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 .
Claim Status
Claims 1-3, 14, and 16-27 are pending.
Claims 4-13 and 15 were cancelled.
Claim 20 is withdrawn as being directed to a non-elected species, the election having been made on 5/9/2024.
Claims 1-3, 14, 16-19, and 21-27 have been examined.
Priority
This application has PRO 63/599,595 filed on 11/16/2023.
Maintained Rejection
Claim Rejections - 35 USC § 112
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 1-2, 14, 16, 21-23 and 26-27 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 specification failed to provide a representative number of a blood brain barrier transcytosis mediator, a neuronal plasma membrane transduction mediator, or a mitochondrial modulator peptide as claimed. The specification disclosed a blood brain barrier transcytosis mediator of SEQ ID NO: 2 (TFFYGGSRGKRNNFKTEEY), a neuronal plasma membrane transduction mediator of SEQ ID NO: 4 (YGRKKRRQRRR), a mitochondrial modulator SEQ ID NO: 1 (WVELHFFN), and a cleavable linker of PLGLAG (SEQ ID NO: 3). The disclosed peptide species is insufficient to represent the entire genus of a peptide with 85% identity to SEQ ID NOs: 1-2 and 4 because the 85% identity of a peptide encompasses insertion, deletion, and/or substitution with one or more natural or non-natural amino acids at any position of SEQ ID NOs: 1-2 and 4, rendering the disclosed single peptide species NOT adequately satisfying written description to represent the entire genus of a peptide with 85% identity to the disclosed SEQ ID NOs: 1-2 and 4 as well as at most one residue different from SEQ ID NO: 3. According to MPEP 2163.05 (I)(B), 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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." Thus, claims 1-2, 14, 16, 21-23 and 26-27 fail to satisfying written description requirements according to according to MPEP 2163.05 (I)(B).
In addition, the specification fails to establish inter-relationship between a peptide sequence structure and its predicted function. The 85% identity to SEQ ID Nos: 1-2 and 4 as well as differing by at most one residue from the polypeptide PLGLAG (SEQ ID NO: 3) encompasses insertion, deletion, and/or substitution with one or more natural or non-natural amino acids at any position of SEQ ID NOs: 1-4. The various modifications of SEQ ID Nos: 1-4 renders unpredictable operability of the broader than enabled SEQ ID NOs: 1-4 as claimed. The specification failed to disclosed which residues within the SEQ ID Nos: 1-4 are conserved not subject to be modified to establish the correlation of a peptide sequence structure and its expected function. See MPEP 2163.05 (I)(B) "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Applicant’s Arguments
The Office has proceeded as if both points l) and 2) must be satisfied to establish written
description under 35 U.S.C. l 12(a) because disclosure of sufficient species is not a necessary requirement of 35 U.S.C. 112(a) when establishment of a reasonable structure-function correlation" for the mitochondrial modulator of SEQ ID NO: 1, the blood brain barrier transcytosis mediator of SEQ ID NO:2, the cleavable linker of SEQ ID NO:3, and the neuronal plasma membrane transduction mediator of SEQ ID NO:4 discussed as follows (Remarks, p6, last para to p7, para 1-6).
The Office WO 2020/229362 to Rassaf et al. discloses extensive mutagenesis analysis of BNIP3 fragments spanning SEQ ID NO: 1. See, e.g., Fig. 6A, Fig. 6B, and paragraph [0042] of the '362 publication. The Office, discloses mutations to SEQ [D NO: 1, while WO2023/079141 also to Rassaf et al., published May 11, 2023 (May 9, 2024 IDS) Fig. 3H, Fig. 3I,, Fig. 10A, Table S2A and Table S2B, of the' 141 publication (Remarks, p7, last para). Applicant cites this material not to provide a disclosure of sufficient species that are "representative of the full variety or scope of the genus," but to demonstrate that "a reasonable structure-function correlation" was present in the art at the time of filing (Remarks, p7, last para to p9, para 1-4).
Turning to SEQ ID NO:2, Applicant again refers to US 7,557,182 (the ‘182 patent) issued July 7, 2009, and provided herewith. In table 2 thereof, 96 angiopep variants are disclosed and assayed for activity. The patent sates "peptides having similar domains as aprotinine and Angiopep-1 and a modified form of Angiopep-1 (amidated, peptide no. 67) were therefore conceived as potential carrier vectors (Remarks, p9, last para to p10, para 1-5).
