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
This action is in response to the papers filed on 04/23/2026. Claims 1-3, 8-12, 14-19, and 25-28 are currently pending as per claims filed on 06/16/2023.
Applicant’s election without traverse of Group I, which include claims 1-3, 8-12, 14-18, drawn to an expression construct comprising an NPC l promoter fragment and an NPC 1 nucleotide sequence, a vector containing the fragment, and a cell containing the vector. in the reply filed on 04/23/2026 is acknowledged.
Claims 19 and 25-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.
The requirement for restriction between Groups I-III is still deemed proper and is therefore made FINAL.
Therefore, claims 1-3, 8-12, and 14-18 are subject to examination to which the following grounds of rejection are applicable. Claims 1, 10, and 17 are independent claims.
Priority
The instant application is a 371 of PCT/GB2021/050597 filed on 03/10/2021, which requests claim foreign priority to UNITED KINGDOM 2003536.6 filed on 03/11/2020.
Thus, the earliest possible priority for the instant application is March 11, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/16/2023 and 04/23/2026 were filed before the mailing date of the non-final office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 15 is objected to because of the following informalities: Claim 15 recites “derived from AAV9” at line 3. Applicant should amend the claim to instead recite “isolated from AAV9”. Appropriate correction is required.
Claim 16 is objected to because of the following informalities: Claim 15 recites “derived from AAV2” at line 1 and “derived from AAV9” at line 2. Applicant should amend the claim to instead recite “isolated from AAV2” and “isolated from AAV9”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 8-12, and 14-18 are rejected 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 which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
PNG
media_image1.png
274
816
media_image1.png
Greyscale
For ease of reference the instant claim 1 is provided below:
Claim 1 recites “that retains the functionality of the of the NPC1 promoter”. There is no antecedent basis for “the NPC1 promoter” and therefore it is unclear what is the applicant intends to claim. Thus, the claim is rendered indefinite.
Claim 1 is unclear in what the applicants intended meaning is with respect to the phrase “retains the functionality” in lines 4 and 9. The functionality is not defined by the claim and the specification does not provide an ascertaining what exactly the applicant intends to claim. Thus, the metes and bounds of the claim cannot be determined and the claim is rendered indefinite. Claim 2-3, 8-12, and 14-18 are indefinite insofar as they depend from claim 1.
Claims 2 and 3 recite, “retains the ability to express hNPC1”. It is unclear what that applicants intended meaning is for these recitations as the claims are drawn to a promoter. A promoter does not have the capacity to “express hNPC1” as it is a regulatory element. Therefore, the claim is indefinite. Amending the claim to recite “retains the functionality of the hNPC1 promoter” would obviate the rejection.
Claim 14 recites the limitation, “naturally derived serotype” at line 2. It is unclear what the intended meaning is for “naturally derived serotype” as the specification does not provide a definition or how a naturally derived serotype may be identified. The claims do not serve to remedy the lack of clarity. Therefore, the claim as written is indefinite.
Claim 15 recites the limitation, “wherein the capsid” at lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 19 depends from claim 14, which fails to recite any “capsid”. Thus, the phrase "the composition of claim 1" at lines 2-2 lacks antecedent basis and the claim is rendered indefinite.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 8-12, and 14-18 are 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.
Claim 1, from which all other claims ultimately depend, is provided below.
PNG
media_image1.png
274
816
media_image1.png
Greyscale
The instant disclosure fails to provide sufficient support pertaining to sequences having identity of 90% to the sequence shown in SEQ ID NO:1, 70% identity to the sequence shown in SEQ ID NOs: 2 and 4, and 90% identity to the sequences of SEQ ID NOs: 3 and 5 that retain the cited functionalities above of the hNPC1. The specification does not provide sufficient support to identify what changes, mutations, fragments, etc. could be made to SEQ ID NOs: 1-5, and that would be encompassed by the structural limitations of claim 1 and still be able to produce functional requirements of the hNPC1 promoter or the hNPC1 gene product as claimed. The instant specification does not provide a sufficient representative sampling of structures that are little as 90% identical to the sequence shown in SEQ ID NO:1, 70% identical to the sequence shown in SEQ ID NOs: 2 and 4, or 90% identical to the sequences of SEQ ID NOs: 3 and 5. Dependent claims 2-3, 8-12, and 14-18 do not serve to overcome the written description deficiencies.
