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
Claims 1, 5, 7, and 14 are currently amended, claims 2-4, 6, and 10 have been cancelled, claim 15 was previously cancelled, and claims 1, 5, 7-9, 11-14 and 16-20 have been considered on their merits.
Withdrawn Objections/Rejections
The objections to the specification have been withdrawn in view of the amendments to the specification.
The claim rejections under 35 USC § 112 have been withdrawn in view of the amendments to the claims.
The claim rejections under 35 USC § 103 have been withdrawn in view of the amendments to the claims.
Claim Objections
Claim 14 is objected to because of the following informalities: In the last line of the claim there appears to be an unnecessary underscore between “the” and “nucleic”. Appropriate correction is required.
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 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.
Claims 1, 5, 7-9, 11-13, and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Murillo Sauca et al. (US 2017/0348435, published 07 December 2017, of record) in view of Cali et al. (The Journal of Biological Chemistry (1991), of record) as evidenced by NCBI (Human sterol 27-hydroxylase mRNA, complete cds, 02 November 1994, of record) and Houten et al. (Direct submission, 21 April 2004, Cloning vector pdLucLRH-1, complete sequence).
This is a new rejection, necessitated by applicants amendment to the claims. A response to applicant’s traversal follows the rejection.
Regarding claim 1, Murillo Sauca et al. teach viral vectors carrying transgenes to host cells (para. [0013]). Murillo Sauca et al. teach said host cells may be hepatocytes (para. [0124]). Murillo Sauca et al. teach the administration of the vectors resulted in the normalization of liver histology compared to untreated animals (para. [0215]). Murillo Sauca et al. teach a vector comprising a 5'ITR and a 3'ITR nucleotide sequences of an AAV2, an EalbPalAT hybrid promoter sequence, and a nucleotide sequence encoding transgene (para. [0096]). While Murillo Sauca et al. demonstrates efficacious delivery of a transgene to hepatocytes of a knockout mouse, the disease being treated differs from that of the instant application. The Murillo Sauca et al. reference is being utilized to demonstrate liver specific promoter comprising a mouse albumin enhancer (Ealb) and a human alpha-1-antitrypsin promoter (Pa1AT) operably linked to a transgene, further comprising a 5’ITR and a 3’ITR sequences from an AAV effectively delivered said transgene to a hepatocyte.
Murillo Sauca et al. do not teach a transgene encoding human sterol 27-hydroxylase.
Cali et al. teach isolation and expression of human sterol 27-hydroxylase cDNAs (p. 7774, 2nd column). Cali et al. teach the construction of an expression vector (claim 8) for the human sterol 27-hydroxylase by inserting an EcoRI fragment corresponding to nucleotides 1-1180 of the sequence of the human sterol 27-hydroxylase cDNA into the EcoRI site of a pCMV plasmid (p. 7775, Experimental Procedures, 2nd column). The expression of human sterol 27-hydroxylase cDNA reads as a transgene encoding human sterol 27-hydroxylase.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the nucleic acid construct of Murillo Sauca et al. comprising the human sterol 27-hydroxylase transgene of Cali et al. with a reasonable expectation of success because Murillo Sauca et al. teach the nucleic acid construct comprising a liver specific promoter comprising a mouse albumin enhancer (Ealb) and a human alpha-1-antitrypsin promoter (Pa1AT) operably linked to a transgene, further comprising a 5’ITR and a 3’ITR sequences from an AAV effectively delivered said transgene to a hepatocyte and Cali et al. teach expression of human sterol 27-hydroxylase cDNAs was known in the art. One would be motivated to utilize the nucleic acid construct comprising the human sterol 27-hydroxylase transgene of Cali et al. with the nucleic acid construct of Murillo Sauca et al. because both Wilson’s disease of Murillo Sauca et al. and CTX of the instant application affect hepatocytes, thus one would be motivated to utilize the same nucleic acid construct to deliver the transgene encoding human sterol 27-hydroxylase.