Turning to SEQ 1D NO:3, Fig 1 of Wang et al. (Sci Rep. 2017 Jul 18;7(1):5755, IDS 11/18/2024), figure 1 shows the prediction of cleavage site from a peptide motif consisting of 16 amino acid residues (from p8 to p8’); thus, figure shows the correlation of the genus of PLGLAG (SEQ ID NO: 3) derivative polypeptides comprising at most one residue different from SEQ ID NO: 3. One observes that PxGLxG are relatively but not strictly invariant, while residues at the second and fifth position are less conserved. Similarly, Eckhard et al. teach MMP-9 cleavable peptide sequence in figure 4 (Matrix Biol. (2016) 49, 37–60) (Remarks, p10 last 4 para to p12, para 1).
Applicant cites Spector so as to provide evidence that one of skill in the art readily
recognizes that "a reasonable structure-function correlation" relevant to SEQ ID NO:4 was
present in the art at the time of filing (Remarks, p12, para 2-6).
Response to Arguments
Applicant's arguments filed 5/1/2026 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s argument (A) is not persuasive because neither WO 2020/229362 nor WO2023/079141 or a combination thereof is sufficient to establish a structure-function correlation for the entire scope of mitochondrial modulator comprising a polypeptide at least 85% identical to the octapeptide WVELHFFN (SEQ ID NO: l).
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Response to argument WO 2020/229362.
Fig 6A is 100% identity to the instant SEQ ID NO: 1, but the peptide of Fig 6B does not read on the limitation of “at least 85% identical to the octapeptide WVELHFFN (SEQ ID NO: l)”. Thus, the comparison does not establish correlation between “at least 85% identical to the octapeptide WVELHFFN (SEQ ID NO: l)” and its function. Furthermore, the examiner could not find [0042] in WO 2020/229362.
Response to argument WO2023/079141.
Fig 3H and 3I show deletion mutants relative to the peptide WVELHFSN not the instant SEQ ID NO: 1. Furthermore, all mutants possess certain activity; thus, the data is insufficient to establish correlation of the genus of a peptide “at least 85% identical to the octapeptide WVELHFFN (SEQ ID NO: l)” and its function.
Fig 10A shows multiple peptide sequences but missing the claimed peptide sequence of WVELHFFN (SEQ ID NO: l). Thus, Fig 10A is insufficient to establish correlation of the genus of a peptide “at least 85% identical to the octapeptide WVELHFFN (SEQ ID NO: l)” and its function.
Similarly, no WVELHFFN can be found in the sequential deletion mutants listed in Table S2A.
The examiner found a single peptide sequence MSQSGEENLQGSWVELHFFN at page 196 among many peptide sequences and the single disclosed peptide sequence at page 196 is insufficient to establish the correlation between the genus of a peptide “at least 85% identical to the octapeptide WVELHFFN (SEQ ID NO: l)” and its function. Disclosure of various peptide sequences is NOT equal to establish a structure-function correlation.
Since neither WO 2020/229362 nor WO2023/079141 is sufficient to establish the correlation between the entire genus of a peptide “at least 85% identical to the octapeptide WVELHFFN (SEQ ID NO: l)” and its function by showing what the critical domain sequence is required for modulating mitochondria, the argument (A) is not persuasive.
Applicant’s argument (B) is not persuasive because the ‘182 patent disclosed the designed 96 peptide sequences based on different charges and amino acid insertions (p19-20, Table 2) without considering other types of modifications to sequence structure such as deletion. In addition, the ‘182 patent disclosed the peptide comprising cysteine to form a disulfide bond or cyclization (col 15, line 40-41) different from applicant’s design. Thus, the ‘182 patent failed to establish the correlation of at least 85% identical to TFFYGGSRGKRNNFKTEEY (SEQ ID NO: 2) with insertion, deletion, and substitution at one or more unspecified positions and its function. In particular, applicant fails to show a correlation structure.
Applicant’s argument (C) is not persuasive because neither Wang et al. nor Eckhard et al. or a combination thereof establishes the correlation of at most one residue from the polypeptide PLGLAG (SEQ ID NO: 3) and protease cleavage.
