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 .
DETAILED ACTION
This action is in response to the papers filed on June 29, 2026. Claims 1-6, 10-17, 19-22 and 26-28 are currently pending. Withdrawn claims 10-17 and 19 and claim 1, 2 and 5 have been amended, and claim 28 has been added by Applicants’ amendment filed on 6/29/2026. No claims have been canceled.
Applicants' previous election of Group 1 directed to an expression cassette, e.g., claims 1-6 wa previously acknowledged. Claims 10-17, 19-22, 26 and 27 were previously withdrawn from further consideration, pursuant to 37 CFR l. l 42(b ), as being drawn to non-elected invention, there being no allowable generic or linking claim. The restriction requirement was previously made FINAL.
Therefore, claims 1-6, and newly added claim 28 are under examination to which the following grounds of rejection are applicable.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/040238, filed July 2, 2021. Applicant’s claim for the benefit of a prior-filed parent provisional application 63/048,405, filed on July 6, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is July 6, 2020.
Response to Arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112
In view of the amendments filed June 29, 2026, the rejection under 35 USC § 112(b) has been considered and found persuasive. As such, the rejection of claims 1-6 has been withdrawn.
Maintained Objections/Rejections in Response to Applicants Arguments or Amendments
Claim Rejections - 35 USC § 102
To the extent that the examiner is interpreting claim 1 as an expression cassette comprising one or more polynucleotides encoding a polypeptide comprising a fragment of the TDP-43 protein, where the phrase “a polypeptide comprising a fragment of the TDP-43 protein” is broadly interpreted as comprising the polypeptide that is 155 aa or less and any additional amino acid flanking one or both sides to the polypeptide that is 155 aa or less, the following rejection stands.
Claims 1 and 2 remain rejected under 35 U.S.C. 102(a(1))(a(2)) as being anticipated by Julien et al. [Cited in IDS filed 2/14/2023; citations are from US Pub. Pub. 2016/0091504].
Regarding claim 1, Julien teaches an expression cassette [para 0059, "The present invention also relates to an expression cassette comprising the sequence of TDP-43WT. TDP- 43A315T or TDP-43G348C"] comprising one or more polynucleotides encoding a polypeptide at least 95% identical to a sequence as set forth in SEQ ID NO: 8 [SEQ ID NO: 1 amino acids 275- 414 of Julien exhibit 100% identity to claimed SEQ ID NO: 8 (See alignment of claimed amino acid sequence of SEQ ID NO: 8 and of Julien’ SEQ ID NO: 1 below)]; para 0097 "TDP-43 polypeptides as well as polynucleotides are well known in the art. For example, see NM_007375.3, Gene Bank AK222754.1 or UniProt 013148 Representative polypeptide sequence (SEQ ID NO:1)"]. Thus, the polynucleotide of Julien encodes a TDP-43
fragment having 140 amino acids in length and reading on a polynucleotide comprising a fragment of the TDP-43 protein consisting of a polypeptide that is 155 amino acids or less.
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Regarding claim 2, Julien teaches the expression cassette of claim 1, wherein the one or more polynucleotides comprise a sequence at least 95% identical to a sequence as set forth in SEQ ID NO: 3 [SEQ ID NO: 2 nucleic acids 859-1314 of Julien exhibit 100% identity to claimed SEQ ID NO: 3; See alignment of claimed nucleotide sequence of SEQ ID NO: 3 and of Julien’ SEQ ID NO: 2 below].
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Thus Julien teaches a nucleotide sequence of 456 nucleotides (positions 859-1314) having 100% sequence identity to the nucleotide sequence of SEQ ID NO: 3 of 456 nucleotides of length.
Thus, by teaching all the claimed limitations, Julien et al., anticipates claims 1 and 2.
Response to Applicant arguments as they apply to the rejection of the claims under 35 U.S.C. 102 over Julien et al.
Beginning on page 7 of remarks filed on June 29, 2026, Applicants essentially argue the following:
As described above, the current claims recite a "TDP-43 protein fragment consisting of a polypeptide that is 155 amino acids or less in length and that is at least 95% identical to the amino acid sequence of SEQ ID NO:4 or 8." The cited art alone or in combination fails to teach such fragments. Instead, the cited art teaches full-length TDP-43.
Applicants’ arguments have been fully considered but they are not persuasive for the following
reason(s):
Regarding 1), as set forth in the paragraph above, claim 1 recites the term comprising in line 2, comprising one or more polynucleotides encoding a polypeptide comprising a fragment of the TDP-43 protein which is broadly but reasonably interpreted as comprising the full length of 155 amino acids or less and any additional amino acids flanking one or both sides of the 155 amino acids fragment. Thus, the polynucleotide of Julien encodes a TDP-43 fragment having 140 amino acids in length and reading on a polynucleotide comprising a fragment of the TDP-43 protein consisting of a polypeptide that is 155 amino acids or less (note that the amino acid of SEQ ID NO: 4 comprises 152 amino acids).
