DETAILED ACTION
Examiner acknowledges receipt of the reply filed 6/29/2026, in response to the restriction requirement mailed 1/28/2026.
Claims 39, 40, 48, and 56-58 are pending and being examined on the merits in this office action . Claims 38, 41-47, and 49-55 have been cancelled.
Claims 57 and 58 are rejoined herein.
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 .
Priority
The filing receipt dated 8/22/2024 provides the following information:
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Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement filed 6/17/2025 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because denoted NPL 8, 9, 21, and 36 do not include full citations, e.g., titles. The denoted NPLs have been struck-through. It has been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Election/Restrictions
Applicant’s election of Group 1 (claims 39, 40, 48, and 56-58) without traverse in the reply filed on 6/29/2026 is acknowledged.
Claims 57 and 58 are rejoined herein. Claim 57 (group 7) was amended on 6/29/2026 to recite a composition/product claim. Accordingly claims 57 and 58 are consistent with the elected composition claims of elected Group 1.
The restriction between Groups 1 and 2, as set forth in the Office action mailed on 1/28/2026 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 38, 41-47, and 49-55 have been cancelled, rendering the restriction requirement of Groups 1-6 as set forth in the office action mailed 1/28/2026 moot.
Applicant’s election of the following species without traverse in the reply filed on 6/29/2026 is acknowledged:
neuron transport moiety- RVG peptide (SEQ ID NO:1)
Ndfip1 peptide- human Ndfip1 (SEQ ID NO: 24)
Fully defined Ndfip1 fusion polypeptide: comprising SEQ ID NOs: 1, 24, and 7 (export/signal peptide)
species of disease to be treated – traumatic spinal cord injury
Claims 39, 40, 48, and 56-58 read on the elected species.
Applicant amended the claims filed 6/29/2026 to be consistent with the elected species. Accordingly, the restriction requirement between species as set forth in the Office action mailed on 1/28/2026 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a continuation or divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
The abstract of the disclosure is objected to for the following minor informality:
The abstract should be amended to recite distinct sentences. As currently written, the abstract is one long run-on sentence.
Claim Objections
Claims 39, 48, 57, and 58 are objected to because of the following informalities:
Claim 39 recites an acronym that should be written out in full name in the first order of appearance within the claims
Claims 48, 57, and 58 should be amended to recite “a traumatic spinal cord injury”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 40, 48, 57, and 58 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 40 recites the limitation "the export/signal peptide". There is insufficient antecedent basis for this limitation in the claim. To overcome this rejection, the claims should be amended to recite “an [[the]] export/signal peptide”
The term “traumatic spinal cord injury” in claims 48, 57, and 58 is a relative term which renders the claims indefinite. The term “traumatic spinal cord injury” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specially, the metes and bounds of what constitutes a “traumatic” spinal cord injury as opposed to “non-traumatic’ spinal cord injury is not clearly set forth. The skilled artisan is not provided any guidance to definitely distinguish ““traumatic” spinal cord injury from other forms of spinal cord injuries.
Claim clarification is required.
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 39, 48, and 56-58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tan (U.S. 2009/0054307), as evidenced by NICHD article, “What are the parts of the nervous system?,” 2018, accessed 8/29/2026 at URL nichd.nih.gov/health/topics/neuro/conditioninfo/parts, and further in view of Narasimhaswamy (U.S. 20140294727) and Son et al (J Control Rel 155:18-25 (2011)).
Tan et al teach a method for the treatment of a disease of the nervous system, especially trauma or hypoxia, in particular in the central nervous system by up-regulation or increasing levels of Ndfip1 (also known as Nedd4-WW Domain Binding Protein 5 or N4WBP5) (abstract, claim 1). Tan teach that Ndfip1 (formally N4WBP5) and/or Nedd4 expression in neural tissue is increased following acute stress, such as caused by traumatic injury. Tan indicates that the prophylaxis and/or treatment of acute diseases and injuries requiring the neuron survival is carried out via increasing levels of expression of Ndfip1 (formally N4WBP5) or Nedd4 or activity or interaction of Ndfip1 (formally N4WBP5) or Nedd4 (para. [0014]). Tan et al teach pharmaceutical compositions and pharmaceutically acceptable carrier, as well as medicaments, and therapeutic compositions (e.g., paras [0043], [0120]-[0134]; claims 10, 13). The compositions can be used to treat traumas on the nervous system (e.g. paras [0002], [0006]-[0008], [0013]-[0020], [0117], [0135]). As evidenced by the NICDH article, the central nervous system is made up of the brain and spinal cord. Thus, Tan et al encompasses treating traumatic injuries of the brain and spinal cord. SEQ ID NO:2 comprises the human Ndfip1 protein sequence. SEQ ID NO:2 of Tan has 100% identity with the Ndfip1peptide of instant SEQ ID NO:24. Example 15 discloses TAT-mediated delivery of Ndfip1 [Ndfip1 fusion protein comprising TAT and Ndfip1 peptide]. TAT is an eleven amino acid sequence from HIV-1 TAT protein that is capable of delivering full-length proteins with biological activity across the cell membrane and, has been shown capable of delivering anti-apoptotic proteins such as Bcl-xL into the brain following ischaemic injury, reducing apoptosis and infarct volume. Example 8 discloses protection to neurons during traumatic brain injury in a mouse model.
