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 Status
Applicant’s submission filed 03/12/2026 has been received and entered. Claims 10, 17, 30 and 31 have been cancelled. Claims 1-9, 11, 15, 16, 23, 25-29 and 33 -42 have been amended. Claims 43-54 have been newly added. Claim 29 remains withdrawn as being directed to non-elected species. Accordingly, claims 1-9, 11, 15, 16, 23, 25-28 and 33 -54 are pending and under current examination.
Status of Prior Rejections / Response to Arguments
The objection to Specification is withdrawn:
Applicant’s amendment to Specification is effective to obviate the objection on record. The objection is withdrawn.
The objection to claims 37-40 is withdrawn, but the objection to claim 1 is maintained:
Regarding claims 37-40: Applicant’s renumbering of the claims is effective to obviate the objection on record. The objection is withdrawn.
Regarding claim 1: Applicant acknowledged the objection in the Remarks but failed to amend claim 1 in the submission, the objection is maintained.
The rejection to claims 37 and 38 under 35 U.S.C. 112(b) is withdrawn, but the rejection to (second) claim 37 (now claim 39) under 35 U.S.C. 112(b) is maintained:
Regarding claims 37-38: Applicant’s amendment to claim 37 is effective to obviate the rejection on record. The rejection is withdrawn.
Regarding (second) claim 37 (now claim 39): Applicant’s amendment to claim recites “a similar amount of full-length protein” renders instant claim indefinite. The rejection is maintained in modified form to address amended limitations.
The rejection to claims 1-2, 4-11, 15-17, 23, 25-28, 30 and 35-36 under 35 U.S.C. 103 over Li et al. in view of Colella et al. is withdrawn:
The rejection to claims 1-11, 15-17, 23, 25-28, 30, 35 and 36 under 35 U.S.C. 103 over Li et al. in view of Colella et al., and further in view of Fasan et al. and Wood et al. is withdrawn:
The rejection is withdrawn based on the discussion in the interview dated 01/21/2026. Specifically, Applicant’s amendment and argument overcome the rejection on record due to the submission of evidence shows that Li “failed to show significant dystrophin expression or functional benefit after intramuscular administration” using the vector system (see p192, right column, Tasfaout et al., Nature. 2024 Aug;632(8023):192-200), which indicates that Li’s AAV vector system fails to produce a (functional) protein by protein splicing.
The rejection to claims 1, 2, 10, 16, 17, 25, 33, 34 and 37-40 under 35 U.S.C 103 over Subramanyam et al. in view of Michalakis et al., as evidenced by Fuster-García et al. is maintained:
Applicant’s amendment to claim 1 limits the vector system is AAV vector system, asserts that Subramanyam et al. differs from instant claims that: (i) different viral vectors: adenoviral vectors (AdV) in Subramanyam compared to adeno-associated viral vectors (AAV) in the present application; (ii) transduction of different types of cells: cardiomyocytes in Subramanyam compared to retinal cells in the present application; (iii) packaging of different transgenes: calcium channels in Subramanyam compared to large retinal proteins in the present application (Remarks, p19-22). Therefore a person of ordinary skill in the art would not have been motivated to replace the AdV of Subramanyam with an AAV as used in the present disclosure, and Michalakis does not cure the deficiencies of Subramanyam (Remarks, p22).
Applicant’s argument is fully considered but not found persuasive. Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See /Inre Keller, 642 F.2d 413, 208 USPQ 871 (CCPA1981); Inre Merck& Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant is also reminded that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, Subramanyam et al. teach using split-intein–mediated protein trans-splicing to reconstitute L-type calcium channels (LTCC) α1C-subunit (6.6 kb size) from two distinct halves (Abstract), both intein-tagged α1C moieties were readily packaged into adenoviral vectors (p15643 right column and figure 4A) for infecting adult cardiac myocytes, and functional split intein–reconstituted LTCCs are produced (figure 3). This teaching demonstrates the method of making split-intein vector systems. Michalakis et al. teach proteins with long amino acid sequences, for example human CACNA1F, CEP290, GPR98, MYO7A, RPl and USH2A protein, which are too long to be encoded by a transgene deliverable by the respectively chosen vector system, in particular AAV vector. To fit the size limitation of AAV vectors "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used (p17, L7-12). Michalakis et al. also teach the same method: each half transgene of interest can be fused to the corresponding split-intein moiety and, only upon co-expression, the intein-mediated trans-splicing occurs and the full transgenic protein is reconstituted. Thus, it would be possible to construct two vectors encoding fragments of the transgenic protein that would upon co-transduction assemble in the target cell into the full-length functional protein (p17, L13-17). An ordinary skill in the art would have been taught or suggested by these teachings about how to make split-intein constructs and use them in AAV system to have an AAV vector system comprising, i.e., two AAV vectors which are "split vectors" to fit the size limitation of AAV vectors. The rejection is maintained in modified form to address amended limitations.
New/modified grounds of rejection are set forth as necessitated by Applicant’s amendment.
New/Maintained Claim Objections
Claims 1, 43 and 51 are objected to because of the following informalities: Claims 1, 43 and 51 recite "a vector system to express a coding sequence in a cell", the phrase should be amended to "a vector system for expressing a coding sequence in a cell" for better clarity.