Wang et al. teach prediction of matrix metalloprotease substrate-cleavage site (Title). Wang et al. suggest a substrate consisting of 16 amino acids (P8 to P8’) of matrix metalloprotease cleavage site, but Wang’s figure 1 did not show the peptide sequence of PLGLAG (SEQ ID NO: 3).
Eckhard et al. shows MMP substrate sequences, but did not show a cleavage site of PLGLAG either.
Because neither Wang et al. or Eckhard et al. teaches a cleavage site of PLGLAG (SEQ ID NO: 3), the combination of Wang et al. or Eckhard et al. is insufficient to establish “at most one residue different from SEQ ID NO: 3”: as a metalloprotease cleavage site.
Applicant’s argument (D) is not persuasive because (i) Spector does not show the tat peptide sequence of YGRKKRRQRRR (SEQ ID NO: 4) as claimed and (ii) Spector’s Tat polypeptide sequences are ≥ 67 amino acid residues in length (p157-160, Table 1), much longer than the 11 amino acids of SEQ ID NO: 4 as claimed. Thus, Spector is insufficient to establish a tat structure and function correlation by showing which amino acid in SEQ ID NO: 4 is required for its function.
Applicant may overcome the rejection by distinctly claiming each domain peptide sequences supported by the original specification of record.
Maintained Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
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.
1. Claims 1-3, 14, 16-18, 21-24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Rassaf et al. (WO 2020/229362 A1, previously cited 6/5/2024) in view of Potocky et al. (J Biol Chem. 2003 Dec 12;278(50):50188-94, previously cited 5/9/2025) in view of Beliveau et al. (WO 2006/086870 A1, previously cited 6/5/2024) in view of Brkic et al. (Mediators of Inflammation Volume 2015, Article ID 620581, 27 pages, previously cited 6/5/2024) in view of Chen et al. (J. Chem. Inf. Model. 2021, 61, 5203−5211, previously cited 6/5/2024).
Claim 1 is drawn a composition comprising a chimeric polypeptide having (at least 85% identity to blood brain barrier transcytosis mediator/SEQ-2)-(at most one modified amino acid in metalloprotease cleavable liker-PLGLAG)-( at least 85% identity to neuronal plasma membrane transduction mediator/SEQ-4)-( at least 85% identity to mitochondrial modulator/SEQ-1).
Rassaf et al. teach a chimeric peptide of TAT-BINP3-8B comprising (i) a neuronal plasma membrane transduction mediator of TAT fusion to (ii) a mitochondrial modulator (Example 6-13) to prevent cell damage and cell death (Abstract). Rassaf et al. show the mitochondrial modulator peptide comprising WVELHFFN with 100% homology to the instant
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SEQ ID NO: 1 shown as follows (Fig. 6A).
Rassaf et al. do not show a Tat peptide sequence with 85% identity to the instant Tat peptide of SEQ ID NO: 4.
Potocky et al. is cited to show a cell penetrating peptide Tat-(47-57) consisting of YGRKKRRQRRR (p50189, col 2, Results, para 1) as an obvious variant and functional equivalence of Tat-(48-60) consisting of GRKKRRQRRRPP (p50188, col 2, para 2; p50191, col
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2, Discussion-para 1). Potocky et al. show beneficial conjugate a cargo of fluorescent label to Tat-(47-57), YGRKKRRQRRR, to deliver fluorescent label to cytoplasm and organelle in the shown in figure 5 as follows. Because Potocky et al. suggest beneficial conjugation of Tat-(47-57), YGRKKRRQRRR, to deliver a cargo/compound to cytoplasm and/or organelles in cytoplasm, one of ordinary skill in the art would have found it obvious to beneficial conjugate Rassaf’s mitochondrial modulator peptide of WVELHFFN to Potocky’s Tat peptide of YGRKKRRQRRR to deliver Rassaf’s mitochondrial modulator peptide WVELHFFN into cytoplasm to interact and prevent BNIP3 translocation to mitochondria (Rassaf et al. p21, line 11-15). See MPEP 2143 (I)(B) Simple substitution of one known element for another to obtain predictable results. In the present case, simple substitution of Rassaf’s Tat peptide with Potocky’s Tat peptide of YGRKKRRQRRR to deliver a conjugated mitochondrial modulator peptide of WVELHFFN to cytoplasm is predictable and obvious. Potocky’s Tat peptide of YGRKKRRQRRR has 100% identity to the instant SEQ ID NO: 4.