Tan does not expressly teach a neuron transport moiety of SEQ ID NO:1.
Narasimhaswamy teach compositions and methods useful for delivering agents to target cells or tissues, for example nerve cells in the central nervous system. The reference further teaches using the compositions to deliver agents, for example therapeutic agents for the treatment of neurologically related disorders (abstract). Narasimhaswamy teach compositions and methods to deliver agents to a cell, e.g cell with acetyl choline receptors (AchR) present on the surface of the cell. The reference teaches methods to deliver agents to a CNS cell (para [0008]). The targeting agent is an RVG peptide or a derivative or a variant thereof (para [0010], [0036]). The RVG peptide comprises YTIWMPENPRPGTPCDIFTNSRGKRASNG (SEQ ID NO: 13) or a variant or a derivative or fragment thereof. SEQ ID NO:13 of Narasimhaswamy has 93.8% sequence identity with the RVG peptide of instant SEQ ID NO:1. The peptide targets delivery to cells which sit entirely within BBB-protected CNS tissue; e.g., brain cells, spinal cord cells, glial cells and other cells supporting neurons, for e.g. astrocytes or “nursing cells” and cells of the central nervous system (e.g., paras [0105]-[0107]). Narasimhaswamy teaches that the RVG peptide can be in a fusion protein and used to deliver agents to the brain or spinal cord (e.g., paras [0073], [0149]-[0150], [0192]-[0193]). Effector agents/therapeutic agents include those that can be useful in the treatment of neuronal injury, e.g., spinal cord injury, stroke and brain injury (para [0184]-[0195], [0225], [0236], [0241], [0247]).
It would have been obvious to one of ordinary skill in the art to prepare a Ndfip1 fusion polypeptide comprising the neuron transport moiety of NO:13 of Narasimhaswamy and the Ndfip1 peptide of Tan et al. Tan expressly taught that Ndfip1 could be used to treat disorders of the central nervous system, especially trauma injuries. As evidenced by the NICDH article, the central nervous system is made up of the brain and spinal cord. Tan taught a fusion protein comprising Ndfip1 and a targeting peptide, Tat (Example 8). The Ndfip1 peptide of Tan (SEQ ID NO:2) has 100% identity with instant SEQ ID NO:24. The skilled artisan would further have recognized that Narasimhaswamy taught RVG as a targeting peptide, SEQ ID NO:13, that could be used in a fusion protein to deliver a therapeutic agent, e.g., Ndfip1, to the spinal cord for treatment of a traumatic spinal cord injury (e.g., paras [0073], [0149]-[0150], [0184]-[0195], [0225], [0236], [0241], [0247]). Thus, the skilled artisan would have been motivated to prepare a fusion protein comprising the RVG peptide of Narasimhaswamy and the Ndfip1 peptide of Tan to target Ndfip1 wherein the RVG peptide could target delivery of Ndfip1 to the central nervous system. The skilled artisan would have had a reasonable expectation of success in preparing the claimed fusion protein because Tan and Narasimhaswamy each taught fusion proteins and treatment of traumatic injuries in the central nervous system.
It further would have been obvious to one or ordinary skill in the art to substitute the targeting peptide TAT of the TAT-Ndfip1 fusion protein of Tan, with the RVG neuronal-targeting peptide of Narasimhaswamy, in order to prepare a TAT-Ndfip1 fusion protein. Narasimhaswamy taught that RVG could target delivery (e.g., Ndfip1) to neuronal cells of the central nervous system. Both Tan and Narasimhaswamy taught treatment of traumatic injuries of the nervous system. A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the TAT peptide for the RVG peptide because TAT and RVG were taught are both explicitly taught as being useful as targeting peptides for delivering proteins with biological activity. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Accordingly, claim 39 is rendered obvious. SEQ ID NO:13 of Narasimhaswamy is 93.8% identity with instant SEQ ID NO:1.
