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 .
This Action is in response to the papers filed July 10, 2026.
Claims 1, 5, 7, 10, 12-14, 19, 24, 40, 71-77 and 85-89 are pending in application. Claims 79-84 have been canceled, claims 1, 5, 10, 12-13, 40, and 73-74 have been amended and claims 85-89 have been newly added by Applicants’ amendment filed on 07/10/2026. Claims 1 and 40 are independent claims.
Applicant’s election without traverse of:
A molecular agent: a transgene encoding a protein
A transgene Delivery Method: viral vector
in the reply filed on 04/10/2025 was previously acknowledged.
Claims 24 and 77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 04/10/2025.
Therefore, claims 1, 5, 7, 10, 12-14, 19, 40, 71-76, and 85-89 are examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US20/46346, filed August 14, 2020.
Applicant’s claim for the benefit of a prior-filed parent provisional application 62/887,439, filed August 15, 2019 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 August 15, 2019
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Objections
The amendments filed 07/10/2026 correct the status of the claims and therefore, the objection is withdrawn.
Claim Rejections - 35 USC § 112 (b)
The rejection of claim 10 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second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn
Applicant’s arguments and amendments filed 07/10/2026 have been considered and are persuasive. In particular, Applicant has amended the claims to correct the antecedent basis.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 12, 40, 73, 79-82 and 84 under 35 U.S.C. 103 as being unpatentable over Ribeiro Mendes de Sousa (US20200190153; Filed 2018-05-07) as evidenced by Witke (2004. Trends in Cell Biology, Vol 14, No 8, pages 461-469) and Giampetruzzi (2019. Nature Communications volume 10, Article number: 3827 (2019); Applicant’s own work) in view of Gijselinck (Cold Spring Harb Perspect Med. 2018 Apr;8(4):a026757) as applied to claims 1 and 40 above, and in further view of Jagaraj (April 2019, Diss. Macquarie University) as evidenced by Boopathy (2017, UMass Chan Medical School, Doctoral Dissertation; previously cited) is withdrawn.
Applicant’s arguments and amendments filed 07/10/2026 have been considered and are persuasive. In particular, Applicant has amended the claims to no longer require cofilin.
Claim Rejections - 35 USC§ 112 d
The rejection of claim 13 under 35 U.S.C. l 12(d) or pre-AIA 35 U.S.C. 112, 4th
paragraph, has been withdrawn
Claim Rejections - 35 USC§ 103
The rejection of claims 1, 14, 40 and 75 under 35 U.S.C. 103 as being
unpatentable over Ribeiro Mendes de Sousa (US20200190153; Filed 2018-05-07) as
evidenced by Witke (2004. Trends in Cell Biology, Vol 14, No 8, pages 461-469) and
Giampetruzzi (2019. Nature Communications volume 10, Article number: 3827 (2019);
Applicant's own work) in view of Gijselinck (Cold Spring Harb Perspect Med. 2018
Apr;8(4):a026757) and Boopathy (2017, UMass Chan Medical School, Doctoral Dissertation; previously cited) has been withdrawn
A response to Applicant’s arguments with regard to a withdrawn rejection is moot. A response to any argument pertaining to a new or maintained rejection can be found below.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112 (a)
Claims 1, 5, 7, 10, 19, 40, 71-72, and 76 remain rejected and claims 85-89 are newly 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.
This rejection has been modified as necessitated by Applicant’s amendment filed 07/10/2026.
While applicant arguments’ amendment have partially overcome some of the issues, some additional issues remain that are discussed below. Independent claims 1 and 40 recite a transgene which is delivered or administered by any dosage to a cell or subject, however the specification does not provide adequate written description for the entire scope of these limitations and thus the claims.
The entirety of the scope of any dosage for the transgene or transgenes that encode an protein to a subject is extremely broad.
The only “effective amount” disclosed in the specification is generally for the case of viral vectors wherein “an amount of active agent can be included in each dosage form to provide between about 1010, 1011, 1012, 1013, 1014, or 1015 genome copies per subject” in treating a NCT defect associated disease such as ALS.
