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 .
Application Status
This action is written in response to applicant’s correspondence received on 6/9/2026. Claims 1-2, 11, 13-15, 23-29, 32-33, 36, 41-42, and 46-48 are pending. Claims 1-2, 13-15, 24, 27-28, 33, and 41-42 have been amended. Claims 46-48 are newly added Claims 3-10, 12, 16-22, 30-31, 34-35, 37-40, and 43-45 have been cancelled. All pending claims are currently under examination.
Any rejection of record in the previous office actions not addressed herein is withdrawn. New grounds of rejection are presented herein that were not necessitated by applicant’s amendment of the claims since the office action mailed 11/06/2023. Therefore, this action is not final.
Nucleotide and/or Amino Acid Sequence Disclosures – New Objection Raised by Newly Submitted Specification
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. In particular, the sequence incorporation statement entitled “Sequence Listing” in the specification refers to the sequence listing file in terms of “KB,” but must refer to the size of the file in terms of “bytes.” See MPEP 2422.03, section I, “ASCII Text File Submitted VIA EFS-Web.”
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112 – New Rejection Not Necessitated by Amendment
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.
Claim 11 is 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.
Regarding claim 11, claim 11 recites that the polypeptide comprises SEQ ID NO: 6 or SEQ ID NO: 7, or the nucleic acid comprises a sequence having 95% identity to SEQ ID NO: 11. SEQ ID NO: 11 is the nucleic acid which encodes the polypeptide SEQ ID NO: 7. Claim 11 is unclear because the metes and bounds of the claim are not properly defined. Claim 11 recites both broad (SEQ ID NO: 11 at 95% identity) and narrow claim language (exact sequences of SEQ ID NOs 6 or 7). A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Claim Rejections - 35 USC § 101 – New Rejection Not Necessitated by Amendment
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 28-29 and 32 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Regarding claims 28-29 and 32, these claims are drawn to “host cells” which comprise a vector which can be human cells (claim 32). While the claims immediately considered on merits recite a composition, the present claims include a method wherein the methods include administration of the vectors into neuronal cells, where furthermore such vectors are administered to subjects which can be human (claims 33 and 41). Accordingly, when the claimed vector compositions in cells are delivered to a human subject, cells of the subject will comprise the composition claimed. Therefore, the claims would encompass cells in a human organism and the human organism itself.
Amending the claims to an isolated host cell or a host cell in vitro will be remedial to obviate this rejection.
Response to Arguments
The Applicant’s arguments filed 6/9/2026 have been considered but are not persuasive. The Applicant argues that amending claim 13 to include limitations from claim 22 are sufficient to overcome the rejection. This argument is persuasive with respect to claims 13-14. Claim 13 has been amended to now require a “vector” which is defined in the specification specifically as comprising a “transgene.” Thus, per the definition in the specification, a “vector” must necessarily encode a “transgene” which is a non-native gene to a vector. However, concerning claims 28-29 and 32, the claims as a whole including claims 33 and 41 include the administration of the cells/vectors to subjects, which can be human. As such, the cells recited are broadly read on human organisms. As discussed above, amending claims 28-29 and 32 to recite that the cells are “isolated” is sufficient to obviate the present 101 rejection.
112(a) Maintained/Updated in Response to Amendment
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, 11, 13-15, 23-29, 32-33, 36, 41-42, 46, and 48 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Regents of the University of California v. Eli Lilly & Co, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding independent claims 1 and 13, these claims are drawn to genera of polypeptides including a genus of polypeptide that is at least 95% identical to SEQ ID NO: 1 and lacking region 521-892 (claim 1 and its dependent claims) or SEQ ID NO: 8 (claim 13 and its dependent claims). Hence, the claims are broadly drawn to genera of amino acid sequences and the nucleic acids which encode them, where the amino acid sequences have up to 5% divergence from either SEQ ID NO: 1 lacking region 521-892 or SEQ ID NO:8. This claim language is problematic because the specification has not shown a sufficient number of species to show possession of these broad, unpredictable genera of the amino acid sequences, where each genus of sequences can comprise up to 5% mutations. Furthermore, claim 1 recites specific functionality of the polypeptide: that it functions as a dominant negative mutant variant of DLK, while claim 13 recites that the polypeptide functions to inhibit hetero/homodimerization. Thus, the claims recite functional limitations. However, no such core structural elements are identified in either SEQ ID NOs 1 region 1-520 or 8 to confer such functionality. Thus, the broad genera of polypeptide sequences and their variants as recited were not shown to be in possession by the Applicant at the time of filing.
Regarding the guidance provided in the specification, the Applicant provides examples, methods, and assays beginning at page 40 of the specification. The specification recites that random mutagenesis of DLK was performed (page 41 final paragraph to page 42 first paragraph). However, no data is presented to accompany any results of random mutagenesis; hence, no critical domains or residues are identified with any specific functionality by the Applicant with the exception of a few tested. For instance, the Applicants tested and reduced to practice the S302A mutation and compared the results to the K185A mutant, where the S302A mutant was found to show protective characteristics (paragraphs 179-181 and Figure 2). Furthermore, the K185 and S302 mutants showed variability in their functionality (see Figure 2); thus, mutations at different residues showed variable, unpredictable results according the data provided in the specification. Furthermore, regarding mutations to DLK, the specification appears to recite that some predicted sites showed no significant variation in neuroprotective functionality (see paragraph 189). Thus, the specification does not appear to teach core structural elements or a specific mutational strategy to characterize the broad genus recited, as different mutations have different and unpredictable effects on the functionality of the protein (paragraph 189). Paragraph 191 recites that a random mutagenesis strategy was employed to identify the mutant G516V, however such a mutant variant does not appear to have been tested or verified with any specific functionality. Furthermore, no mutagenesis analysis and/or characterization of SEQ ID NO: 8 or the nucleic acid encoding the polypeptide SEQ ID NO: 8 (i.e., LZK) appears to have been performed. Thus, the Applicant has not shown possession of the recited variants of either SEQ ID NO: 1 or 8.
Regarding the state of the art, proteins which are phosphorylated such as DLK are known to be uncharacterized and unpredictable, where such proteins are involved with highly complex signaling networks. For instance, Jaskula-Ranga (WO 2018/009562 A1) is a patent document that focuses on methods of using CRISPR to treat retinal degeneration disease (Title, Abstract, throughout). Jaskula-Ranga teaches that:
“in vertebrates, there are several DLK phosphorylation sites, including S643, S302, S295, S302, T306 and S643 which do not appear to be regulated by the known DLK kinases (i.e. JNK and DLK), suggesting the possibility of novel, upstream regulatory kinases,” (page 132, first paragraph).
Thus, Jaskula-Ranga teaches that phosphorylation sites are not all characterized fully, and further that DLK proteins are known to be regulated by unknown DLK kinases (above). Jaskula-Ranga therefore teaches that phosphorylation sites on DLK proteins are not fully characterized or known, and that changing such sites would therefore have unknown effects, as kinases which act on such DLKs are also unknown (above).
Furtthermore, Jin (Jin Y et al. Annu Rev Cell Dev Biol. 2019 Oct 6;35:501-521) is a review article focused on DLK kinases (Title, Abstract, and throughout). Jin teaches that:
The DLK proteins are represented by two members known as MAP3K12 (or DLK) and MAP3K13 (or LZK) in vertebrate genomes and by a single member in most invertebrates (Figure 1). Each full-length kinase consists of approximately 900 amino acids, with the kinase domain at the N terminus, followed by two LZs and a long C terminus. The sequence homology among all members is primarily in the kinase and LZ domains, while the C termini are rich in proline, serine, and acidic amino acids but share little sequence similarity between DLK and LZK in the same species (Figure 1). LZ domains are found in many proteins and generally mediate homo- or heterodimerization. For DLK and LZK, the LZ domains are essential for their activation; mutating a single leucine residue in either LZ abolishes the activity of these kinases to phosphorylate JNK in transfected cell lines,” (page 2, third paragraph).
Thus, Jin teaches that individual point mutations are known to have dramatic effects on the functionality of both DLK and LZK kinases (above).