Nature of the Invention
The instant claims are drawn to an expression construct comprising a transcriptionally functional promoter/promoter fragment and a functional hNPC1 nucleotide sequence encoding the corresponding gene product, e.g., the nucleotide of SEQ ID NO:2 encodes the polypeptide of SEQ ID NO:3 and the nucleotide of SEQ ID NO:4 encodes the polypeptide of SEQ ID NO:5.
Specification Disclosure
PNG
media_image2.png
248
713
media_image2.png
Greyscale
The specification describes only the following sequences relative to the claims at Pg. 8:
The specification does not provide sufficient support for sequences having identity of 90% to the sequence shown in SEQ ID NO:1, 70% identity to the sequence shown in SEQ ID NOs: 2 and 4, and 90% identity to the sequences of SEQ ID NOs: 3 and 5 that retain the cited functionalities above.
The specification states that “An expression construct may be defined as a polynucleotide sequence capable of driving protein expression from a polynucleotide sequence containing a coding sequence. The expression constructs of the present invention comprise NPC1 promoter fragments and human NPCJ (hNPC1). The sequence of NPC1 used in the expression constructs of the present invention is preferably either that of SEQ ID NO: 2 or a hNPC1 nucleotide sequence encoding the polypeptide of SEQ ID NO:3. The sequence of NPC1 used in the expression constructs of the present invention is preferably either that of SEQ ID NO: 4 or a hNPC1 nucleotide sequence encoding the polypeptide of SEQ ID NO:5. The promoter used in the expression constructs of the present invention is a NPC1 promoter fragment, consisting of a nucleic acid sequence of no more than 400 nucleotides in length. The sequence of the NPC1 promoter used in the present invention is preferably that of SEQ ID NO: 1.” (Pg. 14, line 8-18). The NPC1 promoter fragment is described as “The NPC1 promoter fragment of the present invention may be no more than 400, 390, 380, 370, 360, 350, 340, 330, 320, 310, 309, 308 or 307 nucleotides in length” (Pg. 14, line 19). However, the Specification is silent about any fragment/domains of the promoter comprising the nucleotide of SEQ ID NO:1 which is transcriptionally active when linked to the hNPC1 of SEQ ID NO:2 or SEQ ID NO:4. The Specification is silent about fragments of the full length of the nucleotides of SEQ ID NOS: 2 and 4 that encode the corresponding functional hNPC1 protein. The specification does not provide sufficient support to identify what changes, mutations, fragments, etc. could be made to SEQ ID NOs: 1-5, and that would be encompassed by the structural limitations of claim 1 and still be able to produce functional requirements as claimed.
Further, claim 1 of the instant applications includes “comprising language” for the expression construct, which would allow for the addition of ANY nucleic acid components to the recited expression cassette. The specification is silent about which additional polynucleotides could be added and which should NOT be added.
In summary, the specification describes a minimal species for each claimed genus– for sequences having identity of 90% to the sequence shown in SEQ ID NO:1, 70% identity to the sequence shown in SEQ ID NOs: 2 and 4, and 90% identity to the sequences of SEQ ID NOs: 3 and 5 that retain the cited functionalities above.
Guidance Provided by the Art
A thorough search of the art revealed the challenge in characterizing a genotype-phenotype relationship with respect to NPC1 dysregulation. Indeed, Las Heras et al. (Las Heras, M., npj Genom. Med. 8, 21 (2023). https://doi.org/10.1038/s41525-023-00365-w) describes “More than 500 disease-causing variants have been described in different regions of the NPC1 and NPC2 genes. It has been challenging to establish genotype–phenotype correlations, mainly due to the private nature of most NPC1 variants and because even the most common variants (I1061T, P1007A, and G992W) are found in low frequency. However, some studies have shown a correlation between carrying nonsense or frameshift variants and a more severe neurological course. In addition, homozygous variants in SSD are usually deleterious. Variants in the cysteine-rich luminal loop, where the three most frequent variants are found, show a variable clinical impact. Still, they seem to have a minor effect on cellular trafficking.”, and further “Unfortunately, the correlation between NPC1 mutations and clinical phenotypes has not yet been thoroughly investigated at the molecular level.” (Pg. 3, GENOTYPE-PHENOTYPE CORRELATIONS IN NPC DISEASE, 1st paragraph). Moreover, it is apparent from these teaching that mutations within related pathologies can provide defective proteins with residual functions (Pg. 10, CONCLUDING REMARKS).