The working examples do not provide a minimum effective dosage of the transgene or small molecule. Each agent would have its own dosage as small molecules are not administered via the same methods as transgenes in viral vectors, for example.
Regarding the state of the art on dosages of viral vectors in ALS gene therapy treatments (an NCT defect associated disease), Merjane (Med Res Rev. 2023;43:829–854) teaches that previous rat models with AAV vectors to treat ALS have shown that therapeutic intervention is highly dose dependent and that low/medium doses enhance survival with high doses causing enhanced toxicity (p. 840, last paragraph). This highlights the importance of controlling dosage to avoid adverse effects (p. 841, 1st paragraph). Moreover, Merjane teaches when injected intravenously for use in clinical application, the vector doses required to achieve sufficient delivery and transgene expression within the CNS can often lead to liver toxicity and increased risk of tumorigenesis (p. 845, 2nd column).
Regarding the state of the art on dosages of viral vectors in Alzheimer’s gene therapy treatments (an NCT defect associated disease), Dayton (Gene Therapy (2018) 25:392–400) teaches that gene therapy for rat models in the CNS which may be used for ALS or Alzheimer’s disease is dose dependent and dose response is important in the field (p.397-398, bridging paragraph). Moreover, Dayton teaches lower vector dosages should lower the potential for side effects however only the high dose of their vector achieved spinal motor neuron transduction in adults (p. 398, 2nd column).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Therefore, claim 1, 5, 7, 10, 19, 40, 71-72, 76, and 85-89 lack adequate written description.
In response to Applicant’s arguments and amendments filed 07/10/2026 regarding the Written Description rejection,
Applicant’s arguments and amendments have been considered, however they are not persuasive.
Applicant argues that as the scope has been narrowed to just the transgene and the small molecule, there is adequate written description for the breadth of the claims.
The Examiner states that while this obviates the issue of written description for the “agent” previously claimed, this does not address the issue of “therapeutically effective” dosages.
Applicant argues that a person of ordinary skill can readily appreciate without undue burden from reading the present disclosure what an effective amount of the transgene or small molecule is.
Examiner disagrees. The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,' to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The working examples do not provide a dosage of the transgene or transgene encoding a protein to a subject. Each agent (transgene or small molecule) would have its own dosage as small molecules are not administered via the same methods as transgenes in viral vectors.
Dayton is further utilized in the above rejection to provide support for the unpredictability in the art for dosing in order to achieve the effective amount required to treat Alzheimer’s in addition to the references already cited.
As Applicant claims that this is an unexpected discovery in utilizing formin, this further establishes the unpredictability of the art and therefore, a minimum effective dosage is required to be in commensurate with the results of the invention.
Claim Rejections - 35 USC § 103
Claim 1, 5, 7, 10, 13, 19, 40, 71-72, 74 , 76 remain rejected and claims 12, 14, 73, 85-89 are newly rejected under 35 U.S.C. 103 as being unpatentable over Ribeiro Mendes de Sousa (US20200190153; Filed 2018-05-07) as evidenced by Witke (2004. Trends in Cell Biology, Vol 14, No 8, pages 461-469) and Giampetruzzi (2019. Nature Communications volume 10, Article number: 3827 (2019); Applicant’s own work) in view of Boopathy (2017, UMass Chan Medical School, Doctoral Dissertation; previously cited), Gijselinck (Cold Spring Harb Perspect Med. 2018 Apr;8(4):a026757; previously cited), and Dayton (Gene Therapy (2018) 25:392–400)
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 07/10/2026.