Appropriate correction is required.
New/Modified Claim Rejections
New 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.
Claim 39 is 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.
Instant claim 39 recites the AAV vector system of claim 1 having “the gene express a similar amount of full-length protein to the amount of protein expressed by a wild type gene fragment”. However, this phrase is presented in Specification (p145, L10-11) in the condition of using ecDHFR (a degron) in the vector. Since instant claim 1 does not have a limitation of using ecDHFR, this limitation in instant claim is not supported by the Specification.
This is a new matter rejection necessitated by Applicant’s amendment.
New Claim Rejections - 35 USC § 112(b)
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 39 and 42 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.
The term “similar” in claim 39 is a relative term which renders the claim indefinite. The term “similar” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In instant case, it is not clear what amount of full-length protein is considered as a similar amount to the expression of a wide type gene fragment. Moreover, it is not clear what “a wild type gene fragment” refers to, and whether or not the wild type gene fragment would encode a functional protein.
Claims 42 depends from claim 39, and thus inherit the deficiency and are rejected on the same basis.
Claim Interpretation
Instant claims 1, 44 and 52 recite "wherein when the first vector and the second vector are inserted in a cell, the protein product of the coding sequence is produced by protein splicing" and "wherein when the first vector, the second vector, and the third vector are inserted in a cell, the protein product of the coding sequence is produced by protein splicing", since the claim is directed to a vector system (a product), said recitations are the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the recitation is not considered a limitation to be given patentable weight and is of no significance to claim construction. Shoes by Firebug LLC V. Stride Rite Children's Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020). See MPEP 2111.02.
Instant claim 39 is indefinite. In the interest of compact prosecution, the claim is interpreted that the gene would express full-length protein.
New Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 43-44 and 49-50 are newly rejected under 35 U.S.C. 102(a)(1) as being anticipated by Truong et al. (Nucleic Acids Res. 2015 Jul 27;43(13):6450-8). The rejection is necessitated by Applicant’s amendment.
Truong et al. designed and created a split-intein mediated split–Cas9 trans-splicing system.
This system allows the coding sequence of Cas9 to be distributed on a dual-vector system and reconstituted posttranslationally (p6451, left column).
Regarding claim 43, Truong et al. teach the split–intein–Cas9 systems were created by fusing the N- or C-terminal halves of SpCas9 to the corresponding intein halves (p6452, right column). Truong et al. teach a demonstration that the split-intein split-SpCas9 system can be delivered by rAAV (figure 3). The split–Cas9 rAAV constructs comprise two vectors: pAAV crTLR#1 Nv1 and pAAV crTLR#1 Cv1. The first vector (pAAV crTLR#1 Nv1) comprises from 5’-3’: ITR-promoter (U6 and CBh)-CDS1 (N-Cas9)-N-intein-ITR. The second vector (pAAV crTLR#1 Cv1) comprises from 5’-3’: ITR-promoter (U6 and CBh)-C-intein- CDS2 (C-Cas9)-ITR. Therefore Truong et al.’s teaching anticipates instant claim.
Regarding claim 44, following the discussion above, Truong et al. teach nuclease activity was detectable when the two rAAV carrying the two moieties were added to the AAVS1 TLR/+ cell (figure 3B), indicates that the functional Cas9 is produced.
Regarding claims 49 and 50, Truong et al. teach the AAV vectors comprise a bovine growth hormone polyadenylation signal (bGHpA) (figure 3A). Moreover, Truong et al. teach the AAV plasmid used is LITE1.0_pAAV_hSyn_CRY2PHR-NLSVP64_2A_GFP_WPRE bGHpA, which comprising both of WPRE and bGHpA (p6452, left column).
New/Modified 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.
Claims 1, 2, 16, 25, 33, 34 and 37-40 stand and claims 11, 15, 23, 26-27, 35-36 and 41-42 are newly rejected under 35 U.S.C 103 as being unpatentable over Subramanyam et al. (Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15461-6) in view of Michalakis et al. (WO 2018/172961, published 09/27/2018), as evidenced by Fuster-García et al. (Mol Ther Nucleic Acids. 2017 Sep 15;8:529-541) and Mathur et al. (Biochim Biophys Acta. 2015 Mar;1852(3):406-20). The rejection is necessitated by Applicant’s amendment.
Subramanyam et al. teach using split-intein–mediated protein trans-splicing to reconstitute
L-type calcium channels (LTCC) α1C-subunit (6.6 kb size) from two distinct halves, overcoming the difficulty of expressing full-length α1C in cardiomyocytes (Abstract).