Further, the regulatory control of the NPC1 gene is multifaceted and relies on different transcriptionally regulatory factors than recognize the NPC1 transcriptional domains within the promoter, as demonstrated by Garver et al. (Garver, William S et al. Journal of lipid research vol. 49,5 (2008): 1090-102) who teaches “the m-SREBP proteins interacted with SRE sequences positioned within the NPC1 gene promoter region to increase the transcription of the NPC1 gene” (Discussion, 1st paragraph). Thus, Garver et al. provides support for specific transcriptionally regulatory sites within the NPC1 promoter of SEQ ID NO: 1 that are necessary for transcriptional activity within a host cell.
Gévry et al. (Gévry NY., Mol Endocrinol. 2003;17(4):704-715) teaches “these results demonstrate a mechanism of regulation of NPC-1 expression by the cAMP-PKA pathway that includes PKA phosphorylation of CREB, recruitment of the coactivator CREB binding protein and the phosphorylation and acetylation of histone H-3 to transactivate the NPC-1 promoter.” (Abstract). Gévry also teaches that variation in functionality with truncation of the NPC1 promoter as well as various promoter regions containing CRE consensus sequences (Abstract of Gévry et al.)
As such, the integrity of both the promoter and gene sequences are obviously critical and any full length variant or fragment of said sequence characterized by mutations, deletions, or additions, may alter the ability of the of molecule to perform its normal biological function.
To further put this situation in perspective under the broadest reasonable interpretation, the claims encompass any nucleotide that is 90% similar to the sequence of SEQ ID NO: 1 (SEQ ID NO:1 is 307 nucleotides in length), 70% identity to the sequence shown in SEQ ID NOs: 2 and 4 (4760 nucleotides and 4764 nucleotides in length, respectively). That 10% percent variance results in a situation in which even if a 30-contiguous nucleic acid region (10% of 307) is independently varied about the four possible naturally occurring nucleotides there would be 430 different possible molecules. In fact, since contiguous sequences are not a limitation of the instant claims for variable regions, the possible variations could occur anywhere the sequence of SEQ ID NO: 1, meaning the actual number of possible molecules under the claimed genus would be significantly greater than 430. By this rationale, the possible variations in the sequences of SEQ ID NOs: 2-4 would be even larger.
Taken together, the prior art provides clear evidence that a single mutation can alter the biological function of the claimed molecule and the genotype-phenotype relationship of NPC1 mutations are not fully characterized.
Conclusion
Considering the large variation in the genus encompassed by the instant claims, the singular species described in the specification, and the lack of predictability provided by the specification and art for the full scope of the claimed genus, it is reasonable to conclude that applicant did not possess the invention as claimed at the time of filing.
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.
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.
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.
Claim(s) 1-3, 8-12, and 14-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Venditti et al. (WO 2018/237066 Al, IDS filed 06/16/2023) in view of Bauer et al. (Bauer Pet al., Hum Mutat. 2002, of record filed 02/27/2026) and in view of Cheng et al. (Cheng JK et al., ACS Synthetic Biology. 2016)
Regarding claim 1, 8 and 10-12 Venditti teaches constructs that contain polynucleotides comprising sequences of codon optimized NPC1 gene driven by promoters such as EF1a promoters. These promoters are optimized, typically via truncation (Paragraph [0019]). Venditti teaches packaging of these constructs in AAV vectors (for claims 10-12) and their use to treat Niemann-Pick disease type C (Paragraph [0010]). Venditti teaches the gene therapy vector can include the NPC1 gene, which reads on SEQ ID NO:2 of the instant invention (Pg. 39, Paragraph [0200]). The sequence of SEQ ID NO:2 is a known NPC1 nucleotide sequence, Accession NM_000271.5. This NPC1 sequence also reads on claim 8 of the instant application.
Although Venditti does teach the NPC1 gene in the construct is driven by a truncated and optimized promoter, Venditti does not teach that the promoter is an NPC1 promoter comprising at least 250 consecutive nucleotides from SEQ ID NO: 1, or a sequence having at least 90% sequence identity thereof.