Regarding claim 5, Murillo Sauca et al. disclose the Hybrid promoter EalbPa1AT, SEQ ID NO: 5, which has a 99.8% sequence identity with instant SEQ ID NO: 6, which reads as least 95% identity. See sequence search results, result 3, file us-18-041-142-6.rnpbm, for the alignment of Murillo Sauca et al. SEQ ID NO: 5 and instant SEQ ID NO: 6, see results below:
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Regarding claim 7, the human sterol 27-hydroxylase taught by Cali et al. is described in GenBank as Human sterol 27-hydroxylase (CYP27) mRNA, complete cds, GenBank: M62401.1. The alignment of GenBank: M62401.1 (query sequence) with SEQ ID NO: 9 (database sequence) results in an 85% identity (see SEQ ID NO_9 alignment file for complete alignment data), results displayed below:
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Cali et al. teach 99.9% similarity to the segment of SEQ ID NO: 9 corresponding to CYP27A1 (instant SEQ ID NO: 2). The sequences preceding the nucleotides encoding CYP27A1 are the 5’ITR (SEQ ID NO: 7) and EAAT (SEQ ID NO: 6). Following the nucleotides encoding CYP27A1 are the nucleotides encoding a SV40 late polyA signal and the 3’ITR (SEQ ID NO: 8. Murillo Sauca et al. disclose SEQ ID NO: 6 which comprises 5’ and 3’ AAV ITR, which have a 100% identity to instant SEQ ID NO: 7 and 8, see alignment in the rejection of claims 17 and 18 below. While the sequence for the SV40 late poly A is not disclosed independently from the sequence found in instant SEQ ID NO: 9, the sequence is still well-known in the art, as evidenced by the cloning vector of Houten et al. The description of the sequence for the below cloning vector, GenBank AY603758.1, discloses the polyA signal sequence is the SV40 late poly(A) signal from nucleotides 8583 and 8845. See alignment of the nucleotide encoding the polyA signal of the cloning vector with the sequence in between nucleotides position 2489 and 2798 of SEQ ID NO: 9 below:
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Additionally, Murillo Sauca et al. teach each of the AAV vector embodiments also includes a polyadenylation signal sequence, such as synthetic poly(A) signal sequence or any other suitable poly(A) signal (para. [0098]). Further, the selection of a polyadenylation signal is considered to be a matter of design choice given the sequence of the SV40 late poly A signal was known in the art and Applicant has not demonstrated any unexpected property for the poly A signal.
Therefore, the nucleic acid construct of Murillo Sauca et al. with the transgene of Cali et al. as evidenced by Houten et al. would be expected to have at least 95% identity to instant SEQ ID NO: 9, absent evidence to the contrary.
Regarding claims 8, 9, and 19, Murillo Sauca et al. teach the expression vector is an AAV vector (viral vector) (claim 9 and claim 19) (para. [0092]). Therefore, the vector of Murillo Sauca et al. with the transgene of Cali et al. read as an expression vector comprising the nucleic acid construct according to claim 1 (claim 8).
Regarding claims 11, 12, and 16, Murillo Sauca et al. teach viral particles (claim 11) can be produced in a specific packaging cell which is transfected with the nucleic acid construct of the vector to be packaged (para. [0113-0114]). Murillo Sauca et al. teach the method of producing viral particles comprise the steps of culturing a host cell, preferably said host cell is a packaging cell, comprising a nucleic acid construct (claim 12) or expression vector in a culture medium and harvesting the viral particles from the cell culture supernatant and/or inside the cells (claim 16) (para. [0115-0118]).
Regarding claim 13, Murillo Sauca et al. teach the product will be typically included in a pharmaceutical composition or medicament, optionally in combination with a pharmaceutical carrier, diluent and/or adjuvant (para. [0162]).
Regarding claims 17 and 18, Murillo Sauca et al. teach a vector comprising a 5'ITR and a 3'ITR nucleotide sequences of an AAV2, an EalbPalAT hybrid promoter sequence, and a nucleotide sequence encoding transgene (para. [0096]). Murillo Sauca et al. disclose SEQ ID NO: 6 which comprises 5’ and 3’ AAV ITR, which have a 100% identity to instant SEQ ID NO: 7 and 8, see alignment results below:
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Alignment results of instant SEQ ID NO: 7 and SEQ ID NO: 6 of Murillo Sauca et al. The full alignment data has been uploaded to the file wrapper.