Regarding claim 1, Subramanyam et al. teach LTCC α1C subunit is a 2,171-residue protein
containing four homologous domains each with six transmembrane segments and cytoplasmic N and C termini (p15462, left column and figure 1). Subramanyam et al. teach splitting α1C cDNA at the II–III loop and cloned the split-intein fragments of N. punctiforme DnaE intein into the C and N termini of the left ([I–II]N-intein) and right (C-intein[III–IV]) halves, respectively (p15462, left column and figure 2A). Subramanyam et al. also teach both intein-tagged α1C moieties were readily packaged into adenoviral vectors (p15643 right column and figure 4A) for infecting adult cardiac myocytes. This teaching reads on a vector system to express a coding sequence in a cell (herein cardiac myocytes), said coding sequence consisting of a first portion (CDS1, herein α1C I-II), a second portion (CDS2, herein α1C III-IV), said vector system comprising: a) a first vector comprising: said first portion of said coding sequence (CDS1, herein α1C I-II), -a first intein nucleotide sequence coding for a N-Intein, said sequence being located at the 3' end of CDS1; and b) a second vector comprising: said second portion of said coding sequence (CDS2, herein α1C III-IV), a second intein nucleotide sequence coding for a C-Intein, said sequence being located at the 5' end of CDS2.
Subramanyam et al. teach using adenoviral vector for the split-intein approach, and demonstrate that the split-intein approach can be extended to explore the functional properties of many other large proteins in cardiomyocytes (p15465, right column), but do not teach using an adeno-associated viral (AAV), as well as the coding sequence of a gene selected from the group consisting of: ABCA4, MYO7A, CEP290, CDH23, EYS, PCDH15, CACNA1, SNRNP200, RP1, PRPF8, RP1L1, ALMS1, USH2A, GPR98, and HMCN1. However, such was disclosed by Michalakis et al. at the time of instant invention.
Michalakis et al. teach a polynucleotide comprising a promoter comprising a human photoreceptor-specific promoter element, a core promoter and at least one trans gene (Abstract).
Regarding claim 1, Michalakis et al. teach proteins with long amino acid sequences, for
example human CACNA1F, CEP290, GPR98, MYO7A, RPl and USH2A protein, which are too long to be encoded by a transgene deliverable by the respectively chosen vector system, in particular AAV vector. To fit the size limitation of AAV vectors "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used. By the use of split-inteins the packaging limit of the AAV can be bypassed (p17, L7-12). Michalakis et al. teach the same method: each half transgene of interest can be fused to the corresponding split-intein moiety and, only upon co-expression, the intein-mediated trans-splicing occurs and the full transgenic protein is reconstituted. Thus, it would be possible to construct two vectors encoding fragments of the transgenic protein that would upon co-transduction assemble in the target cell into the full-length functional protein (p17, L13-17).
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 Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties, and having an AAV vector systems for large size protein such as CEP290 and MYO7A, based on the same principle as taught by Michalakis et al.. The only difference between instant claim and Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties is the instant claim is using AAV vector system, and the coding sequence of a gene selected from the group consisting of: ABCA4, MYO7A, CEP290, CDH23, EYS, PCDH15, CACNA1, SNRNP200, RP1, PRPF8, RP1L1, ALMS1, USH2A, GPR98, and HMCN1 in AAV vector system. Given that Michalakis et al. teach for these proteins such as CEP290 and MYO7A which are too long to be encoded by a single AAV vector, the "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used (see p17, L7-12), which indicate that the split-intein can also be used in AAV system for addressing the problem of size limitation of AAV vectors, one of ordinary skill in the art would have substituted Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties, and use AAV vector system for other coding sequences such as CEP290 and MYO7A depends on their research interest. This simple substitution of one known element (an AAV vector systems comprising intein-mediated coding gene such as CEP290 and MYO7A) for another known element (an adenoviral vector systems comprising intein-tagged α1C moieties) 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, Subramanyam et al. teach strategy for reconstituting full-length α1C using split-intein–mediated protein splicing. The α1C subunit is split into two halves tagged with fluorophores and flanking N. punctiforme DnaE split inteins, creating CFP[[I–II]N-intein and C-intein[III–IV]YFP, respectively (p 15462, figure 2A). This teaching reads on the N-intein and C-intein encodes for N. punctiforme DnaE split inteins.
Regarding claims 11 and 26-27, Michalakis et al. teach proteins such as human CACNA1F, CEP290, GPR98, MYO7A, RPl and USH2A protein can be constructed by intein-mediated split system (p17, L7-12), wherein for instance, Mathur et al. provide evidence that USH2A causes retinal degeneration (see, i.e., p413, right column) in Usher syndrome, therefore using the coding sequence encodes USH2A protein will be able to correct a retinal degeneration, reads on instant claim 11. Moreover, Fuster-García et al. provide evidence that Usher syndrome is a rare autosomal recessive disease and the most common inherited (see p529, left column), reads on the limitations in instant claims 26-27.
Regarding claim 16, Michalakis et al. teach proteins with long amino acid sequences, for USH2A
example human CACNA1F, CEP290, GPR98, MYO7A, RPl and USH2A protein, which are too long to be encoded by a transgene deliverable by the respectively chosen vector system, in particular AAV vector. To fit the size limitation of AAV vectors "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used. By the use of split-inteins the packaging limit of the AAV can be bypassed (p17, L7-12), this teaching indicates that the coding sequence can be CEP290.
Regarding claim 23, Michalakis et al. teach a pharmaceutical composition comprising a
pharmaceutically acceptable carrier (see p40, L11).