). Moreover, Julien discloses that in one embodiment, that the TDP-43 that be the entirety of SEQ ID NO: 1 or a fragment thereof (Julien, para 0099), wherein the TDP-43 polypeptide can be utilized to understand the progression of neurodegenerative disease in a subject (Julien, para 0049).
Claim Rejections - 35 USC § 103
To the extent that the examiner is interpreting claim 1 as an expression cassette comprising one or more polynucleotides encoding a polypeptide comprising a fragment of the TDP-43 protein, where the phrase “a polypeptide comprising a fragment of the TDP-43 protein” is broadly interpreted as comprising the polypeptide that is 155 aa or less and any additional amino acid flanking one or both sides to the polypeptide that is 155 aa or less, the following rejection stands.
Claim(s) 1-6 remain rejected and claim 28 is newly rejected under 35 U.S.C. 103 as being unpatentable over Julien et al. [Cited in IDS filed 2/14/2023; citations are from US Pub. Pub. 2016/0091504], in view of Foglieni et al. [Cited in IDS filed 2/14/2023]. This is a modified rejection necessitated by the amendments filed June 29, 2026.
Regarding claim 1, Julien teaches an expression cassette [para 0059, "The present invention also relates to an expression cassette comprising the sequence of TDP-43WT. TDP- 43A315T or TDP-43G348C"] comprising one or more polynucleotides encoding a polypeptide at least 95% identical to a sequence as set forth in SEQ ID NO: 8 [SEQ ID NO: 1 amino acids 275- 414 of Julien exhibit 100% identity to claimed SEQ ID NO: 8 (See alignment of claimed amino acid sequence of SEQ ID NO: 8 and of Julien’ SEQ ID NO: 1 below)]; para 0097 "TDP-43 polypeptides as well as polynucleotides are well known in the art. For example, see NM_007375.3, Gene Bank AK222754.1 or UniProt 013148 Representative polypeptide sequence (SEQ ID NO:1)"].
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Thus, the polynucleotide of Julien encodes a TDP-43 fragment having 140 amino acids in length and reading on a polynucleotide comprising a fragment of the TDP-43 protein consisting of a polypeptide that is 155 amino acids or less.
Regarding claim 2, Julien teaches the expression cassette of claim 1, wherein the one or more polynucleotides comprise a sequence at least 95% identical to a sequence as set forth in SEQ ID NO: 3 [SEQ ID NO: 2 nucleic acids 859-1314 of Julien exhibit 100% identity to claimed SEQ ID NO: 3; See alignment of claimed nucleotide sequence of SEQ ID NO: 3 and of Julien’ SEQ ID NO: 2 below].
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Regarding claim 3, Julien discloses expression cassettes functionally linked to promoters and other translational regulatory control elements (para [0174], “’expression cassette’ as used herein refers to the combination of promoter elements with other transcriptional and translational regulatory control elements which are operably linked”). Further, Julien discloses the expression cassette of claim 1, further comprising a polynucleotide encoding a promoter [para 0167, “the expression “human TDP-43 genomic fragment operably linked to a human TDP-43 promoter” refers to a TDP-43 nucleic acid sequence fragment comprising TDP-43 coding sequence, the introns, the 3′ sequence autoregulating TDP-43 synthesis…[and] the human TDP-43 promoter] and a second expression cassette comprising polynucleotide encoding a fluorescent protein [para 0211, "We used TDP- 43wt; GFAP-luc double transgenic mice because the reporter luciferase (luc) allowed the longitudinal and non-invasive biophotonic imaging with CCD camera of the GFAP promoter activity which is a target of activated NF-kB"].
However, Julien does not explicitly teach that a single expression cassette is comprised of a polynucleotide encoding a promoter and a polynucleotide encoding a fluorescent protein.
It would have been obvious for someone of ordinary skill in the art to combine the polynucleotides encoding SEQ ID NO: 8 into a single expression cassette containing a fluorescent protein and a promoter to detect protein expression by translational regulatory control elements in the promoter. Such expression of the fluorescent protein would allow for non- invasive imaging of GFAP promoter activity. A skilled artisan would have had a reasonable expectation of success as controlling gene vector expression encoding a polynucleotide of interest using activation of promoters by transcription factors was known in the before the effective filing date of the claimed invention.
A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
Regarding claim 4, Julien makes obvious the expression cassette of claim 3, yet Julien does not teach the expression cassette comprising a polynucleotide encoding a linker sequence.
However, Foglieni teaches expression cassettes comprising a polynucleotide encoding for a linker sequence.