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Beliveau et al. teach beneficial use of aprotinin conjugated to a compound for transporting a compound or drug across the blood-brain barrier of a mammal and in the treatment and diagnosis of neurological diseases (Abstract). Beliveau et al. teach the conjugated drug compound is a protein (claim 32). Beliveau et al. show a blood brain barrier transcytosis mediator is SEQ ID NO: 70 identified by in vitro model of BBB screening (Table 3). A side-by-side comparison of the peptide of SEQ ID NO: 70 with the instant SEQ ID NO: 2 as follows. Because Beliveau et al. teach the peptide of SEQ ID NO: 70 is beneficially conjugated to a protein drug to increase the conjugated protein drug passing through blood brain barrier, one of ordinary skill in the art would have found it obvious to conjugate Beliveau’s blood brain barrier transcytosis mediator of SEQ ID NO: 70 to Rassaf’s peptide drug of TAT-BINP3-8B to generate a chimeric protein of (TFFYGGSRGKRNNFKTEEY)-(YGRKKRRQRRR)-(WVELHFFN).
Rassaf et al. in view of Potocky et al. in view of Beliveau et al. do not teach the use of a cleavable linker to connect the blood brain barrier transcytosis mediator and TAT-BINP3-8B.
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Brkic et al. teach matrix metalloproteinases(MMPs) and their roles in neurodegenerative diseases comprising Alzheimer’s disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis (Abstract; p5-6, Table 2). Brkic et al. teach Parkinson’s disease (PD) is selective and progressive loss of dopaminergic neurons due to dopaminergic neurons cell death (p11, col 2, 4.3. Parkinson’s Disease (PD)) consistent with applicant’s disclosure of Background in the specification [0005]. Brkic et al. teach MMP-9 protease is primarily localized in neuron of Parkinson’s disease (p5, Parkinson’s disease). Chen et al. teach activatable cell-penetrating peptides (ACPPs) known to be able to decrease the cytotoxicity of cell-penetrating peptide (CPP)-based drug delivery systems (Abstract). Chen et al. show a cleavable linker of PLGLAG as a substrate in response to MMP-9 protease cleavage (Abstract). Because (a) MMP-9 protease is present in brain neurons of patients and (b) activatable cell-penetrating peptides (ACPPs) known to be able to decrease the cytotoxicity of cell-penetrating peptide (CPP)-based drug delivery systems, one of ordinary skill in the art would have found it obvious to further insert Chen’s cleavable linker of PLGLAG into the chimeric protein of (TFFYGGSRGKRNNFKTEEY)-(YGRKKRRQRRR)-(WVELHFFN) to generate (TFFYGGSRGKRNNFKTEEY)-PLGLAG-(YGRKKRRQRRR)-(WVELHFFN) as an MMP-9 activatable cell-penetrating peptide conjugate to decrease the cytotoxicity of cell-penetrating peptide (CPP)-based drug delivery systems as taught by Chen (Abstract). The chimeric polypeptide has 100% identity to the instant SEQ ID NO: 5.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to modify Rassaf’s Tat protein drug with Potocky’s Tat peptide because Potocky et al. suggest beneficial conjugation of Tat-(47-57), YGRKKRRQRRR, to deliver a cargo/compound to cytoplasm and/or organelles in cytoplasm (Fig 5) as described by MPEP 2143 (I)(B) Simple substitution of one known element for another to obtain predictable results. The combination would have reasonable expectation of success because both references teach a Tat peptide conjugated to a cargo to deliver the conjugated cargo into cells.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Rassaf et al. in view of Potocky et al. with Beliveau’s blood brain barrier transcytosis mediator (e.g., SEQ ID NO: 70) because (a) Rassaf et al. in view of Potocky et al. teach administration of a pharmaceutical composition comprising a chimeric protein to treat a disease or condition of brain (p15, line 8-10) and (b) Beliveau et al. teach conjugation of protein drugs with aprotinin (e.g., SEQ ID NO: 70) as a blood brain barrier transcytosis mediator increases their accumulation in the brain parenchyma in vivo (p47, line 1-2; claim 32). The combination would have reasonable expectation of success because both Rassaf et al. and Beliveau et al. teach administration of a protein drug to treat a disease or condition in the brain.