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Alignment results of instant SEQ ID NO: 8 and SEQ ID NO: 6 of Murillo Sauca et al. The full alignment data has been uploaded to the file wrapper.
Regarding claim 20, Murillo Sauca et al. teach a viral particle constituted of capsid proteins derived from the same or different AAV serotype, such as AAV2 ITRs and AAV8 capsid proteins (para. [0105]).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant’s arguments, see Remarks, filed 26 November 2025, with respect to the rejections of claims 1-5, 7, 8, and 12 under 103 have been fully considered and are persuasive in view of the amendments to the claims. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Murillo Sauca (of record) and Cali (of record).
The arguments directed to Kramer and Mason are moot as the new rejection did not rely on Kramer.
Regarding the arguments directed to Cali and Murillo Sauca, on page 7 of the response, while Murillo Sauca et al. demonstrates efficacious delivery of a transgene to hepatocytes of a knockout mouse, the disease being treated differs from that of the instant application. The Murillo Sauca et al. reference is being utilized to demonstrate liver specific promoter comprising a mouse albumin enhancer (Ealb) and a human alpha-1-antitrypsin promoter (Pa1AT) operably linked to a transgene, effectively delivered said transgene to a hepatocyte. The teachings of Cali were relied upon only to demonstrate the isolation and characterization of human sterol 27-hydroxylase, as pointed out in the remarks at p. 7, which is accurate. Delivering transgenes via a viral vector, such as that of Murillo Sauca, is well-known in the art. Therefore, a reasonable expectation of success exists in delivering the transgene of Cali with the viral vector of Murillo Sauca, as both Murillo Sauca and the instant application desire to deliver transgenes to the same types of cells. Additionally, one of ordinary skill in the art would be motivated to utilize the nucleic acid construct comprising the human sterol 27-hydroxylase transgene of Cali et al. with the nucleic acid construct of Murillo Sauca et al. because both Wilson’s disease of Murillo Sauca et al. and CTX of the instant application affect hepatocytes, thus one would be motivated to utilize the same nucleic acid construct to deliver the transgene encoding human sterol 27-hydroxylase.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., successfully express active CYP27A1 in hepatocyte mitochondria) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Murillo Sauca et al. (US 2017/0348435, published 07 December 2017, of record) in view of Cali et al. (The Journal of Biological Chemistry (1991), of record) as evidenced by NCBI (Human sterol 27-hydroxylase mRNA, complete cds, 02 November 1994, of record) and Houten et al. (Direct submission, 21 April 2004, Cloning vector pdLucLRH-1, complete sequence) as applied to claim 1, 5, 7-9, 11-13, and 16-20 above, and further in view of Salen et al. (J Inherit Metab Dis (2017) 40:771–781).
This is a new rejection, necessitated by applicant’s amendment to the claim.
Regarding claim 14, Murillo Sauca et al. in view of Cali et al. are silent to a method for restoring bile acid metabolism in a subject in need thereof.
Salen et al. teach Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by mutations in the cytochrome P450 CYP27A1 gene that result in production of a defective sterol 27-hydroxylase enzyme (Abstract). Salen et al. teach CYP27A1 is a mitochondrial enzyme that is ubiquitously expressed and is responsible for catalyzing multiple hydroxylation reactions in cholesterol metabolism and bile acid synthesis (p. 772, Etiology).
Therefore, it would have been obvious to utilize a therapeutically effective amount of the nucleic acid construct of Murillo Sauca et al. in view of Cali et al. to restore bile acid metabolism with a reasonable expectation of success because Salen et al. teach CTX is a rare autosomal recessive disorder of bile acid synthesis caused by mutations in the cytochrome P450 CYP27A1 gene that result in production of a defective sterol 27-hydroxylase enzyme, which would lead to bile acid metabolism deficiencies and Murillo Sauca et al. in view of Cali et al. teach a construct to express human sterol 27-hydroxylase. One would be motivated to utilize a therapeutically effective amount of the nucleic acid construct of Murillo Sauca et al. in view of Cali et al. to restore bile acid metabolism because Salen et al. suggest development of new treatment approaches, such as gene therapy, may one day provide a much-needed cure for CTX (Salen et al., p. 779, Future Research).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
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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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631