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 .
Priority
This application is a CONTINUATION of PCT application PCT/EP21/68653, filed 12/18/2023. Acknowledgement is made of the applicant’s claim for benefit to the PCT application PCT/EP21/68653, which was filed 07/06/2021.
Election/Restrictions
Applicant's election with traverse of group I, claims 1-12 and 15, drawn to an isolated nucleic acid molecule, in the reply filed on 05/22/2026 is acknowledged. The traversal is on the grounds that it would not be an undue burden on the patent office to examine the unelected Group II claims with the elected Group I claims. This is not found persuasive because: as stated in the office action mailed 04/01/2026, the different groups have acquired a separate status in the art in view of their different classification, and the field of searches required for one group are not required for the other group.
The requirement is still deemed proper and is therefore made FINAL. Accordingly, claims 1-12 and 15 have been considered on the merits. Claims 13-14 are withdrawn from consideration pursuant 37 CFR 1.142(b).
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, there are embedded hyperlinks appears in line 20 on page 23, as well as line 7 on page 32. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “wherein said first nucleic acid sequence comprises or consists of SEQ ID NO:1 or of a functionally equivalent sequence variant thereof” in lines 6-7. The word “of” before the phrase “a functionally equivalent sequence” needs to be deleted.
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 1-12 and 15 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.
Claim 1 recites transitional phrases “comprising or consisting of” renders instant claim indefinite. The transitional term "comprising" is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; while the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. See MPEP 2111.03. In instant claim, using both of the transitional terms in the same claim leads to the scope of the claim indefinite. Moreover, claim 1 also recites the phrase “at least one further nucleic acid sequence” in line 4, which is conflict with the transitional term "consisting of". Therefore PHOSITA would not have been appraised of what are the components in the claimed isolated nucleic acid molecule.
Claims 2-12 and 15 depend from, at least, claim 1, and thus inherit the deficiency and are rejected on the same basis.
Claim Interpretation
As stated above, claim 1 is indefinite due to using both of the transitional phrases “comprising” and “consisting of”. In the interest of compact prosecution, the claim is interpreted as “comprising” the first nucleic acid sequence and the at least one further nucleic acid sequence.
Claim 1 recites “functionally equivalent sequence variant thereof”, the specification provides the definition of “functional variant”: the term "functional variant" refers to a variant of SEQ ID NO: 1 that exhibits a promoter activity of SEQ ID NO: 1, i.e. that exhibits a promoter activity specific of rod photoreceptor cells (see p23, L5-6). The claim is interpreted in light of the definition in the specification.
Claim 2 recites the term “heterologous”, the specification provides the definition: "heterologous" means a nucleic acid other than the nucleic acid that the promoter is operably linked to in a naturally occurring genome (see p11, L21-22). The claim is interpreted in light of the definition in the specification.
Claim 11 is directed to a product. The recitation “for use in the treatment or prevention of an ocular disease in a human or animal” is an intended use. The intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See MPEP 2111.02.
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.
Claim 1-2, 4-12 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Michalakis et al. (WO 2018/172961 A1, as cited in IDS) in view of Mohamed et al. (J Mol Neurosci. 1998 Jun;10(3):235-50, as cited in IDS) and GenBank: AF022380.1 (available in 1998).
Michalakis et al. teach a polynucleotide comprising a promoter comprising a human photoreceptor-specific promoter element, a core promoter and at least one transgene (Abstract).
Regarding claim 1, Michalakis et al. teach a polynucleotide comprising a) a promoter comprising a human rod photoreceptor-specific promoter element (hRPSPE) and b) a transgene (TG) operably linked to the promoter of a) (see p3, L12-17). This teaching reads on “an isolated nucleic acid molecule comprising: a first nucleic acid sequence having promoter activity for the specific expression of an exogenous gene (herein the transgene) in rod photoreceptor cells and at least one further nucleic acid sequence encoding the exogenous gene, operably linked to said promoter” as recited in instant claim. Michalakis et al. do not teach the first nucleic acid sequence (promoter) comprises or consists of SEQ ID NO:1 or a functionally equivalent sequence variant thereof, having at least 80% sequence identity to SEQ ID NO: 1, and is operably linked to the further nucleic acid sequence (transgene). However, this was disclosed by Mohamed et al. and GenBank: AF022380.1 at the time of instant invention.
Mohamed et al. characterized the structural gene and upstream region of the human photoreceptor cGMP phosphodiesterase (PDE6A) gene (Abstract).
