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 .
Claims Status
The amendments and remarks filed 12/15/2025 are acknowledged.
Claims 1-8 and 10-16 are pending.
Claims 9 and 17-18 are cancelled.
Claims 1-2, 6, and 16 are amended.
Claims 1-8 and 10-16 are under examination.
Withdrawn
The objection to claim 6 is withdrawn. Applicant has amended the claim to overcome the objection.
The rejections of claims 2-4 and 15-16 under 35 U.S.C. 112(b) are withdrawn. Applicant has amended claim 2 to overcome the rejections.
The rejections of claims 1-16 under 35 U.S.C. 112(a). Applicant has presented persuasive arguments (see pages 10-12 of the remarks) to overcome the rejections.
The rejections of claims 1-8, 10-12, and 14-16 under 35 U.S.C. 102 are withdrawn. Applicant has amended the claims to overcome the rejections.
Drawings
The drawings are objected to because Figures 1C, 2B, 3B, 4C, 5A, and 5B are in color and there has been no petition filed under 37 CFR 1.84(a)(2). Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
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 1-8, 10-12 and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Julien (WO2016086320; 04/30/2025 11 Page IDS) in view of Schlothauer et al., 2016 (09/15/2025 PTO-892).
Regarding claims 1 and 6, Julien teaches TDP-43 antigen (target protein) binding constructs that comprise at least one heavy chain variable region (VH) and one light chain variable region (VL) that together comprise six CDRs (i.e. an antigen binding site that binds specifically to a target protein) [0047-52]. Julien further teaches that the antigen-binding construct may comprise an Fc domain [0056], and specifically, the antigen-binding construct may be a polypeptide comprising a scFv linked to an Fc region [0060, 0073] and the Fc domain is a human IgG or IgG1 Fc [0075]. Julien also teaches that the antigen-binding constructs can be expressed in a host cell using an expression cassette for the antigen-binding construct [00117] and administered to the subject as part of a vector system [00164] with it being desirable to introduce the construct compositions into the central nervous system [00165]. Julien additionally teaches that the nucleic acids encoding the antigen-binding constructs can be administered in vivo to promote expression of its encoded protein (a method of expressing) by constructing it as part of an appropriate nucleic acid expression vector (expression cassette) and administering it (introducing into the cell) so that it becomes intracellular [00169]. Additionally, Julien teaches specific scFv formatted anti-TDP-43 antibodies, E6_VH1Vk9 and E6_VH7Vk9, and transfecting (introducing) cells with the expression plasmid containing the nucleic acids encoding these antibodies [00203; Example 6] and that the antibodies are expressed in microglial cells (cell of nervous system) [00211-00214].
Regarding the limitation in claim 1 of “and upon expression in the cell, two molecules of the polypeptide form a disulfide-bonded homodimeric bivalent binding member specific for the target protein”, this is inherent in the teachings of Julien. Since Julien teaches a polypeptide identical in structure to that instantly claimed, then this structure would necessarily have the same effects. Further, the polypeptide of Julien would necessarily form a disulfide-bonded homodimeric bivalent binding member when expressed because it has an Fc region. This is evidenced by Yu et al., 2017 (09/15/2025 PTO-892) that teaches that Fc dimerization is the result of extensive interactions between the CH3 domains of the Fc regions through disulfide bonds. Thus, two identical polypeptides comprising Fc domains when expressed, as taught by Julien, would necessarily form a disulfide-bonded homodimeric bivalent binding member (i.e. an antibody).
However, Julien does not specifically teach that the bivalent binding member binds to neonatal Fc receptor (FcRn), but is does not bind to an Fc gamma receptor due to one or more mutations in the IgG Fc region.
Schlothauer teaches recombinant hIgG Fc domains with the Fc mutation P329G that completely abolished FcyR (Fc gamma receptor) interactions (binding) and unaffected FcRn interactions (binding) and Fc stability, and therefore, had abolished immune effector functions, reduced Fc-mediated toxicity, and are for use in therapeutic applications [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to one of ordinary skill in the art to have modified the Fc region of Julien to be a recombinant IgG Fc domain of Schlothauer. One would have been motivated to make this modification because Schlothauer teaches that these Fc domains with a mutation completely abolished FcyR interactions, did not affect FcRn interactions and Fc stability, but had abolished immune effector functions and reduced Fc-mediated toxicity. Further, one would have been motivated to use the Fc domain of Schlothauer because it is a known Fc domain in the art, and it is obvious to use known variations known in the prior art for predictable outcomes. See MPEP 2143 (F). There would be a reasonable expectation of success in making this modification because Schlothauer teaches that this Fc domain can be used in therapeutic applications.
Regarding claims 2-5, Julien teaches that the TDP-43 antigen binding constructs are capable of entering neurons [00177], that the subject may be a human (i.e. human cells) [00159], that the constructs are capable of penetrating the blood brain barrier and capable of reducing the number or frequency of TDP-43 inclusion-positive neurons in the brain [00177], thereby indicating that the binding constructs can be expressed in human brain neurons (cells). Further, since Julien teaches that the antigen-binding construct is capable of reducing the number or frequency of TDP-43 inclusion-positive neurons in the brain, then TDP-43 (antigen; target) is necessarily a protein expressed in the brain.
Regarding claim 7, Julien teaches that the antigen-binding construct (polypeptide) can be an scFv format, which have the VL connected from its C-terminus to the N-terminal end of a VH or have the C-terminal end of the VH is connect to the N-terminal end of the VL [0068] that the variable regions may be connected by a linker peptide that allows the formation of a functional antigen-binding moiety [0069], that the construct may comprise an Fc region, which is the C terminal region of an immunoglobulin heavy chain, capable of stable self-association, and can be an IgG or IgG1 Fc [0073-0075].
Regarding claim 8, Julien teaches that linker can be [G4S]n where n can be 1 [0069].
Regarding claims 10 and 12, Julien teaches that the nucleic acid encoding the antigen-binding construct is inserted into an adeno-associated virus (AAV) vector which may be administered to the subject [0020, 00170, Example 12].
Regarding claim 11, Julien teaches that the antigen-binding constructs can be administered by intracranial administration [00177].
Regarding claim 14, Julien teaches that the polynucleotide insert [in the vector] is operatively linked to an appropriate promoter, such as the E. coli trp promoter (inducible promoter) [00124].
Regarding claims 15 and 16, Julien teaches that the antigen-binding constructs can be used for treatment of a disease characterized by TDP-proteinopathy, and the disease can be Alzheimer’s disease (neurodegenerative disease) [0022-0023], and teaches a method of treating the disease comprising administering to a subject a therapeutically effective amount of the AAV vector comprising at least one nucleic acid sequence that encodes at least one TDP-42 antigen-binding construct as disclosed [0019-0020].
Claims 1-8, 10-12 and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Julien (WO2016086320; 04/30/2025 11 Page IDS) in view of Schlothauer et al., 2016 (09/15/2025 PTO-892), as applied to claims 1-8, 10-12, and 14-16 above, and further in view of Levites et al., 2006 (04/30/2025 11 Page IDS).
The following rejection is in regards to the species election of amyloid beta peptide (Aβ) for the target protein, as set forth in instant claim 6.
The teachings of Julien and Schlothauer are above.
However, Julien and Schlothauer do not specifically teach that the target protein is Aβ.
Regarding claim 6, Levites teaches that Aβ triggers pathological changes that cause Alzheimer’s disease (AD) and teaches recombinant anti-Aβ single-chain variable fragments (scFvs) [see Abstract]. Levites further teaches that to achieve widespread brain delivery, the scFvs were packaged into AAV vectors and injected into AD mouse models, with intracranial delivery of the AAV resulting in widespread neuronal delivery (cell of the nervous system) [see Abstract]. Levites also teaches that expression of the anti-Aβ scFvs decreased Aβ deposition, suggesting that this is an effective strategy to attenuate amyloid deposition, and that this delivery method is a rapid and effective way to evaluate potential modifiers of AD-like pathology in AD mouse models [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the scFv of Julien to specifically be the scFv of Levites targeting Aβ. One would have been motivated to make this modification because Levites teaches that the AAV delivery of these scFvs resulted in widespread neuronal delivery and their expression decreased Aβ deposition, suggesting that this is an effective strategy to attenuate amyloid deposition, and that this delivery method is a rapid and effective way to evaluate potential modifiers of AD-like pathology in AD mouse models. Further, it would have been obvious to make this modification because both Julien and Levites are considered analogous art within the same field of endeavor of treating neurodegenerative diseases. See MPEP 2141.01(a).
Claims 1-8, 10-16 are rejected under 35 U.S.C. 103 as being unpatentable over Julien (WO2016086320; 04/30/2025 11 Page IDS) in view of Schlothauer et al., 2016 (09/15/2025 PTO-892), as applied to claims 1-8, 10-12 and 14-16 above, and further in view of Passini et al., 2003 (09/15/2025 PTO-892).
The teachings of Julien and Schlothauer are above.
However, Julien and Schlothauer do not specifically teach the recombinant AAV vector is of serotype 1 (AAV1).
Regarding claim 13, Passini teaches that AAV1 vectors showed robust transduction in the brain, AAV1 vectors transduced many more cells than AAV2, AAV1 vectors transduced mostly neurons, and AAV1-treated brains showed complete reversal of pathology in all areas of the brain for at least 1 year [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the AAV vector of Julien to specifically be an AAV1 vector as taught by Passini. One would have been motivated to specifically choose an AAV1 vector because Passini teaches that AAV1 vectors showed robust transduction in the brain, AAV1 vectors transduced many more cells than AAV2, AAV1 vectors transduced mostly neurons, and AAV1-treated brains showed complete reversal of pathology in all areas of the brain for at least 1 year. Therefore, based on the teachings of Passini, there would be a reasonable expectation of success in making this modification.
Response to Arguments
The objections to the drawings are maintained. No petition has been filed and granted under 37 CFR 1.84(a)(2) to accept the color drawings.
The rejections of claims 1-8 and 10-16 under 35 U.S.C. 103 over Julien in view of Levites, Schlothauer, and Passini are maintained. On page 14 of the remarks, Applicant argues that Julien does not present any data on, or even discuss, the problem of neuroinflammation caused by expressing large recombinant proteins in the nervous system. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., neuroinflammation caused by expressing large recombinant proteins in the nervous system) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Applicant further argues that Julien does not disclose a single example of a single polypeptide chain containing VH+VL (linked in scFv format) + IgG Fc region, wherein upon expression within a neuron cell, it forms into a bivalent disulfide-bonded homodimer. This is not persuasive because in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., wherein upon expression within a neuron cell) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims are drawn to any cell of the nervous system, not to neurons. Additionally, the Examiner has clearly articulated the teachings of Julien in the rejection above and that Julien teaches antigen-binding constructs that may be a polypeptide comprising a scFv linked to an Fc region and the Fc domain is a human IgG or IgG1 Fc. Further, the Examiner clearly articulated that regarding the limitation of “and upon expression in the cell, two molecules of the polypeptide form a disulfide-bonded homodimeric bivalent binding member specific for the target protein”, this is inherent in the teachings of Julien. Since Julien teaches a polypeptide identical in structure to that instantly claimed, then this structure would necessarily have the same effects. Further, the polypeptide of Julien would necessarily form a disulfide-bonded homodimeric bivalent binding member when expressed because it has an Fc region. This is evidenced by Yu et al., 2017 (instant PTO-892) that teaches that Fc dimerization is the result of extensive interactions between the CH3 domains of the Fc regions through disulfide bonds. Thus, two identical polypeptides comprising Fc domains when expressed, as taught by Julien, would necessarily form a disulfide-bonded homodimeric bivalent binding member (i.e. an antibody). See above. Applicant further argues that Julien provides no example of intracellular Fc-containing ScFv-bivalent homodimer antibodies expressed in neurons and instead, Julien states that an scFv format is preferred for its ability to cross cell membranes and enter cells. This is not persuasive because Applicant’s requirement that Julien reduce to practice its teachings is not the standard in the MPEP, and rather, art is art for all that it teaches and is presumed enabled. See MPEP 2121. More, “disclosed examples and preferred embodiments do no constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).” See MPEP 2123(II).
