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 of Inventive Group II in the reply filed on 11/18/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-6, 8, 10-12, and 29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventive group, there being no allowable generic or linking claim. Election was made in the reply filed on 11/18/2025.
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.
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 18, 22, 23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Plotkin et al. (WO 2017/151884 A1) in view of Royo et al. (Specific AAV Serotypes Stably Transduce Primary Hippocampal and Cortical Cultures with High Efficiency and Low Toxicity, 2008)
Plotkin teaches methods and uses for delivering progranulin to the central nervous system (hereafter CNS) of a mammal comprising a vector comprising a nucleic acid encoding progranulin or a variant thereof. (57) Specifically, Plotkin focuses on methods targeting frontotemporal dementia (hereafter FTD) with a mean onset of 52-58 years. (0001)
Regarding claim 18: Plotkin teaches a vector comprising a rAAV particle comprising an AAV capsid protein with a nucleic acid inserted between a pair of AAV inverted terminal repeats (hereafter ITR) and specifies that the AAV capsid protein may be selected from AAV1. (0012-0013) Plotkin further specifies that use of a modified capsid on a rAAV may bind to brain vascular epithelia tissue at a level upwards of 50-100% greater than that of an unmodified rAAV. (0168) In addition to this, the disclosed invention comprises a nucleic acid encoding progranulin (hereafter GRN), which leads to a transfected cell expressing said progranulin so as to treat the disease. (0009) Specifically, the claimed invention is directed towards increasing human GRN expression to about 5-50% of normal GRN expression, specifically to above 50% of normal GRN expression with respect to lost or reduced GRN expression or function. (0038-0039) In addition to this, Plotkin further specifies the treatment of a mammal, specifically a human, with an endogenous GRN expression loss (0052) and more specifically, the GRN expression loss is caused by FTD. (0055) This reads on the method of claim 18 regarding use of a rAAV1 comprising an AAV1 capsid protein and vector genome comprising inverted ITRs and GRN coding sequence that direct GRN expression in a target cell.
Regarding dose and administration, the method of claim 18 dictates that the single administered dose of the vector be at 1x10^10 – 3.33x10^11 genome copies per gram of brain mass. This converted to vector genomes (another name for genome copies) per kG is between 1x10^6 – 3.33x10^8 vg/kG. Plotkin teaches administration of the construct in a single dose to the mammal’s cisterna magna in claim 28 (pg 48) and further specifies a dose in the range of about 1x10^8 -5x10^8 vg/kg (0129) However, in the interest of specificity, Plotkin technically teaches the dosage in kilograms of body matter, not brain matter.
Royo teaches a transduction study for recombinant AAV vectors and the level at which the doses resulted in neural toxicity. Specifically, AAV1 showed a transduction rate of over 90% of cells, which demonstrates that the serotype AAV1 in particular demonstrates efficient overexpression or downregulation of genes in primary neuronal cultures. (Pg 1, Abstract) AAV1 serotypes were dosed up to 2.5x10^11 genome copies and demonstrated no neural toxicity. (Pg 2, Toxicity) This demonstrates both successful dosing within the claimed range of 1x10^10 – 3.33x10^11 gc/gram, and also safe dosing at that high titer.
Regarding claim 22: Plotkin specifies that the mammal (which can be human, 0052) has frontotemporal dementia. (0055) In addition to this, Plotkin specifies that a major genetic cause of FTD is a deficiency in progranulin, which leads to a GRN haploinsufficiency. (0004)
Regarding claim 23: Plotkin teaches that FTD is the second-most common cause of dementia in individuals younger than 65 years old (0192) and has a mean age onset of 52-58 years. (0001) Furthermore, Plotkin specifies the treatment of adults as an embodiment of the invention. (0070) Taken together, these teachings read on the method of claim 23 of treatment of a patient being at least 35 years of age.
Regarding claim 25: Plotkin states that the vast majority of GRN mutations which have been shown to cause FTD are missense mutations which cause the affected individual to express only 50% of normal transcript levels. (0192) In addition to this, claim 37 states that the method of the invention increases GRN expression to be between about 5-50% of normal GRN expression, and claim 38 states that the method of the invention increases GRN expression to above 50% of normal GRN expression. Lastly, claim 39 states that the method of the claimed invention increases GRN expression to above 50% of normal GRN expression in a human, with respect to lost or reduced GRN expression or function. Taken together, these teachings read on the limitations of claim 25 regarding the patient having a concentration of GRN in CSF that is less than 50% of normal levels or 30% above normal levels.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of use of a rAAV1 comprising a modified capsid protein, ITR sequences, and a nucleotide encoding for GRN expression and transfection into a target cell as taught by Plotkin with the recommended dosage of up to 2.5x10^11 genome copies to create a method of treatment for FTD comprising administering the construct comprising a nucleotide encoding GRN expression at a dose of 1x10^10 – 3.33x10^11 genome copies per gram of brain mass as taught by Royo. A person skilled in the art would have had motivation and a reasonable expectation of success at combining the teachings based on Royo, who states that specifically rAAV1 serotypes showed no neuronal toxicity at a high dose of 2.5x10^11 genome copies and that AAV1 transduced over 90% of cells, making it a reliable and safe method of transfection when compared to even other AAV serotypes.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Plotkin et al. (WO 2017/151884 A1) in view of Royo et al. (Specific AAV Serotypes Stably Transduce Primary Hippocampal and Cortical Cultures with High Efficiency and Low Toxicity, 2008), and Rohrer et al. (Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia, 2016)
Plotkin teaches a method of treatment of FTD using a AAV1 with a modified capsid comprising a GRN nucleotide sequence and Royo teaches the dose at which to administer the construct. Neither Plotkin nor Royo teaches a monitoring method comprising measuring CSF concentration of NfL, T-tau, and/or P-tau, assessing retinal lipofuscin, using MRI to check brain volume, white matter integrity, and thickness of the middle frontal cortex and parietal regions, use of FDG PET to assess hypometabolism in the frontal and/or temporal lobe, and/or measuring EEG to assess slowing of disease related changes.
Regarding claim 28: Rohrer teaches the investigation of NfL concentrations in FTD to examine whether the levels changing are associated with the severity of disease. Rohrer teaches that higher NfL levels are believed to represent axonal degeneration and developed an immunoassay based on single-molecule array which allows for quantification of NfL down to the sub molecular level. (Pg 1330, Introduction) It was found that serum levels of NfL are raised in FTD and higher concentrations are associated with faster rates of brain atrophy, which suggest that serum NfL concentrations reflect the intensity of the disease with higher levels showing correlation with a more rapid disease progression. (Pg 1333, Results) This teaching demonstrates that use of NfL concentrations in FTD is a viable and concrete way to measure disease progression.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of a method of treatment of FTD using a AAV1 with a modified capsid comprising a GRN nucleotide sequence as taught by Plotkin with the dose at which to administer the construct as taught by Royo due to the teachings of Rohrer, which quantify and confirm that measuring NfL is an accurate way to measure FTD disease progression. A person of ordinary skill in the art would have had motivation and a reasonable expectation of success at doing so based on the teachings of Rohrer, who demonstrate that the amount of NfL present in CSF correlate to the intensity of FTD and that higher concentrations are associated with a more rapid disease progression.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Tracy Vivlemore, can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638