Regarding claims 1, 5, 7, 10, 13, and 14, Ribeiro Mendes de Sousa teaches administering an effective amount of constitutively active profilin-1 (Pfn1) to a subject in a method of treating a neurological disorder (i.e. neurodegenerative disease) such as Amyotrophic Lateral Sclerosis (ALS) or other neural degenerative disease such as Alzheimer’s Disease (Claim 1, Claims 4-5, para. 0010). Ribeiro Mendes de Sousa teaches that the composition is formulated for systemic injection (Claim 15, para. 0032). As evidenced by Witke, profilins are small actin-binding proteins which regulate the dynamics of actin polymerization and that the primary role of profilin 1 is regulatory the cytoskeletal architecture and the dynamics of neurons (Abstract, p. 466, last paragraph). Therefore, the administration of Pfn1 by Ribeiro Mendes de Sousa inherently modulates actin polymerization thereby stabilizing the cytoskeleton to the cell.
Ribeiro Mendes de Sousa does not explicitly state that the agent modulates nucleocytoplasmic transport (NCT) in the cell (claim 5) . However, as evidenced by Giampetruzzi, inherently there is a direct link between actin polymerization and NCT which modulates NCT (p. 8, 1st paragraph; p. 6, last paragraph).
Riberio Mendes de Sousa did not teach wherein the transgene administered is a formin.
Boopathy teaches that a method of utilizing constitutively active formin constructs (i.e. transgene encoding a protein) in cells which express ALS mutations in PFN1 and cells demonstrating loss of function in PFN1 (Figure III-1, p. 84; p. 87). The treatment of cells with the formin resulted in an increase in the number of filaments in the wild type cells and in cells with G118V PFN1 particularly there is an increase in filament number (p. 92). Boopathy teaches mutations in PFN1 cause ALS (Abstract) and namely C71G, M114T, G118V, E117G, T109M, R136W, A20T, and Q139L have been identified as mutations in PFN1 in ALS patients. All the residues that are mutated in ALS are conserved in mammals (p. 20, 1st full paragraph). Moreover, PFN1 mutants are proposed to be related to Alzheimer’s disease, PFN1 is associated with Huntington’s Disease (HD), and C9orf72 is linked to FTD with a mutation such as E117G in PFN1 (p. 20, last paragraph; p. 25, 2nd paragraph; p. 106, 1st paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer a constitutively active formin as taught by Boopathy in place of the constitutively active pfn1 as taught by Riberio Mendes de Sousa to an individual with ALS demonstrating a mutation in pfn1 with a reasonable expectation of success. An artisan would be motivated to administer a formin as Boopathy teaches the treatment of cells with the formin resulted in an increase in the number of filaments in the wild type cells and in cells with G118V PFN1 particularly there is an increase in filament number (p. 92). Moreover, it would be obvious based on such teachings to administer the construct to a subject not only with ALS as in Riberio Mendes de Sousa but also with a mutation such as G118V. Moreover, G118V inhibits actin polymerization (p. 93).
However, Ribeiro Mendes de Sousa and Boopathy do not teach that the subject with the neurological disorder such as ALS, FTD, or HD has a mutation in C9ORF72 which demonstrates at least 80 G4C2 repeats.
Gijselinck teaches individuals with ALS, FTLD (FTD) and ALS-FTD have C9orf72 hexanucleotide repeats which range from two repeat units to more than 4000. Normal repeat sizes range between 2 and 24 repeats of G4C2 with some studies establishing the cutoff of non-pathogenic number of repeats as 60. Southern blot hybridization studies visualized the expanded alleles and estimated that the size of most repeat expansions ranged between several hundred and several thousand repeat units in patients (p. 5, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to treat an individual with ALS or FTD who has a mutation in C9ORF72 which shows at least 80 G4C2 repeats as taught by Gijselinck utilizing the ALS and other neurodegenerative disease treatment of Ribeiro Mendes de Sousa and Boopathy with a reasonable expectation of success. An artisan would have been motivated to utilize said treatment method with Gijselinck’s individual patients as they are classified in the same neurodegenerative disease as Ribeiro Mendes de Sousa’s patients, ALS. One would have a reasonable expectation that some of Ribeiro Mendes de Sousa’s patients would also demonstrate such a mutation in C9ORF72 if tested.
