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 .
Claim Interpretation
Claim 42, from which all other presented claims depend from, states use of a MeCP2 promoter. Therefore, any subsequent claims requiring use of a “MeCP2 gene” will be considered satisfied with incorporation of the promoter portion of the MeCP2 gene.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 42-46, 48-49, 53-54, and 57-66 are rejected under 35 U.S.C. 103 as being unpatentable over Kielian et al. (WO 2016/100575) in view of Chen Plotkin et al. (WO 2017/151884) and Krieg et al. (US 10,655,128 B2)
Regarding claims 42 and 54: Kielian teaches composition and methods for the treatment of juvenile neuronal ceroid lipofuscinosis (juvenile Batten disease) and associated disorders and symptoms. (0005) Specifically, Kielian teaches an embodiment of the invention which makes use of the MeCP2 promoter (0074) of which a gene of interest may be operably linked to. (0054) In addition to this, Krieg teaches that MeCP2 is important for synapse maintenance in the brain and essential to normal brain function and that downregulation of MeCP2 is linked to neurological issues. (Col 1, ln 42-46) Kielian fails to teach use of a progranulin (hereafter PGRN) protein.
Chen Plotkin teaches methods and uses for the delivery of PGRN to the central nervous system (hereafter CNS). (57) Chen Plotkin further teaches that the gene may be operably linked, and defines “operably linked” to be when a gene or nucleic acid is placed into a functional relationship with another nucleic acid sequence. (0158) In addition to this, Chen Plotkin teaches an exemplary embodiment of the invention in which the DNA sequences incorporated into the AAV is less than about 4.5kB. (0099) This reads on the nucleic acid construct used in the claimed invention being 3700 to 4700bp in length. Lastly, Chen Plotkin teaches that PGRN is known to be a secreted growth factor which, when mutated to become suppressed, place an individual at risk for the development of neurological diseases such as Alzheimer’s disease and frontotemporal dementia (hereafter FTD). (0006-0007) As such, a person skilled in the art would be motivated to incorporate the transgene PGRN to a construct comprising a MeCP2 promoter as taught by Kielian for the purpose of delivery of PGRN in order to treat the symptoms of the aforementioned neurological diseases due to the teachings of Krieg, who details the importance of MeCP2 in normal brain function and synapse maintenance.
Regarding claim 43: Kielian teaches an example of the invention which comprises a minimal essential promoter from a murine MeCP2 gene. In addition to this, the construct contains a minimal SV40 intron, reading on use of at least one intron. (0034)
Regarding claim 44: Kielian teaches that the promoter used is typically located in the 5’ non-coding region of a gene, proximal to the transcriptional start site of the gene. (0058) As shown in Figure 1 below (see circled area), the minimal essential MeCP2 mouse promoter is located 5’ from the intron sequence, as it is known throughout the art that unless otherwise specified, construct diagrams are typically read 5’-3’.
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Regarding claims 45 and 46: As discussed above, Kielian teaches that the construct may comprise introns. In addition to this, use of the MeCP2 promoter (0074) reads specifically on use of one or more nucleotide sequences of an MECP2 gene. Kielian fails to teach that the introns may be synthetic.
Chen Plotkin teaches that polynucleotides included in the construct of the claimed invention may be synthetic. (0150) One benefit of using synthetic sequences is that they may be generated by site-directed mutagenesis (0170). Due to this, one of ordinary skill in the art would be motivated to incorporate a synthetic intron into the construct taught by Kielian, resulting in a synthetic intron comprising at least one nucleotide sequence from an MeCP2 gene.
Regarding claims 48 and 49: Krieg teaches single-stranded oligonucleotides for activating or enhancing expression of MeCP2, as well as methods for modulating the expression of MeCP2. (57) Regarding the difference between claims 48 and 49, a person skilled in the art would understand that, unless otherwise stated, constructs are read and constructed in the 5’-3’ direction and thus any sequence reading on claim 48 would inherently read on claim 49 as well.
Krieg teaches that MeCP2 plays a role in normal brain function, especially the maintenance of synapses, and mutations of MeCP2 result in defects in synaptic plasticity (Col 1, ln 42-46). Therefore, upregulation of MeCP2 offers a method of treatment for diseases associated with decreased MeCP2 activity. (Col 1, ln 61-62) Specifically, SEQ ID NO. 3 as taught by Krieg matches the claimed SEQ ID NO. 5 by 98.7%, as is shown in the alignment chart below:
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Regarding claim 53: Kielian teaches optional use of a woodchuck post-transcriptional regulatory element in the claimed construct. (0092)
Regarding claims 57 and 58: Kielian teaches use of a composition comprising an AAV vector. (0030)
Regarding claim 59: As illustrated in the above image of Figure 1, Kielian teaches use of a 3’ ITR.
Regarding claim 60: Following the discussion regarding claims 57 and 58, Kielian teaches use of a composition comprising an AAV vector (0030) and use of a minimal MeCP2 promoter sequence (0034). Kielian fails to teach use of said composition comprising a sequence matching the claimed SEQ ID NO. 1. Krieg teaches SEQ ID NO. 3, which matches the claimed SEQ ID NO. 1 by 100% as shown in the alignment chart below:
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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 respective sequences as taught by Krieg with the construct taught by Kielian to create constructs encoding MeCP2 in the intron (claims 48 and 49) and also packaged into an AAV (claim 60). A person skilled in the art would have had motivation and a reasonable expectation of success based on the teachings of Krieg, who states that MeCP2 plays a role in maintaining synaptic plasticity and administration of MeCP2 can aid in treating diseases where the downregulation of MeCP2 causes neurological issues.
Regarding claim 61: Kielian teaches an aspect in which a host cell is transduced with the vector of the claimed invention. (0029)
Regarding claim 62: Kielian teaches that the disclosed composition may be in the form of a pharmaceutical formulation (0025) and may also comprise a pharmaceutically acceptable carrier. (0032)
Regarding claims 63-65: Kielian teaches that the composition may be used as a pharmaceutical formulation (0025), but fails to teach use of the construct to treat a disease caused by PGRN deficiency, particularly FTD.
Chen Plotkin teaches methods and uses for administering a composition to a subject which has reduced or lost PGRN expression (0062) wherein the construct expresses PGRN to be used as a therapy for FTD in the form of an AAV. (0193, Example 1) Chen Plotkin further teaches that the loss of function of PGRN expression is known to lead to neurological diseases such as FTD. (0006) As it has been established by the teachings of Chen Plotkin that administration of PGRN to a patient with a PGRN insufficiency can help with the symptoms of the disease, one of ordinary skill in the art would have motivation and a reasonable expectation of success at incorporating the teachings of Chen Plotkin of treating or preventing a disease characterized by PGRN deficiency in a patient in need thereof (claim 63) with the disease being characterized by PGRN deficiency (claim 64), specifically FTD (claim 65).
Regarding claim 66: Kielian teaches administration of the AAV construct into the cerebrospinal fluid. (0112)
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 Chen Plotkin regarding use of PGRN, synthetic sequences, and use of the PGRN sequence to treat associated diseases with the MeCP2 promoter based construct taught by Kielian. One skilled in the art would have had motivation to do so and a reasonable expectation of success based on the teachings of Chen, who state that PGRN is known to be a secreted growth factor which, when function of the gene is lost, can cause FTD and the teachings of Krieg, who state that MeCP2 plays a role in the maintenance of synapses and normal brain function and that downregulation of MeCP2 causes neurological issues. Chen further teaches that synthetic sequences are beneficial due to their capability for site-directed mutagenesis, and that administration of PGRN to a patient suffering from PGRN loss of function can help treat the symptoms of the disease.
Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Kielian et al. (WO 2016/100575) in view of Chen Plotkin et al. (WO 2017/151884) and Lentz et al. (Viral Vectors for Gene Delivery to the Central Nervous System, 2012)
The teachings of Kielian and Chen Plotkin are disclosed above. Both fail to teach use of two copies both of intronic and exonic murine MeCP2 genes.
Regarding claim 47: Kielian teaches that the definition of nucleic acid/polynucleotide refer to a polynucleotide of any length, and can refer to both introns or exons within the construct. (0068) Furthermore, Kielian teaches use of a mouse MeCP2 gene in Figure 1. (0034) Kielian fails to teach use of two intronic copies of the MeCP2 gene and two non-coding exonic copies of the MeCP2 gene within the construct.
Lentz teaches different aspects of the biology of a vector regarding its usefulness and effectiveness when used in a therapeutic setting. (Pg 1, Abstract) Lentz goes into detail regarding the ideal vector for gene delivery to the CNS, and that the ideal CNS targeting vector must be produced in high enough quantities as to be practical for delivery to patients. (Pg 2, Model of the Ideal Vector for Gene Delivery to the CNS.) One of these features is for the vector to comprise multiple copies of the transgene in each vector, allowing for the production of increased levels of transgene expression in the transduced cells when compared to single gene delivery. (Pg 10, Herpesvirus vectors) Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include multiple copies of the MeCP2 gene in the construct taught by Kielian. One skilled in the art would have had motivation and a reasonable expectation of success at doing so based on the teachings of Lentz, who state that multiple copies of the same gene within the same construct may result in increased levels of transgene expression within the transduced cell.
Regarding use of specifically two copies of both an intronic gene sequence and a non-coding exonic gene sequence, it would be routine optimization to arrive at use of two intronic and exonic sequences used within the same construct. As Lentz teaches the benefit of using multiple copies of the same nucleotide, it would have been obvious to try to incorporate varying numbers of the same genomic sequence to arrive at the highest level of transfection possible of the gene of interest. Furthermore, it is known throughout the art that exonic sequences are inherently non-coding, reading on claim 47 regarding “non-expressing exonic sequences”.
Allowable Subject Matter
Claims 50-52 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.
Regarding claims 50 and 51: There is no prior art on the record that matches the claimed SEQ ID NO. 2 by at least 90%, as is required by both claims 50 and 51.
Regarding claim 52: There is no prior art on the record that matches the claimed SEQ ID NO. 3 by at least 90%, as is required by claim 52.
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.
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/HANNA MARIE THUESON/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638