Given the fact that the Applicant’s specification itself shows a diverse range of unpredictable results concerning individual mutations in the recited protein sequences (e.g., Figure 2, paragraph 189), and furthermore their recited random mutagenesis strategy does not show functional data or a way to predict what mutations may have any functional effects as either creating a dominant negative DLK (claim 1) or inhibitory LZK (claim 13), the Applicant does not appear to have characterized the presently recited genera of polypeptides comprising 5% sequence identity to either SEQ ID NOs 1 region 1-520 or 8 because such a genera and the functionality of its species can not be reliably predicted, nor has the Applicant provided a reliable way to predict how such mutant proteins would function or behave.
Claims 2 ,11 and 46 depend from claim 1 and claims 14, 23-29, 32-33, 36, 41-42 depend from claim 13; these claim do not resolve the 112a issue and are therefore also rejected. Regarding claim 2, while claim 2 recites specific examples of mutations, claim 2 as presently recited can comprise further, uncharacterized mutations. Similarly, while claim 11 recites SEQ ID NOs 6 or 7, claim 11 also recites SEQ ID NO: 11 (region 1-520) with 95% identity to SEQ ID NO: 11. Claim 11 therefore suffers the same 112(a) is sue as claim 1 by reciting SEQ ID NO: 11 at 95% identity.
Regarding claim 15, claim 15 recites that the amino acid is at least 95% identical to residues 158-520, and comprises “at least one mutation” at position 302. Thus, claim 15 is drawn to a larger genus than claim 1 because only region 158-520 is required to be 95% identical to SEQ ID NO: 1, where the amino acid is recited with “at least one” which includes any number of proteins in the region from 1-157. Thus, claim 15 also comprises unpredictable mutations within the recited genus, not only with the 5% variability in region 158-520, but further with respect to the language that “at least one” mutation exists, which is open-ended claim language allowing for any number of mutations between residues 1-157. Claim 48 depends from claim 15, and while claim 48 narrows the percent identity requirement for residues 158-520, which is itself still an unpredictable genus of amino acid sequence as discussed in the state of the art, above, claim 48 still allows for multiple mutations within the 1-157 region of SEQ ID NO: 1.
Furthermore, method claims 33, 36, 41, and 42 recite additional limitations with functional requirements. For instance, claims 33 and 41 recite methods of inhibiting neural cell death (claim 33) or treating or preventing neural cell death (claim 41). Given that the genus of polypeptide recited in these claims itself has not been characterized (i.e., SEQ ID NO: 8), the number of mutants and variants comprised within this genus and their role in treating or preventing or inhibiting neural cell death has also not been characterized.
The state of the art teaches that minor changes in the protein family recited result in dramatic functional changes within the protein. The Applicant has not characterized the recited amino acid sequences to show sufficient possession of the scope of what is claimed.
Response to Arguments
The Applicant’s arguments filed 6/9/2026 have been considered but are not persuasive. The Applicant argues that by narrowing the percent identity requirement for the claimed subject matter the written description rejection is overcome. This argument is not persuasive because it does not address the full merits of the original rejection. For instance, the state of the art teaches that it is known that minor changes in sequences, including single point mutations, can have profound effects on the recited proteins (see above). However, the Applicant does not appear to have provided a structure-function relationship between what point mutations such amino acids can tolerate and retain their function. Furthermore, the Applicant’s specification demonstrates unpredictability with data and predictions with respect to which point mutations would have a predicted effect (see 112(a) rejection, above). Furthermore, although the Applicant has amended the claim to now recite 95% sequence identity, 5% variability in a 520 residue protein still comprises millions of variations (i.e., 26 residues changed, where each residue can be 1 of 20 amino acids). The specification does not offer guidance with respect to which domains or specific residues can tolerate mutations, where it is known in the art that single point mutations can dramatically affect the recited proteins (see rejection, above).
Claim Rejections - 35 USC § 103 – New Rejection Necessitated by Amendment
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.
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.
Claims 1-2, 11, 15, 46, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Borchers (Börchers S et al. Naunyn Schmiedebergs Arch Pharmacol. 2017 Aug;390(8):813-825) in view of GenBank NP_001180440 (‘440, GenBank Accession number of locus NP_001180440, Human MAP3K12 sequence, published 6/25/2017), Chen (Chen X et al. J Neurosci. 2008 Jan 16;28(3):672-80), and Nihalani (Nihalani D et al. J Biol Chem. 2000 Mar 10;275(10):7273-9) and Chamberlain (Chamberlain K et al. Hum Gene Ther Methods. 2016 Feb;27(1):1-12).
Regarding claims 1-2, Borchers is a research article focused on the study of the DLK kinase in HIT-T15 cells (Title, Abstract, and throughout). As an initial matter, the presently recited SEQ ID NO: 1 is the human DLK protein (see specification at page 47). Thus, claim 1 is broadly reciting a human DLK protein comprising a mutation at position 302. Borchers teaches the wildtype DLK protein, and furthermore teaches the mutation at position 302, where the mutation is S302A (e.g., page 815 left column, first paragraph, Figure 2). Borchers teaches that such DLK S302A mutants can be encoded in nucleic acids which encode the polypeptides (for instance, page 814, right column, final paragraph into page 815, left column, first paragraph). Furthermore, Borchers teaches that:
“These data suggest that TNFα induces beta-cell apoptosis through activation of DLK thereby inhibiting the beta-cell protective transcription factor CREB. Furthermore, activation of DLK by a well-known diabetic risk factor supports the role of DLK in the pathogenesis of diabetes mellitus. Thus, the inhibition of DLK might prevent or retard the pathogenesis of diabetes mellitus type 2,” (Abstract).
Thus, Borchers teaches a motivation to inhibit DLK for treatment of disease, and further teaches that it is an important drug target (above, and also “Discussion,” first paragraph).
Borchers further teaches that:
“These findings indicate that TNFα leads to a sustained activation of JNK and DLK; whereby DLK stimulates JNK, JNK activity promotes DLK dimerization and activation which in turn increases JNK activity. Thus, the interruption
of this cycle might constitute a worthwhile drug target,” (page 822, right column, first paragraph)
Furthermore, when Borchers teaches that DLK is an important drug target, they reference Chen (Discussion, first paragraph). Thus, Chen can be viewed as part of the teachings of Borchers. Chen is a research article which teaches the antiapoptotic and trophic effects of dominant negative DLK mutants in dopamine neurons (Title, Abstract, and throughout). Thus, Borchers teaches the therapeutic potential of DLK and references Chen who teaches such therapeutic potential in the form of dominant negative DLK. Borchers furthermore teaches the dominant negative S302A form of DLK, and further teaches DLK role in disease and the benefit of targeting it for treatment (Abstract, Discussion first paragraph).
Borchers, by referencing Chen and teaching/suggesting DLK as a target disease, and by teaching the dominant negative form of DLK S302, teaches the essential subject matter of claim 1 (i.e., a dnDLK that has a mutation at position 302).
Borchers/Chen does not teach that the dnDLK lacks residues 521-892 of SEQ ID NO: 1. Borcher does not appear to explicitly teach the sequence of human DLK (i.e., SEQ ID NO: 1).
Furthermore, Chen teaches methods of packaging shortened domains of the DLK leucine zipper protein (e.g., page 673, left column, third paragraph, “domain of human DLK was obtained by PCR from the human DLK clone using primers for the nucleotide sequence encoding amino acids 372–487”). Thus, the methods of Chen involving packaging leucine zipper domains into AAV vectors includes shorter regions of such proteins. Chen has already taught and reduced to practice truncated versions of dnDLK which are functional and shorter than residues 1-520, and therefore teaches predictability when truncating such proteins (Chen, page 673, left column, third paragraph). Thus, Chen has already taught the strategy of truncating dnDLK proteins, and teaches that shorter constructs have been made and reduced to practice for dominant negative effects (i.e., residues “372-487,” page 673, left column, third paragraph).
In addition, with Chen teaches that “the DN-DLK-LZ construct blocks homodimerization of DLK molecules and thereby prevents autophosphorylation and activation,” (page 676, right column final paragraph to page 677 left column first paragraph). Chen here references Nihalani, and therefore incorporates the teachings of Nihalani. Nihalani teaches that they truncated the DLK protein to include residues 1-520, where such constructs comprise the critical leucine zipper domain for homodimerization (e.g., page 7274, right column, final paragraph to page 7275). Thus, Nihalani, referenced by Chen to teach blockage of homodimerization in the context of therapeutic use, has already taught that the 1-520 region of DLK comprises critical homodimerization domains, where residues 521-892 were expendable (see Results of Nihalani on page 7275).
GenBank ‘440 is sequence data from GenBank which teaches the sequence of human MAP3K12. ‘440 teaches that MAP3K12 is a synonym for DLK (see “Remark” section on page 1 of ‘440). Thus, ‘440 teaches the sequence of the human DLK sequence. An alignment of ‘440 and instant SEQ ID NO: 1 is shown below:
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911
738
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SEQ ID NO: 1 (TOP) aligned with ‘440 (Bottom).
Thus, SEQ ID NO: 1 and ‘440 are a 100% identical match, where position 302 is the serine site taught by Borchers.
Additionally, Chamberlain is a review article that teaches current understanding of vector packaging and designs (Title, Abstract, and throughout). Chamberlain teaches that it is known in the art when using vectors such as AAV vectors, those used by Chen, that considerations must be taken into account including the limited size of nucleic acid which can be packaged into a given vector (see Title and Abstract). Chamberlain teaches that there are known strategies to allow for more efficient packaging of nucleic acid into vectors such as AAVs, including truncating a therapeutic protein to retain only its functional domain (e.g., page 3, right column, second paragraph). Thus, Chamberlain teaches a motivation to truncate a protein to comprise only functional fragments, so that they are more easily packaged into vectors such as AAV vectors (Abstract, page 3, right column).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to make a mutated version of ‘440 comprising the mutation S302A and to truncate the protein to comprise residues 1-520 because Borchers has in fact already taught this mutation and its potential role in therapeutics. Borchers simply did not explicitly teach the human sequence of the protein DLK, but the sequence was already known in the art as taught by ‘440. Thus, Borchers in light of the teachings of ‘440 arrive at the present invention, where the S302A mutation was already known in the art and taught by Borchers. Furthermore, a practitioner would be motivated to make such a mutation in human DLK because Borcher/Chen teach that such mutations are useful for therapeutics against disease, where Chen further teaches that dominant negative DLK mutants have therapeutic benefits (Abstract), and furthermore references Nihalani who teaches such truncation embodiments as those recited (i.e., Nihalani has already taught the truncated version of DLK from residues 1-520 and demonstrated its functionality, as taught and referenced by Chen).
Furthermore, Chamberlain teaches a motivation to truncate a therapeutic protein so that it can be more easily packaged into an AAV vector, such as those taught by Chen, and therefore teaches a motivation to incorporate the truncations taught by Nihalani such as the 1-520 truncation of DLK comprising the active leucine zipper with the AAV vector packaging strategy taught by Chen, to accommodate packaging into an AAV vector.
Regarding claim 11, an alignment of SEQ ID NO: 6 with ‘440 is given below:
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577
802
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SEQ ID NO: 6 (top) aligned with ‘440 (bottom).
As seen above, SEQ ID NO: 6 and ‘440 are a ~99% match with the exception that SEQ ID NO: 6 comprises the S302A mutation. Thus, the S302A DLK mutant rendered obvious by the combination of Borchers/’440 discussed in the rejection of claim 1 also reads on claim 11, where the Borchers/’440 S302A DLK mutant would comprise SEQ ID NO: 6, where furthermore the 1-520 residue truncation is already known as taught by Chen/Nihalani.
Regarding claim 15, as discussed above, the S302A DLK mutant rendered obvious by Borchers/’440/Chen/Nihalani is a 100% match of SEQ ID NO: 1 comprising a mutation at S302 (see rejection of claim 1, above). Thus, the mutant DLK S302 variant rendered obvious by Borchers/’440 also reads on claim 15 because residues 158-520 of the Borchers/’440 DLK polypeptide are at least a 95% match to SEQ ID NO: 1.
Regarding claims 46 and 48, as discussed above, ‘440 is a 100% match of SEQ ID NO: 1, and the mutant truncation variant rendered obvious by Borchers/’440/Chen/Nihalani reads on claims 46 and 48.
Response to Arguments
The Applicant’s arguments filed 6/9/2026 have been considered but are not persuasive. The Applicant argues that the amended claims are now directed to a truncated form of dnDLK, where residues 521-892 are lacking, where the combination of Borchers and Chen do not teach such a protein. This argument is persuasive. However, the teachings of Nihalani were discovered during the search prompted by the Applicant’s amendments, where Nihalani teaches that the 1-520 truncated version of the DLK protein was in fact already known and reduced to practice, where Chen teaches that such a truncated protein retains critical domains to block homodimerization of DLK molecules to prevent autophosphorylation and activation (see above). Thus, the presently recited subject matter, including the S302A mutation and 1-520 residue truncation of DLK, as well as the use of dnDLK truncated variants, are all known prior art elements. Furthermore, contrary to the Applicant’s assertions regarding predictability, the fact that Nihalani has reduced to practice and characterized the functional domains of the 1-520 truncation variant offers evidence for a reasonable expectation of success.
Thus, the combination of prior art elements includes the 1-520 residue version of SEQ ID NO: 1 presently recited, as taught by Nahalani as a known, functional variant of DLK (SEQ ID NO: 1), where furthermore motivation is known to exist to make truncations to retain functional domains as taught by Chamberlain for AAV vector packaging purposes (see above).
Furthermore, contrary to the Applicant’s arguments, the prior art does teach predictability of functionality concerning a 1-520 truncation because Nihalani has already made this truncation, reduced the truncation to practice, and characterized the functional domains required for phosphorylation and dimerization (Nihalani, page 7525). Furthermore, the S302 has similarly already been reduced to practice, as taught by Borchers. Given that the 302 residue resides within the functional domains of the 1-520 truncation, and that both of these elements have been reduced to practice, the prior art teaches a high degree of predictability of success when making the recited amino acid sequence.
The Applicant argues that unexpected results have been obtained. This argument is not persuasive because the claim language does not include the recited unexpected results, and is instead simply drawn to SEQ ID NO: 1 which has been truncated to comprise residues 1-520 with an additional 302 mutation. Thus, the Applicant is arguing elements which are not present within the claim (e.g., elements such as potency and max efficacy in relation to WT or other mutations does not appear in the language of claim 1).
New 103 Rejection Not Necessitated by Amendment
Claims 13, 23-29, 32-33, 36, 41-42, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Chalberg (WO 2020/168111 A1, published 8/20/2020) in view of Chen 2 (Chen M et al. Cell Rep. 2018 Mar 27;22(13):3587-3597) and GenBank AAI11727 (GenBank Accession Number AAI727, hereafter ‘727, human MAP3K13 protein sequence, published 2006).
Regarding claim 13, Chalberg is a patent document that teaches therapeutic strategies for gene therapies, where leucine zipper kinases/proteins are administered using therapeutic compositions and vectors (Title, Abstract, and see throughout). Chalberg teaches that LZK can be administered in such a therapeutic vector (e.g., Abstract). Chalberg teaches that such therapeutic proteins are dominant negative/inhibitory (Abstract). Chalberg teaches that vectors comprise encoded nucleic acid sequecnes to deliver such polypeptides (paragraph 33). Chalberg teaches that the inhibitor/therapeutic can comprise functional fragments of LZK (paragraph 81). Chalberg teaches that human subjects are administered their therapeutics (e.g., paragraphs 26-27).
Chalberg, while teaching LZK, and that such polypeptides are encoded in nucleic acids and comprised in vectors, does not teach the specific sequence presently recited: SEQ ID: 8.
Chen 2 is a research article that focuses on the role of LZK in astrocyte reactivity in mammalian CNS (Title, Abstract). Chen 2 teaches that LZK is also known as MAP3K13 (Abstract). Chen 2 teaches that “LZK overexpression in astrocytes enhanced astrogliosis and reduced lesion size” and that “identification of LZK as a critical cell-intrinsic regulator of astrocyte reactivity expands our understanding of the multicellular response to CNS injury and disease, with broad translational implications for neural repair,” (Abstract). Chen teaches that LZK/MAP3K13 plays an important role in CNS repair after injury (Introduction, final paragraph, and page 3588).
Furthermore, ‘727 teaches the amino acid sequence of human MAP3K13 (i.e., LZK, see pages 2-3 of ‘727). An alignment of instant SEQ ID NO: 8 with ‘727 shows 100% sequence identity with human MAP3K13 (see page 1 of ‘727). Thus, SEQ ID NO: 8 is simply the known sequence of human LZK/MAP3K13, as taught by ‘727.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the LZK sequences taught by Chalberg to include LZK/MAP3K13 as taught by Chen 2, and specifically the human MAP3K13 protein as taught by and evidenced by ‘727, because such a combination is the simple substitution of one known prior art element for another with predictable success. In the present case, the practitioner would simply substitute the LZK sequences taught by Chalberg for the known human LZK sequence taught by ‘727, where furthermore the LZK/MAP3K13 gene is already known to be critical in neuronal repair and recovery per Chen 2, which would motivate such a substitution. In addition the results are predictable because Chen 2 has already reduced to practice the overexpression of the MAP3K13/LZK gene and shown taught its functionality in CNS cells. As Chalberg is directed to therapeutic cellular interventions using LZK and DLK genes, the teaching of Chen 2 that MAP3K13 (LZK) is a critical element of neuronal repair would motivate the combination.
Regarding claims 23-26, Chalberg teaches that the sequence can be comprised in a rAAV vector (e.g., paragraphs 91), where furthermore the vector can be AAV2.7m8 (paragraph 94).
Regarding claim 27, Chalberg teaches that the expression cassette in vectors can comprise WPRE (Table 2, page 19, final row).
Regarding claims 28-29, Chalberg teaches that that the vectors of their invention can be introduced into a retinal ganglion (e.g., paragraph 97).
Regarding claim 32, Chalberg teaches that the vectors are introduced into retinal ganglions to treat disease (paragraph 98), where furthermore “administration” is taught to be in human cells (paragraph 22). Thus, Chalberg teaches that such vectors are administered into retinal ganglions (paragraph 98).
Regarding claims 33, 36, 41, Chalberg teaches a method of treatment of retinal ganglion cells by administration of the vectors of their invention and therefore teaches the active steps of the methods recited in claims 33, 36, and 41 (paragraphs 97-98). Chalberg teaches transfection of the vectors to host cells (paragraph 43).
Regarding claim 42, Chalberg teaches that the subject can have glaucoma (paragraph 97).
Regarding claim 47, as discussed above, ‘727 is 100% identical to SEQ ID NO: 8 and therefore comprises SEQ ID NO: 8 (see rejection of claim 13).
Claims 14 is rejected under 35 U.S.C. 103 as being unpatentable over Chalberg (WO 2020/168111 A1, published 8/20/2020) in view of Chen 2 (Chen M et al. Cell Rep. 2018 Mar 27;22(13):3587-3597) and GenBank AAI11727 (GenBank Accession Number AAI727, hereafter ‘727, human MAP3K13 protein sequence, published 2006), as applied to claims 13, 23-29, 32-33, 36, 41-42, and 47, above, and further in view of Nihalani (Nihalani D et al. J Biol Chem. 2000 Mar 10;275(10):7273-9) Yan (Yan D et al. Neuron. 2012 Nov 8;76(3):534-48), and Chamberlain (Chamberlain K et al. Hum Gene Ther Methods. 2016 Feb;27(1):1-12).
A discussion of Chalberg, Cheng 2, and ‘727 with regards to claim 13 is given above and incorporated here. Chalberg/Cheng 2.’727 renders obvious SEQ ID NO: 8 encoded in a vector. Furthermore, Chalberg teaches that functional fragments of LZK and also DLK can be used in their therapeutic approaches (paragraph 81 also paragraph 108). Chalberg teaches that their methods comprise dominant negative DLKs which form inactive heterodimers with endogenous DLKs (paragraph 7).
Chalberg/Cheng 2/’727 does not specifically teach that the LZK comprises SEQ ID NO: 8 and is fewer than 150 residues.