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 Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties, and having an AAV vector systems for coding gene to correct a retinal degeneration such as USH2A or a coding gene CEP290, and/or further having pharmaceutically acceptable vehicle carry the vector system as taught by Michalakis et al.. The only difference between instant claim and Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties is the coding sequences of instant claim is the coding sequence of CEP290 or USH2A. Given that Michalakis et al. teach CEP290 or USH2A is too long to be encoded by a single AAV vector, the "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used (see p17, L7-12), one of ordinary skill in the art would have substituted Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties, and use this AAV system for coding sequence CEP290 or USH2A based on the same principle depends on their research interest. This simple substitution of one known element (an AAV vector systems comprising intein-mediated coding gene CEP290 or USH2A) for another known element (an adenoviral vector systems comprising intein-tagged α1C moieties) 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 15, Subramanyam et al. teach splitting α1C cDNA at the II–III loop and cloned the split-intein fragments of N. punctiforme DnaE intein into the C and N termini of the left ([I–II]N-intein) and right (C-intein[III–IV]) halves, respectively (p15462, left column and figure 2A). Subramanyam et al. also teach both intein-tagged α1C moieties were readily packaged into adenoviral vectors (p15643 right column and figure 4A) for infecting adult cardiac myocytes. This teaching indicates a construct comprising [I–II]N-intein and a construct having C-intein[III–IV]. Michalakis et al. teach AAVs vectors having the elements are arranged in 5' to 3' direction in the following order: L-ITR-promoter-transgene-R-ITR (p38, L15-16).
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 Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties, and having an AAV vector systems with the elements in an order as 5’-3’: L-ITR-promoter-transgene (i.e., intein-mediated coding sequence)-R-ITR as taught by Michalakis et al.. The only difference between instant claim and Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties is instant claim is an AAV system and the elements are in the order of 5’-3’: ITR-promoter- (CDS1-N-intein or C-intein-CDS2)-ITR. Given that Subramanyam et al. teach the arrangement of intein-tagged protein in a construct, and Michalakis et al. teach AAVs having the elements are arranged in 5' to 3' direction in the following order: L-ITR-promoter-transgene-R-ITR (p38, L15-16), one of ordinary skill in the art would have substituted Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties, and have an AAV system with the elements in an order of L-ITR-promoter-transgene (i.e., intein-mediated coding sequence)-R-ITR. This simple substitution of one known element (an AAV vector systems comprising L-ITR-promoter-transgene (i.e., intein-mediated coding sequence)-R-ITR) for another known element (an adenoviral vector systems comprising intein-tagged α1C moieties) 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 25, Subramanyam et al. teach strategy for reconstituting full-length α1C using split-intein–mediated protein splicing. The α1C subunit is split into two halves tagged with fluorophores and flanking N. punctiforme DnaE split inteins, creating CFP[[I–II]N-intein and C-intein[III–IV]YFP, respectively (p 15462, figure 2A). Therefore the split intein is a DnaE intein.
Regarding claim 33, Subramanyam et al. teach using split-intein–mediated protein trans splicing to reconstitute LTCC α1C-subunit from two distinct halves, overcoming the difficulty of expressing full-length α1C in cardiomyocytes (Abstract).
Regarding claim 34, Subramanyam et al. teach in heart, LTCCs mediate excitation– contraction (EC) coupling, control excitability, and regulate gene expression (p15461, left column). LTCC comprises α1C fragments, α1C fragments can encode dihydropyridine-resistant channels (see Abstract). Since this α1C protein expresses in the normal heart, it is considered as wild-type protein.
Regarding claims 35-36, Michalakis et al. teach using an intein-mediated split system for proteins with long amino acid sequences, for example human CACNA1F, CEP290, GPR98, MYO7A, RPl and USH2A protein (p17, L7-12), Michalakis et al. also teach the functional fragments and variants of these proteins are included (see p17, L3), and the functional fragments and variants also maintain the function of the respective protein (p17, L4-7). Since under the broadest reasonable interpretation (BRI), the functional fragments which retain the protein function is also considered as variants, therefore the teaching reads on the limitation of instant claims.
Regarding claims 37 and 39, Subramanyam et al. teach using split-intein–mediated protein trans-splicing to reconstitute LTCC α1C-subunit from two distinct halves, overcoming the difficulty of expressing full-length α1C in cardiomyocytes (Abstract).
Regarding claim 38, Subramanyam et al. teach (split-intein–tagged α1C fragments) similar to endogenous LTCCs, recombinant channels targeted to dyads, triggered Ca2+ transients, associated with caveolin-3, and supported β-adrenergic regulation of excitation–contraction coupling (Abstract). Moreover, the functional analysis shows WT α1C and spliced WT α1C having similar electrophysiological properties (see i.e., figure 3).
Regarding claim 40, Subramanyam et al. teach the size of α1C is 6.6 Kb (P15461, right column).
Regarding claims 41-42, since Michalakis et al. teach proteins with long amino acid sequences, for example human CACNA1F, CEP290, GPR98, MYO7A, RPl and USH2A protein, which are too long to be encoded by a transgene deliverable by the respectively chosen vector system, in particular AAV vector. To fit the size limitation of AA V vectors "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used. By the use of split-inteins the packaging limit of the AAV can be bypassed (p17, L7-12). The size of USH2A coding sequence is up to 15 kb, which is evidenced by Fuster-García et al. (p529, right column). This teaching reads on the coding sequence of the gene is at least 9 kb (as recited in instant claim 39) and 14 kb (as recited in instant claim 40).
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 Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties, and having an AAV vector systems for coding gene USH2A, which is up to 15kb, as taught by Michalakis et al.. The only difference between instant claim and Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties is instant claim uses a AAV vector system and the coding sequence is USH2A, which is up to 15kb. Given that Michalakis et al. teach USH2A is too long to be encoded by a single AAV vector, the "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used (see p17, L7-12), one of ordinary skill in the art would have substituted Subramanyam et al.’s adenoviral vector systems comprising intein-tagged α1C moieties, and use AAV vector for coding sequence USH2A based on the same principle depends on their interest. This simple substitution of one known element (an AAV viral vector systems comprising intein-mediated coding gene USH2A, which is up to 15kb) for another known element (an adenoviral vector systems comprising intein-tagged α1C moieties) 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.).
Claims 1-2, 16, 25, 33, 34 and 37-40 stand and claims 3, 11, 15, 23, 26-27, 35-36 and 41-42 are newly rejected under 35 U.S.C 103 as being unpatentable over Subramanyam et al. (Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15461-6) in view of Michalakis et al. (WO 2018/172961, published 09/27/2018), as evidenced by Fuster-García et al. (Mol Ther Nucleic Acids. 2017 Sep 15;8:529-541) and Mathur et al. (Biochim Biophys Acta. 2015 Mar;1852(3):406-20), as applied to claims 1, 2, 11, 15, 16, 23, 25-27 and 33-42 above, further in view of Fasan et al. (US 2013/0330773 A1, published in 2013) and Wood et al. (US 10066027 B2, patented 09/04/2018).
The teaching of Subramanyam et al. in view of Michalakis et al. is set forth above.
Regarding claim 3, Subramanyam et al. in view of Michalakis et al. do not teach the nucleotide sequence of first intein and second intein. However, the sequences of the first and second intein are prima facie in view of Fasan et al. and Wood et al..
Fasan et al. teach methods and compositions that utilize synthetic molecules and genetically encoded polypeptides to generate macrocyclic peptide-containing molecules with a hybrid peptidic/non-peptidic backbone (Abstract).
Wood et al. teach a split intein comprising an N-terminal intein segment, which can be immobilized, and a C-terminal intein segment, which has the property of being self-cleaving, and which can be attached to a protein of interest (Abstract).
Regarding claim 3, Fasan et al. teach intein is a fusion product of a split intein: Npu-PCC73102 DnaE (SEQ ID NO:66-SEQ ID NO:67) (parag 0035), intein sequences that can be used within the invention can be derived by fusing together the N-fragment and C-fragment of a naturally occurring split intein. Split inteins include, but are not limited to…Npu-PCC73102 DnaE (SEQ ID NO:66-SEQ ID NO:67) (parag 0204), this teaching indicates SEQ ID NO:66 is the sequence of N-fragment of Npu-PCC73102 DnaE. SEQ ID NO:66 is 100% identical to SEQ ID NO:1 in instant claim (sequence alignment is attached).
Moreover, Wood et al. teach exemplary sequences of the N-terminal intein segment and the C-terminal intein segment in table 1 (p21-22), SEQ ID NO:8 is native DnaE NPU C-terminal intein segment. SEQ ID NO:8 is 100% identical to SEQ ID NO:2 in instant claim (sequence alignment is attached).
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 Subramanyam et al.’s split-intein, and use N-inteins as taught by Fasan et al. and C-Intein as taught by Wood et al.. The only difference between instant claim and Subramanyam et al.’s split-intein is instant claim teach the nucleic acid sequence of intein, given that Fasan et al. and Wood et al. teach the sequence of N-intein and C-intein, one of ordinary skill in the art would have substituted Subramanyam et al.’s split DnaE with Fasan et al. and Wood et al.’s which sequences are showed. The simple substitution of one known element (DnaE which has fusion N-fragment and native C-fragment) for another known element (Subramanyam et al.’s split DnaE) is 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.).
Claims 1-2, 16, 25, 33, 34 and 37-40 stand rejected and claims 4-7, 9, 11, 15, 23, 26-27, 35-36 and 41-42 are newly rejected under 35 U.S.C 103 as being unpatentable over Subramanyam et al. (Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15461-6) in view of Michalakis et al. (WO 2018/172961, published 09/27/2018), as evidenced by Fuster-García et al. (Mol Ther Nucleic Acids. 2017 Sep 15;8:529-541) and Mathur et al. (Biochim Biophys Acta. 2015 Mar;1852(3):406-20), as applied to claims 1, 2, 11, 15, 16, 23, 25-27 and 33-42 above, and further in view of Colella et al. (WO 2016/139321 A1, published in 2016). The rejection is necessitated by Applicant’s amendment.
The teaching of Subramanyam et al. in view of Michalakis et al. is set forth above.