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Rassaf et al. in view of Potocky et al. and Beliveau et al. with (i) Brkic’s teaching of MMP-9 and (ii) Chen’s cleavable linker of PLGLAG because (a) Rassaf et al. in view of Potocky et al. and Beliveau et al. teach a composition comprising a cell-penetrating peptide conjugate to treat a disease or condition of brain (p15, line 8-10) and to prevent cell damage and cell death (Abstract), (b) Brkic et al. teach MMP-9 protease is primarily localized in neuron of Parkinson’s disease (p5, Parkinson’s disease), and (c) Chen et al. teach beneficially using an activatable cell-penetrating peptide comprising a cleavable linker of PLGLAG to decrease the cytotoxicity of cell-penetrating peptide (CPP)-based drug delivery systems (Abstract). The combination would have reasonable expectation of success because both Rassaf et al. and Chen et al. teach a cell-penetrating peptide (CPP)-based drug delivery system.
With respect to claims 2, 18, and 26, Rassaf et al. teach the therapeutic protein formulated for delivery to a patient (p4, line 23-25; claim 16).
With respect to claims 3-4, 16-17, and 21-24, the prior art chimeric polypeptide has 100% identity to the instant SEQ ID NO: 5 shown as follows
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Applicant’s Arguments
Both Brkic and Chen teach that the claimed compositions would be cleaved prior to their encountering the blood brain barrier, rendering them incapable of accessing neuron cells across the blood brain barrier or modulating the mitochondria of those cells (Remarks, p14, last 3 para).
The Office declines to view the references in their entirety because "applicant failed to
provide data to show elevated MMP-9 in patient's serum causes loss of function for the intended use of the chimeric polypeptide" (Remarks, p15, whole page).
Response to Arguments
Applicant's arguments filed 5/1/2026 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s arguments (i) is not persuasive for the reasons as follows.
The claims are directed to a chimeric polypeptide composition NOT a method of using the chimeric polypeptide composition as argued by applicant. Furthermore, one of ordinary skill in the art would have found it obvious to administer an inhibitor of metalloproteinases (doxycycline) known in the art to prevent degradation of the chimeric polypeptide by serum metalloproteinases as evidenced by Zhao et al. (Contraception 79 (2009) 469–478). The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See MPEP 2144.
Response to argument Brkic, although one would expect certain amount of the claimed compositions to be cleaved prior to their encountering the blood brain barrier, one would also expect to perform pharmacokinetic and pharmacodynamic experiments for dosage optimization to determine suitable dosage range for the chimeric polypeptide to enter the brain in the presence of chimeric polypeptide degraded prior to their encountering the blood brain barrier. Furthermore, one may also administer an inhibitor (e.g., doxycycline) as a common knowledge to prevent degradation of the chimeric polypeptide by serum metalloproteinases. Thus, no evidence of teaching away this invention by Brkic as argued by applicant.
Response to argument Chen, one of ordinary skill in the art would recognize the chimeric polypeptide can be administered to non-cancer patients, not limited to treating a cancer patient as argued by applicant. Thus, no evidence of teaching away this invention by Chen as argued by applicant.
Applicant’s arguments (ii) is not persuasive because applicant narrowly interprets the teachings of cited prior art references. See response to arguments (i)(A)-(i)(C) above. Applicant’s arguments deviates from the thinking process of “one or ordinary skill in the art; thus, the examiner requests applicant to show data to support the arguments. Argument does not replace evidence where evidence is necessary. See MPEP 2145 (I). Furthermore, a person of ordinary skill in the art is NOT a person requiring explicitly teachings from a specific prior art reference as argued by applicant. A person of ordinary skill in the art is well defined as a person of ordinary creativity 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 ___, 82 USPQ2d at 1396. See MPEP 2141.03 (I). Based on the definition of “one or ordinary skill in the art” by MPEP 2143.03 (I) and reviewing the cited references in their entirety, the examiner concludes that one of ordinary skill in the art would have found it obvious to combine multiple patents together like pieces of a puzzle to generate the chimeric polypeptide as claimed. Examples of rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143(I).