Bauer et al. teaches the complete genomic sequence of 57,052 kb corresponding to the transcribed region of human NPC1 including several exonic and intronic single nucleotide polymorphisms (SNPs). Bauer et al. describes sequencing of all exons, splice sites, and the promoter region of NPC1 in 12 unrelated Caucasian NP-C patients revealed nine novel and four known most likely disease-causing mutations (Abstract of Bauer). These promoter mutations are provided at table 2 of Bauer. Bauer specifically teaches amplification and sequences of the NPC1 promoter (Pg. 32, 2nd full paragraph) and the NPC1 gene sequence from the teachings of Bauer (which comprises the promoter sequence of SEQ ID NO: 1 from the instant application) were uploaded to GenBank (GenBank: AF338230.2).
Although Bauer discloses the sequence for the native NPC1 promoter, the combined teachings of Venditti and Bauer do not disclose the use of the NPC1 promoter within a vector comprising an NPC1 gene construct.
PNG
media_image3.png
601
1011
media_image3.png
Greyscale
Cheng et al. teaches a transcriptomics guided workflow for the design of promoters that includes “To do so, we established a workflow to design these elements by (1) analyzing the transcriptomics profile of a specific cell line under a desired, representative cell culture condition, (2) identifying key genetic motifs using bioinformatics that can be used to rationally construct synthetic promoters, (3) building synthetic promoters using conventional DNA synthesis and molecular biology techniques, and (4) evaluating the performance of these synthetic promoters using model proteins” (Abstract and Fig 1 of Cheng, Fig. 1 provided below).
Cheng teaches the protein expression can be tuned based on alteration in the transcription factor binding sites and that “…these synthetic promoters had an overall reduced sequence footprint compared to reference promoters, thus increasing the overall utility for applications such as (heterologous) metabolic pathway designs and gene delivery vector designs, akin to efforts in reducing the regulatory sequence footprint in a conventional metabolic engineering host (Conclusion, 1st paragraph).
It would have been prima facie obvious to a person having ordinary skill in the art at the time of the instant application to have modified the viral vector comprising the gene construct of
Venditti to include a promoter based on the known NPC1 gene described by Bauer and use the transcriptomics guided workflow as taught by Cheng to produce an optimized viral vector containing a gene construct encoding NPC1 operably linked to an NPC1-based synthetic promoter. One would have been motivated to include the NPC1-based promoter as restoring NPC1 under its native promoter would provide a gene specific and tunable promoter to arrive at construct capable of producing NPC1 at desirable levels, versus a constitutively active non-native EF1a promoter with a reasonable expectation of success.
Regarding Claims 2-3, which are drawn to further limiting the following optional selection of claim 1 “a NPC1 promoter fragment nucleotide sequence consisting of no more than 400 nucleotides in length, wherein the sequence comprises at least 250 consecutive nucleotides from SEQ ID NO: 1”. As the promoter of claim 1 is rendered obvious by the combined teachings of Venditti, Bauer and Cheng, any domain comprised within the full length of the promoter would have been rendered obvious. Regarding Claims 14-16, the teachings of Venditti, Bauer, and Cheng render obvious the construct of claims 1 and 10-12 as described above in the 103 rejection. Moreover, Venditti teaches the serotypes of viral vector may be selected multiple serotypes, including from any of AAV 1-9. With AAV 2/9 (genome derived from AAV2 and capsid AAV9) being specifically noted as one embodiment (Pg. 41, Paragraph [0207]).
Regarding Claims 17-18, the teachings of Venditte, Bauer, and Cheng together render obvious the expression construct of claims 1 and 10. Moreover, Venditte teaches host cells comprising the vector containing the expression construct (Pg. 28, Paragraph [0142] of Venditte).
Cheng teaches specifically the use of HEK293 cells and says “…HEK293 are important industrial hosts commonly used to produce protein therapeutics”. A person having ordinary skill in the art at the time of the instant application would recognize that HEK293 cells are commonly used as host for viral vectors comprising sequences encoding a protein of interest, such as described by Cheng. Therefore, it would have been obvious to one of ordinary skill in the art to incorporate HEK293 cells as host cells to produce NPC1 from the expression construct as taught Venditte, Bauer, and Cheng together. One would have been motivated to use HEK293 cells with a reasonable expectation of success as they are well characterized and commonly used tools for such a purpose.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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, Maria G. Leavitt can be reached at (571) 272-1085. 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./KODYE LEE ABBOTT/Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights