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Claims 1-6, 8, 10-12, and 29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventive group, there being no allowable generic or linking claim.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 Interpretation
New claim 43 is directed towards a method in which a single dose is sufficient to provide 10^3 genome copies. This is interpreted as follows: prior art reading on a dose being sufficient to provide at least 10^3 genome copies or greater as satisfying the method of claim 43.
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, 25, and 40 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) and Hinderer et al. (JP 2019512005 A)
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 claims 18 and 43: 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) This also reads on the method of claim 43, as the dose taught by Plotkin details the delivery of up to 3.33x10^11 genome copies per gram of brain mass, which when converted to GC per uG is roughly 3.33x10^17 GC per uG of brain mass, which renders the invention as taught by Plotkin capable of delivering 10# GC/uG in the medulla, as the cisterna magna is part of the medulla. However, in the interest of specificity, Plotkin 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.
Regarding claim 40: Plotkin and Royo both fail to teach use of a CB7 promoter comprising a cytomegalovirus immediate-early enhancer with a chicken beta-actin promoter, chimeric intron, and rabbit beta globin poly A tail. Hinderer et al. teaches compositions comprising gene therapy for MPS I, including Hurler syndrome (a neurodegenerative disease). (Pg 1, Abstract) Hinderer further teaches that the expression cassette comprises a CB7 promoter as it promotes intramedullary expression paired with a CMV enhancer, and splice acceptor of the rabbit beta-globin gene . (Pg 11, 3rd paragraph) Hinderer further specifies that the rabbit beta-globin functions as a signal for transcription termination. (Pg 46) Lastly, Hinderer teaches in Example 5 that the AAV construct comprises a chimeric intron. (Pg 56, Example 5) Importantly, Hinderer specifies that the invention is suitable for injection directly into the cisterna magna. (Pg 5)
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.
It would be further obvious to incorporate the teachings of Hinderer into the teachings of Plotkin and Royo to create a construct comprising a CB7 promoter comprising a cytomegalovirus immediate-early enhancer with a chicken beta-actin promoter, chimeric intron, and rabbit beta globin poly A tail. One of ordinary skill in the art would have been motivated to do so as Hinderer teaches that the claimed invention is suitable for the treatment of neurodegenerative disorders via injection into the cisterna magna and comprises a promoter specific to the promotion of intramedullary expression along with a rabbit beta-globin functions as a signal for transcription termination.
Claims 28 and 42 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), 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.
Regarding claim 42: Rohrer details a method of measuring neurofilament light chain concentrations, indicative of progranulin levels, by the collection of serum from patients, which resulted in accuracy levels down to subfemtomolar concentrations. (Pg 2, Methods).
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.
Response to Arguments
Applicant's arguments filed 04/09/2026 have been fully considered but they are not persuasive. Applicant argues that the teachings of Plotkin of the calculation of a dosage based on body weight fails to read on the calculation of the invention as claimed of dosage based on brain mass, and that Royo fails to remedy said defect as the teachings of Royo are in vitro. However, Plotkin teaches the same method of administration to the cisterna magna intraventricular space (claim 28). As such, Plotkin teaches both the construct and route of administration taught in the claimed invention. A person skilled in the art would have the ability to calculate the appropriate dosage of the construct in light of ICM injection regardless if the dose was measured in whole body weight or brain mass.
Regarding the teachings of Royo being in vitro as opposed to in vivo as is the claimed invention, Applicant claims this is not relevant to the invention as Royo teaches use of an in vitro study. However, "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. One skilled in the art would have motivation to consider the teachings of Royo in the calculation of a dose for ICM injection as Royo teaches at what doses said constructs show toxicity to cells in vitro, as the teachings of Royo serve as a guideline to avoid cell toxicity when using said AAV constructs in vivo.
Lastly, Applicant argues that Rohrer fails to read on the claimed invention as Rohrer teaches a measurement of NfL using serum neurofilament light chain protein. However, Rohrer relies on literature stating measurements of NfL found in CSF as the control for their study (Pg 5,Results) as the point of Rohrer was to make an accurate method of measuring NfL that was applicable to a routine clinic environment. (Pg 7, Comment: “If you can’t measure it, you can’t improve it”) As such, a person skilled in the art would understand that either method of measurement, be it from serum or CSF, would yield the same result.
As such, the 35 U.S.C. 103 rejections of claims 18, 22, 23, 25, and 28 are upheld.
Allowable Subject Matter
Claims 41, 44, and 45 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Both SEQ ID NOs 24 and 3 are free of the art based on sequence search, and render said aforementioned claims allowable over the prior art.
Conclusion
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 extension fee 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 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.
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/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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