Regarding claim 1, Mohamed et al. teach the structural gene and upstream region of PDE6A gene. To begin functional analysis of the PDE6A promoter, approx 4 kb of sequence were determined upstream of the transcription start point (tsp) (Abstract). Mohamed et al. teach the upstream region of PDE6A (-176 to 146) binds retina specific nuclear proteins in nucleotides (figure 5), which initiate transcription in the retina (p248, left column). Mohamed et al. teach electrophoretic mobility
shift assays generate a retina-specific bandshift using a 322-bp fragment containing the putative
promoter region or a multimer of the RET1-like site. DNA footprinting assays revealed footprints
over the primary transcription startpoint and the RET1-like and TATA box regions. These
results indicate that a 220-bp segment of the PDE6A gene upstream region is important for
tissue-specific expression (Abstract). Moreover, Mohamed et al.’s teaching is provided in GenBank: AF022380.1, which is the nucleotide sequence of Homo sapiens rod photoreceptor cGMP phosphodiesterase alpha subunit (PDE6A) gene including the promoter sequence. The SEQ ID NO:1 in instant claim is 99.6% identical to GenBank AF022380.1 (alignment is provided below).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Michalakis et al.’s polynucleotide comprising a promoter comprising a human rod photoreceptor-specific promoter element (hRPSPE) and a transgene operably linked to the promoter, and use the PDE6A promoter which is also capable of driving the gene expression specifically in Rod photoreceptor in retina, as taught by Mohamed et al.. The only difference between instant claim and Michalakis et al.’s polynucleotide comprising the hRPSPE promoter is instant claim uses the PDE6A promoter which comprises SEQ ID NO:1 or a functionally equivalent sequence variant thereof, having at least 80% sequence identity to SEQ ID NO: 1. Given that Mohamed et al. teach the structure and upstream region characterization of the PDE6A gene as well as the sequences of PDE6A promoter (as provided in GenBank AF022380.1), one of ordinary skill in the art would have substituted the hRPSPE promoter, and have used the PDE6A promoter as well as optimized the promoter sequence to increase the tissue specificity and promoter activity depends on their research interest. This simple substitution of one known element (PDE6A promoter which comprises SEQ ID NO:1 or a functionally equivalent sequence variant thereof, having at least 80% sequence identity to SEQ ID NO: 1) for another known element (hRPSPE promoter) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 2, Michalakis et al. teach a polynucleotide comprising a) a promoter comprising a human rod photoreceptor-specific promoter element (hRPSPE) and b) a transgene (TG) operably linked to the promoter of a) (see p3, L12-17). Mohamed et al. also teach the transgene comprises a nucleic acid encoding a protein that maintains or improves the physiological function of rods (p3, L29-30). The transgene comprises i.e., a nucleic acid encoding the human rod cyclic nucleotide-gated channel beta subunit (hCNGBl), ABCA4, AIPLl, BESTl, CACNAlF, CLN3, CLRNl, CNGAl, CEP290, CRBl… (p3, L31-32 and p4, L1). This teaching reads on that the first nucleic acid and the further nucleic acid are heterologous.
Regarding claim 4, following the discussion above, Michalakis et al. teach transgene comprises a nucleic acid encoding a protein that maintains or improves the physiological function of rods. In certain exemplary embodiments, the transgene: (i) comprises a nucleic acid encoding the human rod cyclic nucleotide-gated channel beta subunit (hCNGBl), ABCA4, AIPLl, BESTl, CACNAlF, CLN3, CLRN1, CNGA1, CEP290, CRB1… (p3, L32 to p4, L1). Herein the transgenes which encoding a protein that maintains or improves the physiological function of rods are considered as therapeutically effective nucleic acids.
Regarding claims 5 and 11, Michalakis et al. teach an expression cassette comprising promoter of the human rhodopsin gene and cDNA of the human CNGB1a subunit of the rod photoreceptor cGMP
Phosphodiesterase (p61, Example 1).
Regarding claims 6 and 7, Michalakis et al. teach a viral vector comprising the polynucleotide, which comprising a) a promoter comprising a human rod photoreceptor-specific promoter element (hRPSPE) and b) a transgene (TG) operably linked to the promoter of a) (see p5, L9-10 and p3, L12-17). In certain exemplary embodiments, the virus is selected from the group consisting of AAV2, AAV5, AAV8, AVV9 or variants thereof (p5, L11-12).
Regarding claim 8, following the discussion above, Michalakis et al. teach the term "AAV vector" as used in the context of the invention refers to a complete virus particle, i.e., including a linear, single-stranded AAV nucleic acid genome associated with an AAV capsid protein coat (p23, L18-20).
Regarding claim 9, following the discussion above, Michalakis et al. teach a vector is used to transport the promoter and transgene of the invention into a suitable host cell (p22, L27-28). For instance, the rod photoreceptor in retinal which expresses eGFP after injecting rAAV.hRHO194.eGFP vector is the host cell of the vector (see Example 3).
Regarding claims 10, following the discussion above, Michalakis et al. teach the pharmaceutical composition comprising the polynucleotide and/or the viral vector (p25, L27-28), wherein the polynucleotide comprising a) a promoter comprising a human rod photoreceptor-specific promoter element (hRPSPE) and b) a transgene (TG) operably linked to the promoter of a) (see p3, L12-17).
Regarding claim 12, Michalakis et al. teach for use in the therapy of a disease of the retina, in particular retinal degeneration. In certain exemplary embodiments, the retinal degeneration is selected from the group consisting of night blindness, blindness, retinal degeneration, retinal dystrophy and retinitis pigmentosa (p5, L28-30).
Regarding claim 15, following the discussion above, Michalakis et al. teach the pharmaceutical composition comprising the polynucleotide and/or the viral vector (p25, L27-28), wherein the polynucleotide comprising a) a promoter comprising a human rod photoreceptor-specific promoter element (hRPSPE) and b) a transgene (TG) operably linked to the promoter of a) (see p3, L12-17), this is considered as a kit comprising the polynucleotide since it is used for transfecting the transgene specifically to rod photoreceptors.
Claim 1-12 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Michalakis et al. (WO 2018/172961 A1, as cited in IDS) in view of Mohamed et al. (J Mol Neurosci. 1998 Jun;10(3):235-50, as cited in IDS) and GenBank: AF022380.1 (available in 1998), as applied to 1-2, 4-12 and 15 above, further in view of Cooper et al. (Genome Res. 2006 Jan;16(1):1-10).
The teaching of Michalakis et al., Mohamed et al. and GenBank: AF022380.1 is set forth above.
Regarding claim 3, Mohamed et al. teach a longer promoter sequence may greatly enhance the tissue specific gene expression: expression constructs containing as little as 222 bp of bovine opsin sequence upstream of the TSP were shown to promote tissue-specific reporter gene expression, and this expression was greatly enhanced on inclusion of additional upstream sequence (see p236, left column). Michalakis et al., Mohamed et al. and GenBank: AF022380.1 do not teach the first nucleic acid has a sequence length of 800 to 1000 bp. However, this was disclosed by Cooper et al. at the time of instant invention.
Cooper et al. identified 387 fragments that function as promoters in at least one of 16 cell lines by measuring promoter activity in high-throughput transient transfection reporter assays (Abstract).
Regarding claim 3, Cooper et al. teach a longer promoter increase the tissue specific expression. Specifically, Cooper et al. teach on average, the sequence -300 to -50 bp of the transcription start sites (TSS) positively contributes to core promoter (Abstract), putative negative elements were identified −1000 to −500 bp upstream of the TSS (Abstract), which may be involved in the control of tissue-specific expression of gene (see p7, left column, “Core promoters and upstream regulatory elements” part).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Michalakis et al.’s polynucleotide comprising a promoter comprising a human rod photoreceptor-specific promoter element (hRPSPE) and a transgene operably linked to the promoter, and use the PDE6A promoter which is also capable of driving the gene expression specifically in Rod photoreceptor in retina, as taught by Mohamed et al., and further expand the promoter sequence to about 1000 bp (i.e., 800 bp-1000 bp) as taught by Cooper et al.. The skilled artisan would have been motivated to include more upstream nucleotides to have the promoter length to about 1000 bp since Cooper et al. teach −1000 to −500 bp upstream of the TSS may be involved in the control of tissue-specific expression of gene (p7, left column), therefore selecting and optimizing such promoter which includes about 1000 bp nucleotides comprising the tissue- specific region as taught by Mohamed et al. is benefit to obtain a promoter with both high promoter activity and high cell specificity. There would be a reasonable expectation of success of having a promoter which has a length of about 1000 bp since Mohamed et al. teach the transcription start point (tsp) as well as the sequence which is important for tissue-specific expression (i.e., figure 3), an ordinary skill in the art can select and optimize the sequence accordingly.
Conclusion
No claims are allowed.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
Sequence Alignment
Instant SEQ ID NO:1 v.s. GenBank: AF022380.1
PNG
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747
846
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Greyscale
PNG
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450
736
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Greyscale
Prosecution Insights