On page 15 of the remarks, Applicant argues that Levites does not remedy the deficiencies of Julien as it fails to disclose a single polypeptide chain comprising VH, VL, and an IgG Fc region, which when expressed within a neuron cell, forms into a bivalent disulfide-bonded homodimer. This is not found persuasive because no such deficiency exists, see above, and in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant further argues that that Julien has zero in vivo data and therefore, one would not have had any reasonable expectation that the scFv-Fc homodimers of the invention could be made in situ in the brain. This is not found persuasive because again, art is art for all that it teaches and reduction to practice is not required. See MPEP 2121. The Examiner has addressed the limitation of “and upon expression in the cell, two molecules of the polypeptide form a disulfide-bonded homodimeric bivalent binding member specific for the target protein” in the response and rejections above and the response will not be reiterated and is incorporated herein.
Further on pages 15-17 of the remarks, Applicant argues that the instant specification provides data demonstrating the superior expression level and the lack of neurotoxicity of expressing an scFv-Fc dimer in the brain, in contrast to the low efficiency and high neurotoxicity of expressing a traditional antibody in brain cells, citing Examples 3-5 of the instant specification, summarizing that the experimental data in the instant specification show that the scFv-Fc recited in the claims is durably expressed, secreted, and reduces plaque load comparably to chronic passive IgG therapy, with superior PK and no neurotoxicity, which is unexpected from the scFv approaches discussed in the cited art. This is not persuasive because the Examples Applicant points to for support of the alleged unexpected results are not commensurate in scope with the instant claims because the instant claims are drawn to any scFv-Fc protein, and not to the specific anti-Aβ scFv-IgG for AAV-mediated delivery used in the Examples. Further, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the scFv-Fc is durably expressed, secreted, and reduces plaque load with superior PK and no neurotoxicity) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Applicant additionally argues that Julien’s in vitro expression of TDP-43 binders provides no guidance or reasonable expectation on whether scFv-Fc dimers of the present invention could have been expressed successfully in the neural cells without causing neurotoxicity. This is not found persuasive because in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the scFv-Fc dimers are expressed in neural cells without causing neurotoxicity) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Even if the claims did recite these features, Julien teaches expressing polypeptides identical in structure to that instant claimed in cells of the nervous system, and therefore, these polypeptides would necessarily have the same effects as those instantly claimed since function flows from structure. See MPEP 2112.01(II).
On pages 17-18 of the remarks, Applicant argues that the teachings of Schlothauer do not remedy the deficiencies of Julien, and that Schlothauer provides no teaching or suggestion on expression of Fc-engineered antibodies inside central nervous system (CNS) cells via AAV or other gene therapy methods and provides no discussion of CNS-specific constraints, such as processing in neurons/astrocytes and secretion efficiency. This is not found persuasive because no such deficiency of Julien exists, see above. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., CNS-specific constraints, such as processing in neurons/astrocytes and secretion efficiency) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Applicant additionally argues the alleged unexpected results as discussed previously. The arguments regarding the alleged unexpected results have been addressed above, will not be reiterated, and are incorporated herein.
On pages 19-20 of the rejections, Applicant argues the teachings of Passini do not remedy the deficiencies of Julien and that Passini’s AAV1 payload is an enzyme rather than a single chain VH-VL-Fc bivalent homodimer antibody engineered to retain FcRn binding but abolish FcyR binding, targeting specific pathogenic proteins in neurodegenerative diseases, and that a skilled artisan could not simply have substituted Passini's serotype choice into Julien's constructs without addressing the fundamentally different payload requirements and processing constraints. First, this is not found persuasive because no such deficiency of Julien exists, see above, and in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., targeting specific pathogenic proteins in neurodegenerative disease) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, Applicant has not provided any objective evidence as to why one would avoid using the AAV1 of Passini. Applicant further argues that Passini's AAV1 data show neuronal preference but they do not address astrocyte transduction or its therapeutic implications for antibody payloads and that Passini does not use the AAV1 for delivery into mature CNS. This is not found persuasive because in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., astrocyte transduction or its therapeutic implications for antibody payloads, and delivery into mature CNS) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Applicant additionally argues the alleged unexpected results as discussed previously. The arguments regarding the alleged unexpected results have been addressed above, will not be reiterated, and are incorporated herein.
Conclusion
No claims are 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 Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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