18 of UniProt, which correspond to the signal peptide of human IL10, have 100% sequence identity to SEQ ID NO: 5 of instant claim 6, and residues 19-178 of UniProt, which corresponds to the mature segment of human IL10, have 100% sequence identity to SEQ ID NO: 4 of instant claim 4.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the IL-10 polypeptide of Ransohoff to specifically comprise the human IL-10 polypeptide comprising residues 1-178 of UniProt. One would have been motivated to make this modification because UniProt teaches that this is the sequence of human IL-10. Further, since this is a known sequence in the art, it is obvious to use known variations known in the prior art for predictable outcomes. See MPEP 2143 (F).
Claims 1-2 and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Ransohoff et al., 2000 (instant PTO-892) in view of Yu et al., 2015 (12/20/2024 PTO-892), Pandini et al., 2016 (instant PTO-892), and Skaper et al., 2011 (instant PTO-892), as applied to claims 1-2 and 7-8 above, and further in view of Xu (WO 2003074660; 08/07/2025 PTO-892).
The teachings of Ransohoff, Yu, Pandini, and Skaper are above. To reiterate, Yu teaches that linker peptides are mostly required to connect fusion partners to better maintain their individual structures and functions, and maintain necessary distance to reduce steric hinderance and/or permit favorable domain-domain interaction between two protein moieties [page 156, left column, third paragraph – right column, first paragraph].
However, Ransohoff, Yu, Pandini, and Skaper do not specifically teach that the Nsp-IL10 polypeptide comprises a linker with the sequence of SEQ ID NO: 6.
Regarding claim 9, Xu teaches a linker peptide for fusion proteins [see page 1] with the sequence of “Gly-Gly-Ser-Gly” [see page 25, lines 24-25].
The linker of Xu has 100% sequence identity to SEQ ID NO: 6 of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the linker of Yu to specifically comprise the linker of Xu. One would have been motivated to make this modification because Xu teaches that this linker is suitable for use in fusion proteins, and further, since this is a known sequence in the art, it is obvious to use known variations known in the prior art for predictable outcomes. See MPEP 2143 (F).
Claims 1-2 and 4-11 are rejected under 35 U.S.C. 103 as being unpatentable over Ransohoff et al., 2000 (instant PTO-892) in view of Yu et al., 2015 (12/20/2024 PTO-892), Pandini et al., 2016 (instant PTO-892), and Skaper et al., 2011 (instant PTO-892), as applied to claims 1-2 and 7-8 above, UniProt, 1991 (12/20/2024 PTO-892), as applied to claims 4-6 and 10 above, and Xu (WO 2003074660; 08/07/2025 PTO-892), as applied to claim 9 above.
The teachings of Ransohoff, Yu, Pandini, Skaper, UniProt, and Xu are above.
However, Ransohoff, Yu, Pandini, Skaper, UniProt, and Xu do not specifically teach that the Nsp-IL10 polypeptide comprises SEQ ID NO: 7.
Regarding claim 11, SEQ ID NO: 7 of the instant claim comprises multiple sequences for different components as shown below:
Residues 1-18 of SEQ ID NO: 7 correspond to SEQ ID NO: 5 for the signal peptide.
Residues 19-22 and 37-40 of SEQ ID NO: 7 correspond to SEQ ID NO: 6 for the linker.
Residues 23-36 of SEQ ID NO: 7 correspond to SEQ ID NO: 2 for the Nsp polypeptide.
Residues 37-40 of SEQ ID NO: 7 correspond to SEQ ID NO: 6 for the linker.
Residues 41-200 of SEQ ID NO: 7 correspond to SEQ ID NO: 4 for the IL-10 polypeptide.
To reiterate the teachings above, Pandini teaches an NGF (1-14) protein with the sequence of SSSHPIFHRGEFSV [see Abstract and page 3, see Scheme 1] which has 100% sequence identity to SEQ ID NO: 2 of the instant application, UniProt teaches that residues 1-18 of human IL10 is a signal peptide and residues 19-178 is the mature protein chain segment [see page 5-6] and teaches the sequences of the signal peptide [see page 7] and the mature segment [see page 8]. Residues 1-18 of UniProt have 100% sequence identity to SEQ ID NO: 5 of the instant application and residues 19-178 of UniProt have 100% sequence identity to SEQ ID NO: 4 of the instant application. Xu teaches a linker peptide for fusion proteins [see page 1] with the sequence of “Gly-Gly-Ser-Gly” [see page 25, lines 24-25] which has 100% sequence identity to SEQ ID NO: 6 of the instant application.
These individual sequences when put together create a sequence with 100% sequence identity to SEQ ID NO: 7 of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the individual sequences, as taught above by the respective art, to arrive at SEQ ID NO: 7 of the instant claim. One would have been motivated to use these sequences for each of the components that form SEQ ID NO: 7 because they are known sequences in the art, and it is obvious to use variations known in the prior art for predictable outcomes. See MPEP 2143 (F).
Conclusion
No claims are allowed.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675