Regarding claims 4-7 and 9, the claims are related to the regulatory elements of AAV viral vector, including a promoter (claim 4), 5'-terminal repeat (5'-TR) nucleotide sequence and a 3'-terminal repeat (3'-TR) nucleotide sequence (claim 5), a polyadenylation signal nucleotide sequence and/or a nucleotide sequence coding for a degradation signal (claim 6), wherein the degradation signal be CL1, PB29, SMN, CIITA, ODc or ecDHFR (claim 7), as well as a enhancer or regulatory nucleotide sequence, operably linked to the coding sequence (claim 9). Subramanyam et al. in view of Michalakis et al. do not teach these elements in the AAV vector. However, this was disclosed by Colella et al. at the time of instant invention.
Colella et al. teach constructs, vectors, relative host cells and pharmaceutical compositions which allow an effective gene therapy, in particular of genes larger than 5 Kb (Abstract).
Regarding claims 4-7 and 9, Colella et al. teach dual AAV vectors are generated by splitting a large transgene expression cassette in two separate halves each packaged in a single normal size (NS;
< 5 kb) AAV vector (i.e., CDS1 and CDS2, see p1, L21-23). Colella et al. teach the AAV vector further comprises a promoter sequence operably linked to the 5 'end portion of said first portion of the coding sequence (CDS1)(reads on the limitation of instant claim 4, see p5, L25-26); the vector further comprises a 5 '-terminal repeat ( 5 '-TR) nucleotide sequence and a 3 '-terminal repeat (3 '-TR) nucleotide sequence (reads on the limitation of instant claim 5, see p5, L27-28). Colella et al. teach a degradation signal is comprised in at least one of the vectors (p37, L26), such as inclusion of CL1degradation signal (p34, L8) reads on the limitation of instant claims 6 and 7; Colella et al. teach the vector further comprises at least one enhancer nucleotide sequence, operably inked to the coding sequence (p6, L14-15), reads on the limitation of instant claim 9.
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 Subramanyam et al. in view of Michalakis et al.’s protein trans-splicing vector system, and have regulatory elements in the AAV vector for regulating the gene expression as taught by Colella et al.. The skilled artisan would have been motivated to add regulatory elements such as promoter, terminal repeat, degradation signal, as well as enhancer in the vector, since Colella et al. teach these regulatory elements can regulate gene/protein expression, for instance, the degradation signal can mediate the degradation of the mRNA/protein in which it is included (see p12, lines 30-31). There would be a reasonable expectation of success of adding regulatory elements in the AAV vector system, since Colella et al. teach the position of the regulatory elements (i.e., see p5, L25).
Claims 1-2, 16, 25, 33, 34 and 37-40 stand and claims 8, 11, 15, 23, 26-28, 35-36 and 41-42 are newly rejected under 35 U.S.C 103 as being unpatentable over Subramanyam et al. (Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15461-6) in view of Michalakis et al. (WO 2018/172961, published 09/27/2018), as evidenced by Fuster-García et al. (Mol Ther Nucleic Acids. 2017 Sep 15;8:529-541) and Mathur et al. (Biochim Biophys Acta. 2015 Mar;1852(3):406-20), as applied to claims 1, 2, 11, 15, 16, 23, 25-27 and 33-42 above, further in view of Bachmann et al. (J Biol Chem. 2015 Nov 27;290(48):28792-804). The rejection is necessitated by Applicant’s amendment.
The teaching of Subramanyam et al. in view of Michalakis et al. is set forth above.
Regarding claims 8 and 28, Subramanyam et al. in view of Michalakis et al. do not teach the recited nucleophile amino acid serine, threonine, or cysteine. However, this was disclosed by Bachmann et al..
Bachmann et al. teach novel GOS-TerL split intein identified from metagenomic databases as the first intein harboring the combination of Ser1 and Cys+1 residues (p28792, left column).
Regarding claims 8 and 28, Bachmann et al. teach the catalytically critical amino acids involved at the two splice junctions are cysteine, serine, or threonine (p28792, left column). Therefore the design of intein would follow such principles that an intein will be placed in front of such nucleophilic amino acid that is required for protein splicing. It appears instant claim 28 is following the same principle of designing split sites (aa Cys1150, Ser1168, Ser1090 of the ABCA4 protein).
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 Subramanyam et al. in view of Michalakis et al.’s protein trans-splicing vector system, and have the intein split on positions of cysteine, serine, or threonine as taught by Bachmann et al.. The skilled artisan would have been motivated to use these positions for intein split since Bachmann et al. teach that they are catalytically critical amino acids involved at the two splice junctions (p28792, left column). There would be a reasonable expectation of success of using these amino acids as spit position since Bachmann et al. teach the protein splicing reaction (figure 1).
Claims 43-47 and 49-54 are newly rejected under 35 U.S.C. 103 as being unpatentable over Truong et al. (Nucleic Acids Res. 2015 Jul 27;43(13):6450-8) in view of Michalakis et al. (WO 2018/172961, published 09/27/2018). The rejection is necessitated by Applicant’s amendment.
Truong et al. designed and created a split-intein mediated split–Cas9 trans-splicing system.
This system allows the coding sequence of Cas9 to be distributed on a dual-vector system and reconstituted posttranslationally (p6451, left column).