2. Claims 1-3, 14, 16-18, 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. as applied to claims 1-3, 14, 16-18, 21-24, 26, and further in view of Biosynthesis (https://www.biosyn.com /faq/why-acetylate-and-amidate-a-peptide.aspx. 11/11/2008, previously cited 5/9/2025).
Claim 25 is drawn to the peptide of SEQ ID NO: 6 comprising an Acetyl cap at the N-terminus and an amino cap at C-terminus of the chimeric polypeptide of SEQ ID NO: 5.
Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. teach a chimeric polypeptide of SEQ ID NO: 5 as applied to claims 1-3, 14, 16-18, 21-24, and 26.
Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. do not teach modification of SEQ ID NO: 5 with acetylation and amidation.
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Biosynthesis teaches N-Terminal Acetylation and C-Terminal Amidation of Peptides (Description). Biosynthesis teaches such modifications with various advantages shown above (Advantages). Thus, one of ordinary skill in the art would have been taught and/or motivated to modify SEQ ID NO: 5 with N-Terminal Acetylation and C-Terminal Amidation, reading on claim 25.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to modify the chimeric polypeptide of SEQ ID NO: 5 taught by Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. with Biosynthesis’s teaching of N-Terminal Acetylation and C-Terminal Amidation for peptides because Biosynthesis teaches N-Terminal Acetylation and C-Terminal Amidation of peptides comprising mimicking natural peptides to increase permeability of cells, increasing stability against protease digestion, and enhancing bioactivity of the modified peptide (Advantages). The combination would have reasonable expectation of success because the references teach peptides, and N-Terminal Acetylation and C-Terminal Amidation can be introduced during chemically synthesis of a peptide.
Response to Arguments
Applicant's arguments filed 5/1/2026 have been fully considered but they are not persuasive. See response to arguments above.
3. Claims 1-3, 14, 16-19 and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. as applied to claims 1-3, 14, 16-18, 21-24, 26, and further in view of Naoi et al. (Mechanisms of Ageing and Development 111 (1999) 175–188, previously cited 5/9/2025) and Salat et al. (Journal of Parkinson’s Disease 3 (2013) 255–269, previously cited 5/9/2025).
Claim 19 is drawn the composition further comprising a dopamine precursor.
Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. teach a composition comprising the instant chimeric polypeptide SEQ ID NO: 5 to deliver a mitochondrial modulator peptide comprising WVELHFFN to treat a disease or condition by preventing cell damage and cell death (p8, Detailed Description of the Invention, line 7-11), including neurodegenerative disease or disorder (p15, line 16-17), as applied to claims 1-3, 14, 16-18, 21-24, and 26.
Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. do not teach the composition further comprising a dopamine precursor.
Naoi et al. teach Cell death of dopamine neurons in aging and Parkinson’s disease (Title) and Parkinson’s disease (PD) is also caused by selective cell death of dopamine neurons in the brain region (Abstract). Because Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. teach a composition comprising the instant chimeric polypeptide SEQ ID NO: 5 capable of treating a neurodegenerative disease or disorder (p15, line 16-17) by preventing cell damage and cell death (p8, Detailed Description of the Invention, line 7-11), one of ordinary skill in the art would have found it obvious to administer the chimeric polypeptide taught by Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. to treat Parkinson’s disease taught by Naoi et al. by preventing dopamine neuron cell damage and cell death in the brain region. Salat et al. is cited to show Levodopa, a dopamine precursor, is an effective and well-tolerated dopamine replacement agent used to treat Parkinson’s disease (PD) known in the art (Title and Abstract; p256, Table 1-2). Because (a) Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. and further in view of Naoi et al. teach a composition comprising the instant chimeric polypeptide SEQ ID NO: 5 capable of treating Parkinson’s disease by preventing dopamine neuron cell damage and cell death and (b) Salat et al. teach Levodopa, a dopamine precursor, is an effective and well-tolerated dopamine replacement agent used to treat Parkinson’s disease (Abstract), one of ordinary skill in the art would have found it obvious to combine the instant chimeric polypeptide SEQ ID NO: 5 and Salat’s Levodopa for the same purpose to treat Parkinson’s disease, reading on claims 19 and 27.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. with (ii) Naoi et al. and Salat et al. because (a) Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. in view of Chen et al. teach a composition comprising the instant chimeric polypeptide SEQ ID NO: 5 to treat neurodegenerative disease or disorder (p15, line 16-17) by preventing cell damage and cell death (p8, Detailed Description of the Invention, line 7-11), (b) Naoi et al. teach Parkinson’s disease (PD) is also caused by selective cell death of dopamine neurons in the brain region (Abstract), and (c) Salat et al. teach Levodopa, a dopamine precursor, is an effective and well-tolerated dopamine replacement agent used to treat Parkinson’s disease (Abstract; p256, Table 1-2). The combination would have reasonable expectation of success because both Rassaf et al. and Salat et al teach a compound for the same purpose to treat Parkinson’s disease.