However, the above references do not explicitly state that the gene constructs are administered intravascularly, or more specifically intravenously.
Dayton teaches administering AAV vectors for ALS or Alzheimer’s through intravenous routes for widespread gene transfer (p. 392, 2nd column, p. 393, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer the therapy of Boopathy, Gijselinck and Ribeiro Mendes de Sousa comprising a formin to a subject with ALS or Alzheimer’s via intravenous injection as taught by Dayton with a reasonable expectation of success. An artisan would have been motivated to do so as Dayton demonstrates that efficient gene transfer occurs through intravenous injection (p. 393 1st column, 2nd column).
Regarding claim 19, the combined teachings of Boopathy, Gijselinck and Ribeiro Mendes de Sousa make obvious a method of treating Alzheimer’s Disease, Huntington’s Disease and Frontotemporal Dementia as discussed in the rejection of claim 1 above with mutations in C9ORF72 such as repeat expansions. Moreover, Ribeiro Mendes de Sousa teaches that their therapy is administered as a gene construct (i.e. transgene) via AAV viral vector wherein the viral vector is a recombinant adeno associated virus (i.e. rAAV) (para. 0030-0031, Claim 10-13)
Regarding claims 40, 71-73, 85, 87, and 88, the combined teachings of Ribeiro Mendes de Sousa, Boopathy, Gijselinck, and Dayton make obvious a method of treating Alzheimer’s Disease, Huntington’s Disease and Frontotemporal Dementia as discussed in the rejection of claim 1 above with mutations in C9ORF72 such as repeat expansions. Gijselinck additionally teaches that the ALS patients with the mutations additionally are ALS-FTD patients, which would indicate a subject having a neurodegenerative disease such as frontotemporal dementia (FTD) being treated by the method of Gijselinck and Ribeiro Mendes de Sousa. Therefore, a person of ordinary skill in the art would have a reasonable expectation of success in treating FTD patients with the method of Ribeiro Mendes de Sousa through the administration of a molecular agent such as a transgene encoding constitutively active formin in an rAAV delivery method.
Regarding claim 74 and 75, combined teachings of Ribeiro Mendes de Sousa, Boopathy, Gijselinck, and Dayton make obvious the method of claim 40. Moreover, Boopathy teaches a constitutively active formin (Figure III-1, p. 84; p. 87).
Regarding claim 76, combined teachings of Ribeiro Mendes de Sousa, Boopathy, Gijselinck, and Dayton make obvious the method of claim 40. Moreover, Ribeiro Mendes de Sousa teaches that PFN1 is administered as a gene construct (i.e. transgene) via AAV viral vector wherein the viral vector is a recombinant adeno associated virus (i.e. rAAV) (para. 0030-0031, Claim 10-13).
Regarding claim 86 and 89, combined teachings of Ribeiro Mendes de Sousa, Boopathy, Gijselinck, and Dayton make obvious the method of claims 1 and 40. Moreover, Dayton teaches intravenous administration for the AAV therapy (p. 393, 2nd column).
Therefore, the invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments and amendments filed 02/13/2026 and 01/14/2026 regarding the 103 rejection of claims 1, 5, 7, 10, 12-14, 19, 40, 71-76, and 85-89 over the references Ribeiro Mendes de Sousa, Witke, Giampetruzzi, Boopathy, and Gijselinck
Applicant’s arguments and amendments have been considered, however they are not persuasive.
Applicant argues that as the molecular agent has been limited to formin, the rejection is overcome.
The Examiner has modified the rejection as necessitated by the change of scope in the amendments made to address the formin limitation.
Applicant further argues that Boopathy previously cited does not cure the deficiencies as it does not state that formin is utilized for treatment as its intended use.
The Examiner disagrees. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). The treatment method steps are provided by the other references while the motivation to utilize formin within the treatment method steps are detailed above by Boopathy such as an increase in filament number.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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