Regarding claim 43, Truong et al. teach the split–intein–Cas9 systems were created by fusing the N- or C-terminal halves of SpCas9 to the corresponding intein halves (p6452, right column). Truong et al. teach a demonstration that the split-intein split-SpCas9 system can be delivered by rAAV (figure 3). The split–Cas9 rAAV constructs comprise two vectors: pAAV crTLR#1 Nv1 and pAAV crTLR#1 Cv1. The first vector (pAAV crTLR#1 Nv1) comprises from 5’-3’: ITR-promoter (U6 and CBh)-CDS1 (N-Cas9)-N-intein-ITR. The second vector (pAAV crTLR#1 Cv1) comprises from 5’-3’: ITR-promoter (U6 and CBh)-C-intein- CDS2 (C-Cas9)-ITR.
Regarding claim 44, following the discussion above, Truong et al. teach nuclease activity was detectable when the two rAAV carrying the two moieties were added to the AAVS1 TLR/+ cell (figure 3B), indicates that the functional Cas9 is produced.
Regarding claims 49 and 50, Truong et al. teach the AAV vectors comprise a bovine growth hormone polyadenylation signal (bGHpA) (figure 3A). Moreover, Truong et al. teach the AAV plasmid used LITE1.0_pAAV_hSyn_CRY2PHR-NLSVP64_2A_GFP_WPRE bGHpA, which comprising both of WPRE and bGHpA (p6452, left column).
Regarding claim 45 and 46, Truong et al. do not teach the coding sequences. However, this was disclosed by Michalakis et al. at the time of instant invention.
Michalakis et al. teach a polynucleotide comprising a promoter comprising a human photoreceptor-specific promoter element, a core promoter and at least one trans gene (Abstract).
Regarding claims 45-46, Michalakis et al. teach proteins with long amino acid sequences, for
example human CACNA1F, CEP290, GPR98, MYO7A, RPl and USH2A protein, which are too long to be encoded by a transgene deliverable by the respectively chosen vector system, in particular AAV vector. To fit the size limitation of AAV vectors "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used. By the use of split-inteins the packaging limit of the AAV can be bypassed (p17, L7-12). Michalakis et al. teach the same method: each half transgene of interest can be fused to the corresponding split-intein moiety and, only upon co-expression, the intein-mediated trans-splicing occurs and the full transgenic protein is reconstituted. Thus, it would be possible to construct two vectors encoding fragments of the transgenic protein that would upon co-transduction assemble in the target cell into the full-length functional protein (p17, L13-17).
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 Truong et al.’s AAV vector systems comprising coding sequence of Cas9, and having an AAV vector systems for other large size protein such as CEP290 and USH2A, based on the same principle as taught by Michalakis et al.. The only difference between instant claim and Truong et al.’s dual AAV vector systems comprising coding sequence of Cas9 is that the coding sequence of instant claim is a gene selected from the group consisting of: ABCA4, MYO7A, CEP290, CDH23, EYS, PCDH15, CACNA1, SNRNP200, RP1, PRPF8, RP1L1, ALMS1, USH2A, GPR98, and HMCN1. Given that Michalakis et al. teach for these proteins such as CEP290 and MYO7A which are too long to be encoded by a single AAV vector, the "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used (see p17, L7-12), which indicate that the split-intein can also be used in AAV system for addressing the problem of size limitation of AAV vectors, one of ordinary skill in the art would have substituted Truong et al.’s AAV system, and use this AAV system for other coding sequences such as CEP290 and MYO7A depends on their research interest. This simple substitution of one known element (an AAV vector systems comprising intein-mediated coding gene such as CEP290 and MYO7A) for another known element (Truong et al.’s AAV system comprising coding sequence of Cas9) 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 47, following the discussion above, Truong et al. teach in AAV vector a strong synthetic mammalian promoter (CBh) is used. Truong et al. do not teach using promoters such as Rhodopsin promoter (RHO) promoter in both first and second AAVs. However, Michalakis et al. teach promoters in the AAV vectors, such as murine rhodopsin (Rho) gene promoter (i.e., see p2, L15).
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 Truong et al.’s AAV vector systems comprising coding sequence of Cas9, and use an RHO promoter in the AAV vectors as taught by Michalakis et al.. The only difference between instant claim and Truong et al.’s dual AAV vector systems comprising coding sequence of Cas9 is that instant claim use promoters such as Rho in the AAV vectors. Given that Michalakis et al. teach the RHO promoter is rod-specific (p61, L6), one of ordinary skill in the art would have substituted Truong et al.’s AAV system, and use this RHO promoter when they want to specifically express the protein in rod cells. This simple substitution of one known element (an AAV vector systems comprising RHO promoter) for another known element (Truong et al.’s AAV system comprising CBh 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 claims 51-52, following the discussion above, Truong et al. teach all the elements in AAV system, but do not teach the AAV serotype as AAV2 or AAV. However, Michalakis et al. teach to fit the size limitation of AAV vectors "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used. By the use of split-inteins the packaging limit of the AAV can be bypassed (p17, L7-12). Michalakis et al. also teach the AAVs can be AAV2, AAV5, AAV8, AVV9 or variants thereof (p40, L4). Moreover, Michalakis et al. teach the method: each half transgene of interest can be fused to the corresponding split-intein moiety and, only upon co-expression, the intein-mediated trans-splicing occurs and the full transgenic protein is reconstituted.