Response to Arguments
Applicant's arguments filed 5/1/2026 have been fully considered but they are not persuasive. See response to arguments above.
Maintained 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, 14, 16-18, 21-24, and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of U.S. Patent No. 12,540,166 B2 (the ‘166 patent, previously rejected as 17/608,655) in view of Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al.
Claim 1 of the ‘166 patent disclosed a chimeric polypeptide comprising (i) a cellular uptake signal and (ii) a BNIP3 fragment comprising a peptide motif of WVELHFFN (SEQ ID NO: 8) or its homolog peptide sequence comprising no more than 2 mismatched residues corresponding to SEQ ID NO: 8.
Claim 9 of the ‘166 patent disclosed the cellular uptake signal selected from SEQ ID No 32 as YGRKKRRQRRR with 100% identity to the instant SEQ ID No: 4.
Claims 1 and 9 of the ‘166 patent do not teach the chimeric peptide further fusion to a blood brain barrier transcytosis mediator to the therapeutic peptide.
The relevancy of Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al. as applied to claims 1-3, 14, 16-18, 21-24, and 26 described above not repeated here.
Because Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al. teach beneficial fusion the chimeric peptide taught by claims 1 and 9 of the ‘655 application to a blood brain barrier transcytosis mediator via an MMP-9 protease cleavable linker to pass through blood brain barrier in response to MMP-9 at a disease site in the brain, one of ordinary skill in the art would have been taught and/or motivated to combine claims 1 and 9 of the ‘166 patent with Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al.
Thus, claims 1 and 9 of the ‘166 patent in view of Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al. are obvious to the instant claims 1-3, 14, 16-18, 21-24, and 26.
Response to Arguments
Applicant's arguments filed 5/1/2026 have been fully considered but they are not persuasive. See response to arguments above.
Claims 1-3, 14, 16-18, 21-24, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,344,644 (the ‘644 patent, previously rejected under 18/413,753) in view of Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al.
Claim 1 of the ‘644 patent disclosed a mitochondria membrane translocation inhibitor of SEQ ID NO: 3 (WVELHFFN with 100% identity to the instant claim 1).
Claim 1 of the ‘644 patent does not teach the peptide of SEQ ID NO: 3 further fusion to a Tat or a blood brain barrier transcytosis mediator.
The relevancy of Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al. as applied to claims 1-3, 14, 16-18, 21-24, and 26 described above not repeated here.
Because Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al. teach beneficial fusion the peptide taught by claims 1 and 18 of the ‘753 application to Tat peptide and a blood brain barrier transcytosis mediator via an MMP-9 protease cleavable linker to pass through blood brain barrier in response to MMP-9 at a disease site in the brain, one of ordinary skill in the art would have been taught and/or motivated to combine claim 1 of the ‘644 patent with Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al.
Thus, claim 1 of the ‘644 patent in view of Rassaf et al. in view of Potocky et al. in view of Beliveau et al. in view of Brkic et al. and in view of Chen et al. are obvious to the instant claims 1-3, 14, 16-18, 21-24, and 26.
Response to Arguments
Applicant's arguments filed 5/1/2026 have been fully considered but they are not persuasive. See response to arguments above.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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/J.L/Examiner, Art Unit 1658
12-June-2026
/Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
Prosecution Insights