Regarding SEQ ID NO: 8, SEQ ID NO: 8 is portion of human MAP3K13/LZK, as taught by ‘727 (pages 2-3). With regard to LZK and its relationship to DLK, Yan teaches that: “mammalian genomes encode two closely related DLK family kinases known as
MAP3K12/DLK/MUK/ZPK and MAP3K13/LZK,” (Introduction, third paragraph). Thus, Yan teaches that it was known that DLK and LZK are closely related proteins, and further teaches that these proteins share similar structural domains (e.g., Figure 1B). Indeed, an alignment of instant SEQ ID NO: 1 (DLK) is shown below with instant SEQ ID NO: 8 (LZK):
PNG
media_image3.png
424
1004
media_image3.png
Greyscale
As seen above, SEQ ID NO: 8 comprises a high sequence similarity with instant SEQ ID NO: 1 (i.e., WT DLK, per the specification), where 91% positive identity exists between SEQ ID NO: 8 and residues 405-520 of DLK (above).
Regarding region 405-520 of MAPKKK proteins such ash DLK, Nihalani teaches such a truncation of DLK comprising residues 405-520 of DLK, where based upon the alignment above corresponds to SEQ ID NO: 8 (see page 7274, right column final paragraph to page 7225, “F-DLK(405-520)”). Nihalani teaches that this region, 405-520, comprises the critical leucine zipper domain of DLK, which is the domain which allows for oligomerization, and therefore teaches that this region itself is sufficient for binding of DLK (i.e., the leucine zipper domain see page 7225, left column). Thus, SEQ ID NO: 8 is simply the leucine zipper domain of LZK, which shares a high sequence homology with the leucine zipper domain of DLK, where truncations comprising only this domain have already been reduced to practice and have shown to be the critical region for oligomerization of DLK proteins, the therapeutic goal of Chalberg.
Additionally, Chamberlain is a review article that teaches current understanding of vector packaging and designs (Title, Abstract, and throughout). Chamberlain teaches that it is known in the art when using vectors such as AAV vectors, those used by Chalberg, that considerations must be taken into account including the limited size of nucleic acid which can be packaged into a given vector (see Title and Abstract). Chamberlain teaches that there are known strategies to allow for more efficient packaging of nucleic acid into vectors such as AAVs, including truncating a therapeutic protein to retain only its functional domain (e.g., page 3, right column, second paragraph). Thus, Chamberlain teaches a motivation to truncate a protein to comprise only functional fragments, so that they are more easily packaged into vectors such as AAV vectors (Abstract, page 3, right column).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the vectors comprising SEQ ID NO: 8 rendered obvious by Chalberg, Chen 2/’727 to include an amino acid which is fewer than 150 amino acids as taught by Nihalani because such a combination is the simple combination of known prior art elements with predictable success. In the present case, the goal of Chalberg is to form inactive oligomerizations of DLK and LZK variants, where the homolog of SEQ ID NO: 8, DLK, has already been identified to comprise a homologous region of SEQ ID NO: 8 to comprise the leucine zipper domain which is the domain that is responsible for oligomerization. Thus, the practitioner would be motivated to use SEQ ID NO: 8 comprising fewer than 150 residues (e.g., SEQ ID NO: 8) because this is the known domain that is responsible for the outcome and goal of Chalberg: to generate inactive heterodimers. Further, Nihalani has already taught and reduced to practice the inventive concept of truncating an MAPKKK homolog (DLK) to comprise residues 405-520 alone and has shown that such a truncation is functional for the desired goal of Chalberg to make heterodimers. Furthermore, the sequence homology between DLK and LZK is very high indicating a high degree of predictability and success when adopting the same truncation strategy to include the leucine zipper domain alone with the LZK protein.
Furthermore, Chamberlain teaches a motivation to truncate a therapeutic protein so that it can be more easily packaged into an AAV vector, such as those taught by Chalberg.
Response to Arguments
The Applicant’s arguments filed 6/9/2026 have been considered. With respect to the original 102 rejection, the Applicant argues that the claim language was misinterpreted, where a definition from the specification was misapplied to claim 13. This argument is persuasive, and the original 102 rejection with respect to claim 13 and its dependent claims is withdrawn. Claim 13 was subsequently searched again, and a new rejection not necessitated by amendment has been presented for claim 13 and its dependent claims (see 103 rejection, above). As such, the present action is not final, as new rejections have been made not as a result of amendment.
Conclusion
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/D.C.R./ Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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