Regarding claims 53-54, as discussed above, Michalakis et al. teach proteins with long amino acid sequences, for example human CACNA1F, CEP290, GPR98, MYO7A, RPl and USH2A protein, which are too long to be encoded by a transgene deliverable by the respectively chosen vector system, in particular AAV vector. To fit the size limitation of AAV vectors "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used. By the use of split-inteins the packaging limit of the AAV can be bypassed (p17, L7-12). Michalakis et al. teach the same method: each half transgene of interest can be fused to the corresponding split-intein moiety and, only upon co-expression, the intein-mediated trans-splicing occurs and the full transgenic protein is reconstituted. Thus, it would be possible to construct two vectors encoding fragments of the transgenic protein that would upon co-transduction assemble in the target cell into the full-length functional protein (p17, L13-17).
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 Truong et al.’s AAV vector systems comprising coding sequence of Cas9, and having an AAV vector systems (i.e., AAV 2 or AAV8) for other large size protein such as CEP290 and USH2A, based on the same principle as taught by Michalakis et al.. The only difference between instant claim and Truong et al.’s dual AAV vector systems comprising coding sequence of Cas9 is that the coding sequence of instant claim is a gene selected from the group consisting of: ABCA4, MYO7A, CEP290, CDH23, EYS, PCDH15, CACNA1, SNRNP200, RP1, PRPF8, RP1L1, ALMS1, USH2A, GPR98, and HMCN1. Given that Michalakis et al. teach for these proteins such as CEP290 and MYO7A which are too long to be encoded by a single AAV vector, the "split vector" technologies using the development of an intein-mediated split system for gene therapy can be used (see p17, L7-12), which indicate that the split-intein can also be used in AAV system for addressing the problem of size limitation of AAV vectors, one of ordinary skill in the art would have substituted Truong et al.’s AAV system, and use this AAV syatem for other coding sequences such as CEP290 and MYO7A depends on their research interest and select suitable AAV serotype as needed (i.e., AAV2 or AAV8). This simple substitution of one known element (AAV2 or AAV8 vector systems comprising intein-mediated coding gene such as CEP290 and MYO7A) for another known element (Truong et al.’s AAV system comprising coding sequence of Cas9) 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.).
Claims 43-54 are newly rejected under 35 U.S.C. 103 as being unpatentable over Truong et al. (Nucleic Acids Res. 2015 Jul 27;43(13):6450-8) in view of Michalakis et al. (WO 2018/172961, published 09/27/2018), as applied to claims 43-47 and 49-50 above, further in view of Fasan et al. (US 2013/0330773 A1, published in 2013) and Wood et al. (US 10066027 B2, patented 09/04/2018). The rejection is necessitated by Applicant’s amendment.
The teaching of Truong et al. in view of Michalakis et al. is set forth above.
Regarding claim 48, Truong et al. in view of Michalakis et al. do not teach the nucleotide sequence of first intein and second intein. However, the sequences of the first and second intein are prima facie in view of Fasan et al. and Wood et al..
Fasan et al. teach methods and compositions that utilize synthetic molecules and genetically encoded polypeptides to generate macrocyclic peptide-containing molecules with a hybrid peptidic/non-peptidic backbone (Abstract).
Wood et al. teach a split intein comprising an N-terminal intein segment, which can be immobilized, and a C-terminal intein segment, which has the property of being self-cleaving, and which can be attached to a protein of interest (Abstract).
Regarding claim 48, Fasan et al. teach intein is a fusion product of a split intein: Npu-PCC73102 DnaE (SEQ ID NO:66-SEQ ID NO:67) (parag 0035), intein sequences that can be used within the invention can be derived by fusing together the N-fragment and C-fragment of a naturally occurring split intein. Split inteins include, but are not limited to…Npu-PCC73102 DnaE (SEQ ID NO:66-SEQ ID NO:67) (parag 0204), this teaching indicates SEQ ID NO:66 is the sequence of N-fragment of Npu-PCC73102 DnaE. SEQ ID NO:66 is 100% identical to SEQ ID NO:1 in instant claim (sequence alignment is attached).
Moreover, Wood et al. teach exemplary sequences of the N-terminal intein segment and the C-terminal intein segment in table 1 (p21-22), SEQ ID NO:8 is native DnaE NPU C-terminal intein segment. SEQ ID NO:8 is 100% identical to SEQ ID NO:2 in instant claim (sequence alignment is attached).
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 Truong et al.’s split-intein, and use N-inteins as taught by Fasan et al. and C-Intein as taught by Wood et al.. The only difference between instant claim and Truong et al.’s split-intein is instant claim teach the nucleic acid sequence of intein, given that Fasan et al. and Wood et al. teach the sequence of N-intein and C-intein, one of ordinary skill in the art would have substituted Truong et al.’s split DnaE with Fasan et al. and Wood et al.’s which sequences are showed. The simple substitution of one known element (DnaE which has fusion N-fragment and native C-fragment) for another known element (Truong et al.’s split DnaE) is 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.).
Conclusion
No claims are allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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