Foglieni discloses the parallel implementation of two split GFP technologies, the GFP bimolecular and trimolecular fluorescence complementation (biFC and triFC) in the context of TDP-43 self-assembly [page 1 para 1], comprising a polynucleotide encoding a linker sequence [page 2, para 3 - Fig. 1 A and C "For both tagged variants, the S11 beta-strand of GFP was spaced from Tau by a relatively short, nine amino acid-long linker"]. Furthermore, Foglieni teaches that a linker sequence can be “engineered to carry a short antibody epitope, in order to facilitate the independent analysis of fusion constructs” [page 6 para 1 “The presence of noth TDP-43 forms in the same cells was confirmed by immune staining…specific for the epitopes inserted in the respective linkers”]. Foglieni also teaches that “Expression of the two TDP-43 tagged variants with GFP 1-10 also resulted in a nuclear signal produced by the T 11β1-TDP- 43/GFP 1_10 biFC complex” (page 3, last paragraph).
With the aim of understanding TDP-43 assembly, it would have been obvious to modify the expression cassette rendered obvious by Julien to incorporate a linker sequence carrying an epitope linking a small GFP fragment, with a TDP variant to arrive at the claimed invention. The incorporation of Foglieni’s linker sequence allows for the visualization of successful fusion constructs within living cells, containing the TDP variant. Furthermore, due to the oligomeric structure of TDP-43, it would have been obvious to incorporate small fragment tags such as T10- 11 to visualize the direct protein interactions with inner protein domains. A skilled artisan would have had a reasonable expectation of success as localization of nuclear TDP-43 using two TDP- 43 tagged variants with GFP 1-10 resulting in a nuclear signal produced by the T 11β 1-TDP- 43/GFP 1_10 biFC complex (Fig. 2D) was known in the before the effective filing date of the claimed invention.
The rationale to support a conclusion that the claim would have been obvious is that a method of enhancing a particular class of devices (methods, or products) has been made part of the ordinary capabilities of one skilled in the art based upon the teaching of such improvement in other situations. One of ordinary skill in the art would have been capable of applying this known method of enhancement to a "base" device (method, or product) in the prior art and the results would have been predictable to one of ordinary skill in the art. See Intel Corp. v. PACT XPP Schweiz AG, 61 F.4th 1373, 1380-81, 2023 USPQ2d 297 (Fed. Cir. 2023). See also MPEP 2143(I)(C).
Regarding claim 5, the combined teachings of Julien and Foglieni render obvious the expression cassette of claim 1, 3 and 4. Moreover, Foglieni teaches the linker sequence is present between the polynucleotide encoding the fluorescent protein (page 2 para 3 , "For both tagged variants, the S11 beta-strand of GFP was spaced from Tau by a relatively short, nine amino acid-long linker"). Foglieni teaches that parental plasmids each encoding for one of the two C-terminal consecutive β strands T10 and T11 of GFP22 followed by a peptide linker was used to subclone of cDNAs encoding a protein of interest (page 2, last paragraph).
Regarding claim 6 and 28, Julien renders obvious the expression cassette of claims 1 and 3. Moreover, Foglieni teaches that the fluorescent protein is a fluorescent donor protein or a fluorescent acceptor protein of a proximity detection protein pair (page 1 para 2, "Fluorescent sensors are applied to determine protein interactions in cells. One prominent example is FRET from donor to acceptor fluorophores coupled to binding partners"). See Legend Fig 2. C. “Dimerization of the tagged TDP-43 proteins steers T10 and T11 in an orientation and distance allowing triFC”
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A skilled artisan would have been motivated to utilize FRET donor to acceptor fluorophores to determine protein interactions within cells. Thus, it would have been obvious to modify Julien’s construct to select a GFP 1-10 to dimerize tagged TDP-43 proteins and nuclear colocalization in triFC with a reasonable expectation of success
Response to Applicant arguments as they apply to the rejection of the claims under 35 U.S.C. 102 over Julien et al. in view of Foglieni et al.
Beginning on page 5 of remarks filed on June 29, 2026, Applicants essentially argue the following:
The cited art alone or in combination fails to teach such fragments. Instead, the cited art teaches full-length TDP-43. The inventors have demonstrated in the examples of the application that full-length TDP-43 failed to function as biosensors. Accordingly, the current claims are non-obvious over the cited art, since they provide novel TDP-43 fragments that may be used as biosensors.
Further, dependent claims 3, 5, 6, and 28 also recite encoding fluorescent proteins. Claims 6 and 28 discuss a fluorescent protein that is a fluorescent donor protein or a fluorescent acceptor protein of a proximity detection protein pair. The cited references do not teach or suggest the combination of the claimed fragment of the TDP-43 protein and a fluorescent donor protein, much less a fluorescent protein that is a fluorescent donor protein or a fluorescent acceptor protein of a proximity detection protein pair.
Applicants’ arguments have been fully considered but they are not persuasive for the following
reason(s):
Regarding 2), as set forth in the paragraph above, the instant claims are not limited to the specific nucleotide sequence of SEQ ID NOS 3 or 7 encoding the ubiquitinated and cleaved form of TDP-43 known as pathologic TDP-43, TDP-43 fragment, or TDP-43 prion. That is the amino acid of SEQ ID NO: 4 ( e.g, 262-414 TDP-43).The fact that Applicants have demonstrated that “terminal truncations that were 224 amino acids in length (see, table 2, page 34-35, para. [0172], cell line 191-414) failed to function as biosensors.” Is not disputed. However, the instant claims are broadly directed to a polypeptide encoding a polypeptide at least 95% identical to a sequence as set forth in the amino acid sequence of SEQ NO:4 or SEQ ID NO:8. See claim 5. Thus, the instant claims do not exclude terminal truncations of the TDP-43 protein.
Furthermore, the instant claims are not limited to any specific functional limitations associated with the claimed structure. The examiner notes that although Julien doesn’t expressly use the term “biosensor”, Julien uses immunofluorescence to detect mutant TDP-43 polypeptides (para 0213) and biomarkers to determine progression of neurodegenerative disease (para 0049), and the instant claims are silent on the limitation that the TDP-43 polypeptides are utilized in a biosensor. Additionally, Foglieni teaches a fluorescent donor protein or a fluorescent acceptor protein of a proximity detection protein pair (page 1 para 2, "Fluorescent sensors are applied to determine protein interactions in cells. One prominent example is FRET from donor to acceptor fluorophores coupled to binding partners"), and that the GFP sensor can be used to detect a protein of interest (pp. 10 para 2).
Regarding 3), in contrast to applicants’ arguments “ much less a fluorescent protein that is a fluorescent donor protein or a fluorescent acceptor protein of a proximity detection protein pair”, Foglieni is relied upon to satisfy the deficiency of Julien, as Julien does not explicitly teach a fluorescent donor protein or a fluorescent acceptor protein of a proximity detection protein pair. Foglieni teaches the use of fluorescence to determine protein interactions in cells (pp. 1, para 3). Foglieni discloses the parallel implementation of two split GFP technologies, the GFP bimolecular and trimolecular fluorescence complementation (biFC and triFC) in the context of TDP-43 self-assembly [page 1 para 1], comprising a polynucleotide encoding a linker sequence [page 2, para 3 - Fig. 1 A and C "For both tagged variants, the S11 beta-strand of GFP was spaced from Tau by a relatively short, nine amino acid-long linker"]. Furthermore, Foglieni teaches that an example of these types of sensors is a complementation of polypeptide fragments that display fluorescence when in proximity of a fluorophore such as GFP (pp. 1, para 3), and that a combination of using trimolecular complementation and bimolecular complementation aids in the visualization of protein interactions/self-assembly and level of protein expression (pp. 1, para 1-2). One of ordinary skill in the art would have been motivated to apply the fluorescence-complentation technique taught by Foglieni to the TDP-43 interaction system of Julien as Julien is concerned with methods of diagnosing a disease via an expression construct comprising the TDP-43 polypeptide or fragment thereof (Julien, para 0002), while Foglieni teaches a method of visualizing protein interactions involving TDP-43. The incorporation of Foglieni’s linker sequence allows for the visualization of successful fusion constructs within living cells, containing the TDP variant. Furthermore, due to the oligomeric structure of TDP-43, it would have been obvious to incorporate small fragment tags such as T10- 11 to visualize the direct protein interactions with inner protein domains. A skilled artisan would have had a reasonable expectation of success as localization of nuclear TDP-43 using two TDP- 43 tagged variants with GFP 1-10 resulting in a nuclear signal produced by the T 11β 1-TDP- 43/GFP 1_10 biFC complex (Fig. 2D) was known in the before the effective filing date of the claimed invention.
New Grounds of Rejection
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This is a new rejection necessitated by Applicant’s amendments to the claims. Claim 5 depends on claim 1. Claim 1 newly requires that “a polypeptide comprising a fragment of the TDP-43 protein, wherein the TDP-43 protein fragment consists of a polypeptide that is 155 amino acids or less in length”. Claim 5 broadens the scope of the claimed polynucleotide, permitting that it may be “a polynucleotide encoding a polypeptide at least 95% identical to a sequence as set forth in the amino acid sequence of SEQ NO:4 or SEQ ID NO:8.”
Applicants may cancel the claim, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Katriel B Kasayan whose telephone number is (571)272-1402. The examiner can normally be reached 10-4p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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