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 .
Election/Restrictions
Applicant’s election without traverse of Group 1, claims 1-15, in the reply filed on 06 February 2026 is acknowledged.
Claims 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06 February 2026.
Claim Status
Claims 16-20 have been withdrawn and claims 1-15 have been examined on their merits.
Claim Interpretation
Claim 3 discloses the language “the engineered AAV viral capsid comprises an amino acid sequence of SEQ ID NO: 3”. The language of the claim is interpreted as any amino acid sequence found in the sequence of SEQ ID NO: 3, thus not requiring the sequence as a whole. If this is not the intention of the claim, it is recommended to change the article “an” to “the”.
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 5-6 and 15 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 5, in the first line of the claim refers to the engineered AAV vector of claim 5. Since the claim depends upon itself the metes and bounds of the claim are unclear. The language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds". See, e.g., the following decisions: In re Hammack, 427 F 2d. 1378, 1382, 166 USPQ 204, 208 (CCPA 1970); In re Venezia 530 F 2d. 956, 958, 189 USPQ 149, 151 (CCPA 1976); In re Goffe, 526 F 2d. 1393, 1397, 188 USPQ 131, 135 (CCPA 1975); In re Watson, 517 F 2d. 465, 477, 186 USPQ 11, 20 (CCPA 1975); In re Knowlton 481 F 2d. 1357, 1366, 178 USPQ 486, 492 (CCPA 1973). For the purpose of compact prosecution, the claim is interpreted as depending from claim 4.
Claim 6, in the first line of the claim refers to the engineered AAV vector of claim 6. Since the claim depends upon itself the metes and bounds of the claim are unclear. The language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds". See, e.g., the following decisions: In re Hammack, 427 F 2d. 1378, 1382, 166 USPQ 204, 208 (CCPA 1970); In re Venezia 530 F 2d. 956, 958, 189 USPQ 149, 151 (CCPA 1976); In re Goffe, 526 F 2d. 1393, 1397, 188 USPQ 131, 135 (CCPA 1975); In re Watson, 517 F 2d. 465, 477, 186 USPQ 11, 20 (CCPA 1975); In re Knowlton 481 F 2d. 1357, 1366, 178 USPQ 486, 492 (CCPA 1973). For the purpose of compact prosecution, the claim is interpreted as depending from claim 5.
Claim 15 recites the phrase “transactivator of transcription (TAT) sequence (SEQ ID NO: 4)”, which renders the claim indefinite because it is unclear whether the limitation in parenthesis (SEQ ID NO) are part of the claimed invention. MPEP § 2173.05(d) states, description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.
Therefore, it is unclear whether the SEQ ID NO in parentheses is exemplary or a limitation of the claim. As such, the claim is interpreted as requiring any TAT sequence.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Sah et al. (WO 2019/067840 A1, published 04 April 2019).
Regarding claims 1-3, Sah teaches an adeno-associated virus (AAV) particle comprising a capsid and a viral genome, wherein said capsid delivers the AAV particle to a nervous system, and wherein said viral genome comprises a polynucleotide sequence encoding Frataxin (a therapeutic molecule, claim 1b) and one or more microRNA binding sites (Abstract). Sah teaches the amino acid sequence of the capsid is SEQ ID NO: 2, which comprises a TLAVPK insertion after amino acid residue 588 in reference to wild-type AAV9 capsid protein VP1 (claims 1a and 2) (see search results, file us-18-549-948-3.rag, Result 17). The sequence of Sah reads on an amino acid sequence of instant SEQ ID NO: 3 (claim 3).
Regarding claims 4-5, Sah teaches tissue-specific expression elements can be used to restrict expression to certain types of cell types such as, nervous system promoters (claim 4) which can be used to restrict expression to neurons or subtypes of neurons, astrocytes, or oligodendrocytes (claim 5) (para. [0099]).
Regarding claim 6, the viral genome comprises a promoter, to include Synapsin and GFAP promoters (para. [0104]).
Thus, the reference anticipates the subject matter of claims 1-6.
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 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Sah et al. (WO 2019/067840 A1, published 04 April 2019) as applied to claims 1-6 above, and further in view of Gao et al. (US 2020/0392500 A1, published 17 December 2020, IDS ref.) and Wang et al. (Cell Reports 24, 2540-2552, published 4 September 2018, IDS ref.).
Sah anticipate the subject matter of claims 1-6, and thus, also render them obvious.
Regarding claims 7-9, Sah does not teach wherein the therapeutic molecule comprises one or more inhibitor of one or more neural anti-regenerative pathway targets, to include let-7 miRNA or anti-let-7 tough decoy (TuD) RNA. For clarity of the record claims 8 and 9 identify let-7 miRNA and anti-let-7 TuD RNA as neural anti-regenerative pathway target/inhibitor.
However, Gao teaches rAAV-based compositions comprising miRNA inhibitors (Abstract). Gao teaches it may be desirable to deliver the virions to the CNS of a subject, to include neuronal cells, glial cells, and astrocytes (para. [0087]). Gao teaches the use of rAAV for the delivery of miRNA antagonists, to include anti-oncogenic miRNA, Let-7, as a target for inhibition (claim 8) (para. [0110]). Gao teaches miRNA inhibitors of Let-7, specifically TuD Let-7 inhibitors (claim 9) (para. [0113]). Since Gao teaches an AAV vector comprising the TuD Let-7 inhibitors, this reads on an AAV vector comprising a therapeutic molecule comprising an inhibitor of a neural anti-regenerative pathway target (claim 7).
The limitations in claim 8 are presented in the alternative, therefore, the receptor of CSPGs is not required.
Additionally, Wang teaches the Lin28/let-7 axis plays a role in axon regeneration in the mammalian CNS (Abstract). Wang teaches Lin28a/b are both necessary and sufficient for supporting axon regeneration in mature sensory neurons through their regulatory partners, let-7 microRNAs (miRNAs) (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the engineered AAV vector of Sah with the therapeutic molecule of Gao with a reasonable expectation of success because both Sah and Gao teach AAV vectors comprising therapeutic molecules. One would be motivated to utilize the engineered AAV vector of Sah with the therapeutic molecule of Gao because Wang teaches let-7 miRNAs play a role in regeneration in the CNS and both Sah and Gao teach AAV virions capable of delivering a therapeutic molecule to the CNS of a subject.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 7-8 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Sah et al. (WO 2019/067840 A1, published 04 April 2019) as applied to claims 1-6 above, and further in view of Lang et al. (WO 2013/155103 A1, published 17 October 2013) and Ohtake et al. (Scientific Reports, 6:37152, published 16 November 2016).
Sah anticipate the subject matter of claims 1-6, and thus, render them obvious.
Regarding claims 7-8 and 10, Sah does not teach wherein the therapeutic molecule comprises one or more inhibitor of one or more neural anti-regenerative pathway targets, to include a receptor of chondroitin sulfate proteoglycans (CSPGs). For clarity of the record claim 8 and 10 identify CSPGs as neural anti-regenerative pathway targets, therefore, the inhibitors of CSPG read as neural anti-regenerative pathway targets.
However, Lang teaches methods of inhibiting the activity of LAR family phosphatases in a cell (Abstract). Lang teaches in some embodiments, the LAR family phosphatase is a receptor protein tyrosine phosphatase sigma (PTPσ) (para. [0007]). Lang teaches the cell is a neural cell, glial cell, glial progenitor cell, or a neural progenitor cell (para. [0009]). Lang teaches The LAR family of phosphatases consists of three members: LAR itself, receptor protein tyrosine phosphatase Sigma (RPTPσ) and receptor protein tyrosine phosphatase delta (RPTPδ), wherein PTPσ and PTPf (LAR itself) have been implicated as receptors for CSPG, a principal constituent of the glial scar and perineuronal net (para. [0078]). Lang teaches all members of the LAR family share a wedge domain, which mediates home/heterophilic interactions (para. [00206]). Lang teaches the utilization of peptide mimetics of the wedge domain tagged to a cytosolic localizing TAT sequence, LAR activity was successfully abolished in neurotrophin signaling paradigms (para. [00206]). Lang teaches orthologous sequence in RPTPσ and RPTPδ and designed a wedge domain peptide for each target (para. [00206]). Lang teaches the peptides were coined intracellular LAR blocking peptide (ILP), intracellular Sigma blocking peptide (ISP) and intracellular delta blocking peptide (IDP) (para. [00206]). Lang teaches the therapeutic peptides can be expressed in cells being treated using gene therapy to inhibit LAR family signaling via a vector including a nucleotide encoding the therapeutic peptides (para. [00124]). Lang teaches said vectors include viral vectors, such as AAV vectors (para. [00128]).
Additionally, Ohtake teaches following CNS injuries, a family of extracellular matrix (ECM) molecules, the chondroitin sulfate proteoglycans (CSPGs), are highly upregulated by reactive scars and potently inhibit axon growth into and beyond the lesion area (p. 1). Ohtake teaches two members of the LAR subfamily, PTPσ and LAR, bind CSPGs with high affinity and mediate their suppression of axon elongation (p. 1). Ohtake teaches pharmacological blockade of LAR or PTPs with small peptides stimulated regrowth of serotonergic axons and functional recovery after transection or contusion spinal cord injury (SCI) (p. 1). Ohtake teaches pharmacological inhibition of either PTPσ or LAR induces significant regrowth of several projection fiber tracts after SCI, including serotonergic, corticospinal and sensory fibers, and improves functional recovery (Conclusions). Ohtake teaches given widespread expression of these RPTPs in adult CNS their suppression should promote growth of other tracts, such as the rubrospinal, reticulospinal and propriospinal axons, therefore, because PTPσ and LAR conveyed CSPG signaling by both convergent and divergent pathways, blocking both RPTPs simultaneously should produce additive effects in promoting axon regeneration (Conclusion).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the engineered AAV vector of Sah with the therapeutic molecule of Lang in view of Ohtake with a reasonable expectation of success because both Sah and Lang teach AAV vectors comprising therapeutic molecules. One would be motivated to utilize the engineered AAV vector of Sah with the therapeutic molecule of Lang in view of Ohtake because the teachings of Lang in view of Ohtake suggest pharmacological inhibition of CSPG receptors induces significant regrowth of several projection fiber tracts after SCI, including serotonergic, corticospinal and sensory fibers, and improves functional recovery and Ohtake suggests blocking multiple RPTPs simultaneously should produce additive effects in promoting axon regeneration.
The limitations in claim 8 are presented in the alternative, therefore, the let-7 miRNA is not required.
Regarding claims 11 and 12, the teachings of Sah in view of Lang and Ohtake to not specifically teach an AAV vector comprising at least three inhibitors of CSPG receptors.
However, it would have been obvious to one of ordinary skill in the art to utilize the engineered AAV vector of Sah with at least three therapeutic molecules of Lang in view of Ohtake with a reasonable expectation of success because their combined teachings suggest blocking multiple RPTPs simultaneously should produce additive effects in promoting axon regeneration. One would have been motivated to utilize the engineered AAV vector of Sah with at least three therapeutic molecules of Lang in view of Ohtake because Lang teaches the relationship between all three CSPG receptors LAR, PTPσ, and PTPδ, thus, the combination of an engineered vector comprising inhibitors of all three CSPG receptors would have been considered obvious.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Sah et al. (WO 2019/067840 A1, published 04 April 2019) in view of Lang et al. (WO 2013/155103 A1, published 17 October 2013) and Ohtake et al. (Scientific Reports, 6:37152, published 16 November 2016) as applied to claims 7-8 and 10-12 above, and further in view of Liu et al. (Scientific Reports, 7:2193, published 19 May 2017).
Regarding claim 13, Sah in view of Lang and Ohtake do not teach wherein the at least three selective antagonist peptides are expressed as a single peptide separated by self-cleaving 2A peptides. However, the utilization of self-cleaving 2A peptides to express multiple peptides was known in the art.
Liu teaches 2A “self-cleaving” peptides have garnered increased interest for their polycistronic nature, small size and high “cleavage” efficiency (Abstract). Liu teaches Co-expression of multiple genes at a desired ratio is highly attractive for a broad array of basic research and biomedical applications including expression of multiple subunits of complex multimeric proteins in gene therapy (p. 1). Liu teaches 2A peptides have also been successfully
employed by several different groups for polycistronic and bi-cistronic multigene expression (p. 1). The teaches of Liu provide useful information that may guide thoughtful design of bi-, tri-, and quad-cistronic constructs that yield desired ratios of gene co-expression (p. 7).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the 2A self-cleaving peptides of Liu with the engineered AAV vector suggested by Sah in view of Lang and Ohtake with a reasonable expectation of success because Liu teaches 2A self-cleaving peptides were known in the art to facilitate the expression of multiple peptides from a single peptide. One would have been motivated to utilize the 2A self-cleaving peptides of Liu with the engineered AAV vector suggested by Sah in view of Lang and Ohtake because applying a single AAV vector would simplify the application of the vector system and the expression of all three peptides would be expected to have an additive effect.
Regarding claims 14 and 15, Lang teaches the utilization of peptide mimetics of the wedge domain tagged to a cytosolic localizing TAT sequence, LAR activity was successfully abolished in neurotrophin signaling paradigms (para. [00206]). Specifically, Lang utilized HIV-TAT (para. [00209]). The cytosolic localizing TAT sequence (claim 15) reads as a conjugate which promotes traversal of the peptide across the plasma membrane of a transduced cell into the extracellular space (claim 14). As indicated in the 112(b) rejection of claim 15, the claim is interpreted as requiring any TAT sequence.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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