Further regarding claim 39, Narasimhaswamy teaches that the RVG peptide can comprise SEQ ID NO:13 or a derivative or a variant thereof (para [0010], [0036]). Son
et al teach a RVG peptide that targets neuronal cells (abstract). The RVG can bind specifically to the acetylcholine receptor (nAchR) on neuronal cells to enable entry into neuronal cells and spread throughout the brain (p. 18). Son et al disclose successful RGV-mediated delivery of siRNA [delivery cargo] to the brain via neuronal cells. Id. The RVG peptide sequence is YTIWMPENPRPGTPCDIFTNSRGKfRASNG (p. 19) and has 100% identity with instant SEQ ID NO:1. The RVG peptide of Son et al is deemed to be a variant or derivative of the RGV peptide YTIWMPENPRPGTPCDIFTNSRGKRASNG (SEQ ID NO:13) of Narasimhaswamy.
Regarding claims 48 and 56-58, Tan et al teach pharmaceutical compositions and pharmaceutically acceptable carrier, as well as medicaments, and therapeutic compositions (e.g., paras [0043], [0120]-[0134]; claims 10, 13). The terms “agent”, “compound”, “active agent”, “pharmacologically active agent”, “medicament”, “active” and “drug” may be used interchangeably (para [0043]). The compositions can be used to treat traumas on the nervous system (e.g. paras [0013]-[0014], [0020], [0117]).
Narasimhaswamy teach delivery of therapeutic agents to treat spinal cord injuries, including traumatic injuries (e.g. paras [0105]-[0106], [0192]-[0193], [0205], [0225], [0236]-[0239]).
Accordingly, claims 39, 48, and 56-58 are rendered obvious.
Claim(s) 39, 40, 48, and 56-58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tan (U.S. 2009/0054307), as evidenced by NICHD article, “What are the parts of the nervous system?,” 2018, accessed 8/29/2026 at URL nichd.nih.gov/health/topics/neuro/conditioninfo/parts, and further in view of Narasimhaswamy (U.S. 20140294727) and Son et al (J Control Rel 155:18-25 (2011)), as applied to claims 39, 48, and 56-58 above, and further in view of NovoPro, (Commonly used leader peptide sequences for mammalian cells expression, 2018, accessed 8/29/2026 at URL novoprolabs.com/support/articles/commonly-used-leader-peptide-sequences-for-efficient-secretion-of-a-recombinant-protein-expressed-in-mammalian-cells-201804211337.html).
The teachings of Tan, NICHD, Narasimhaswamy and Son et al are set forth above. Narasimhaswamy discloses reparation of recombinant proteins in mammalian cells (Example 1-3). Tan discloses reparation of recombinant proteins in mammalian cells (e.g., Example 8, 16). Narasimhaswamy further teaches that the proteins can comprise a signal sequence or leader sequence to direct the peptide through a membrane of a cell. Such a sequence refers to an amino acid sequence which can be naturally present on the peptides or provided from heterologous sources by recombinant DNA techniques (para [0160]).
The references do not teach the export/signal peptide of SEQ ID NO:7.
NovoPro discloses commonly used leader peptide sequences for mammalian cells expression. Leader sequence peptide is a sequence of 16 to 20 amino acids at the of some eukaryotic proteins that determines their ultimate destination. Proteins that are made and function in the cytosol lack leader sequences. Proteins destined for specific organelles require signal sequences appropriate for each organelle. The leader sequence for a protein destined to enter the endoplasmic reticulum always contains hydrophobic amino acids that become embedded in the lipid bilayer membrane, and it functions to guide the nascent protein to a receptor protein that marks the position of a pore in the membrane. Once the protein passes into the cysternal lumen through the pore, the leader segment is cleaved from the protein. Due to complex disulfide bonds and distinct glycosylation patterns preventing folding and expression in prokaryotic expression hosts, many secreted proteins necessitate production in more complex eukaryotic expression systems. Commonly used leader peptide sequences for efficient secretion of a recombinant protein expressed in mammalian cells include the VSV-G sequence of SEQ ID NO:7.
It would have been obvious to one of ordinary skill in the art to incorporate an export/signal sequence of SEQ ID NO:7 into the N-terminus of a Ndfip1 fusion polypeptide to allow for efficient processing of the fusion polypeptide via the endoplasmic reticulum following protein synthesis. The skilled artisan would have had a reasonable expectation of success because Tan and Narasimhaswamy taught methods of recombinant protein synthesis, as well as viral vectors and mammalian cells. NovoPro taught leader sequences that were known and commonly used in the prior art, including that of VSV-G (SEQ ID NO:7).
Accordingly, it claim 40 is rendered obvious.
Claims 39, 40, 48, and 56-58 rendered obvious in view of the teachings of the cited references.
Conclusion
No claims are allowed.
Claims 39, 40, 48, and 56-58 are pending and are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654
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