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 .
This action is in response to the amendment filed 08/29/2025, in which claims 1 and 5 were amended. Claims 1-5 are currently pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Information Disclosure Statement
Receipt of acknowledgment of the information disclosure statements both filed on 05/12/2025 have been received and all references have been considered.
Claim Objections
The previous objection of withdrawn claim 11 has been withdrawn in view of applicant’s amendment filed on 08/29/2025.
Claim Rejections - 35 USC § 101
The previous rejection of claim 5 under 35 U.S.C 101 has been withdrawn in view of applicant’s amendment filed on 08/29/2025.
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.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable by Brown (US 2015/0011607) in view of GenBank Accession No. NM_000295 (April 23rd, 2019) and Cowan et al (US 2019/0010490 A1; Jan. 10, 2019).
Regarding claim 1, The specification describes the use of a sense shRNA1, comprising of SEQ ID NO: 39, and an antisense shRNA1, comprising SEQ ID NO: 40, wherein both the sense and antisense are required for the dsRNA.
Brown teaches compounds, compositions, and methods useful for reducing α-1 antitrypsin target RNA and protein levels via the use of siRNA (see Example 6, dsRNAs). Additionally, Brown teaches that the nucleic acid molecules of their invention can be inserted into expression constructs, e.g., viral vectors, wherein the expression constructs can be delivered to a subject [0435]. Brown teaches a preference of the dsRNA length to be between 21-23 bps [0113]. Brown also teaches that the dsRNA molecules of their invention may comprise modifications, e.g. 2’-Omethyl nucleosides [0033]. Brown describes nucleic acid sequences that target and hybridize to the Human alpha-1-antitrypsin gene, having the GenBank Accession number NM_000295.4 [0026]. Genbank Accession No: NM_000295.4 shows 100% identity at positions 1178 to 1198 to SEQ ID NO: 39 as well as 100% identity at positions 1198 to 1178 to SEQ ID NO: 40 (See Appendices III and IV).
Brown does not teach the specific sequences of SEQ ID NOs: 39 and 40.
Cowan teaches genome-targeting RNAs, or guide RNAs for use in genome editing of
alpha-1-antitrypsin (SERPINAI), wherein said genome-targeting RN As are useful in a method of treatment of a patient with alpha-I antitrypsin deficiency (Abstract). Cowan teaches “the method further comprises introducing into the cell two guide ribonucleic acid (gRNAs) and a polynucleotide donor template comprising at least a portion of the wild-type SERPINA1 gene, and wherein the one or more DNA endonucleases is two or more Cas9 endonucleases that effect a pair of double-strand breaks (DSBs), the first at a 5′ DSB locus and the second at a 3′ DSB locus, within or near the SERPINA1 gene or other DNA sequences that encode regulatory elements of the SERPINA1 gene, or within or near a safe harbor locus that facilitates insertion of a new sequence from the polynucleotide donor template into the chromosomal DNA between the 5′ DSB locus and the 3′ DSB locus that results in permanent insertion or correction of the chromosomal DNA between the 5′ DSB locus and the 3′ DSB locus within or near the SERPINA1 gene or other DNA sequences that encode regulatory elements of the SERPINA1 gene, or within or near a safe harbor locus and restoration of AAT protein activity, and wherein the first guide RNA comprises a spacer sequence that is complementary to a segment of the 5′ DSB locus and the second guide RNA comprises a spacer sequence that is complementary to a segment of the 3′ DSB locus” [0040]. Cowan teaches SEQ ID NO: 63447, this sequence is 22 nucleotides in length and comprises a spacer sequence that is 100% identical to SEQ ID NO: 40 of the instant invention [0061 and 0169] (See Appendix I). SEQ ID NO: 63447 of Cowan is also the reverse complement of SEQ ID NO: 39 of the instant application which is 100% identical to SEQ ID NO: 40 of the instant application (See Appendix II). SEQ ID NO: 63447 is described in Cowan as a guide RNA for editing a SERPINA1 (alpha-1-trypsin) gene in a cell from a patient with alpha-1-trypsin deficiency (Page 56, Claim 70).
It would have been obvious to the ordinary skilled artisan at the effective filing date of the instant application to have designed RNA molecules to inhibit the expression of human α-1- trypsin. There is sufficient motivation for the ordinary skilled artisan to design RNA inhibitors of human α-1-trypsin according to the present invention since Brown explicitly describe RNA inhibitors targeting human α-1-trypsin sequence. Moreover, the prior art also discloses multiple sequence structures that comprise the sequences set forth in the instant claims, e.g. Cowan et al. described above, which both disclose a nucleic acid sequence that comprises the entire sequence of SEQ ID NO: 39 of the present invention, and is known in the art to bind nucleic acid encoding human α-1-trypsin. A person skilled in the art seeking alternative nucleic acid structures to be used to inhibit the expression of human α-1-trypsin in an effort to treat conditions associated with the expression of this gene would have been motivated to combine the cited references in the design of the instant invention.
Furthermore, although the prior art does not specifically disclose the ribonucleic acid consisting of 19, 20, or 21 nucleotides in length comprising a sequence selected from SEQ ID NO: 39 and 40, it is clear that for at least SEQ ID NO: 39 and 40, the oligonucleotide SEQ ID NO: 63477 of Cowan et al. differs by a single nucleotide of these sequences. The instantly claimed compounds, are considered to be obvious analogues of the prior art compounds due to the close structural similarity to the prior art compounds, and to the extent that there does not appear to be a critical role for the additional nucleotide in the prior art compound. It is also noted that both the prior art compound and the instantly claimed compounds are designed to bind nucleic acid encoding human alpha-1-trypsin.
Regarding claims 2-4, Brown also teaches that the dsRNA molecules of their invention may comprise modifications, e.g. 2’-O-methyl nucleosides [0033].
Cowan teaches the compositions of the disclosure comprise one or more modified guide ribonucleic acids (gRNAs) [0064 and 0065]. Cowan teaches the modifications can comprise one or more nucleotides modified at the 2′ position of the sugar, such as a 2′-O-alkyl, 2′-O-alkyl-Oalkyl, or 2′-fluoro-modified nucleotides, 2′-fluoro, 2′-amino or 2′ O-methyl modifications on the ribose of pyrimidines, abasic residues, desoxy nucleotides, or an inverted base at the 3′ end of the RNA [0064 and 0065]. Cowan teaches SEQ ID NOs: 62,564-68,297 are 22 bp spacer sequences for targeting a SERPINA1 gene (other than as a safe harbor locus) with an Acidominococcus, Lachnospiraceae, and Francisella novicida Cpf1 endonuclease [0169].
It would have been obvious to the ordinary skilled artisan at the effective filing date of the instant application to have designed RNA molecules to inhibit the expression of human alpha-1-trypsin. There is sufficient motivation for the ordinary skilled artisan to design RNA inhibitors of human alpha-1-trypsin according to the present invention since Brown explicitly describe RNA inhibitors targeting human alpha-1-trypsin sequence as well as the modification of the dsRNA molecules such as 2’-O-methyl nucleosides. Moreover, the prior art also discloses multiple sequence structures that comprise the sequences set forth in the instant claims, e.g. Cowan et al. described above, which both disclose a nucleic acid sequence that comprises the entire sequence of SEQ ID NO: 39 of the present invention, and is known in the art to bind nucleic acid encoding human alpha-1-trypsin. A person skilled in the art seeking alternative nucleic acid structures to be used to inhibit the expression of human alpha-1-trypsin in an effort to treat conditions associated with the expression of this gene would have been motivated to combine the cited references in the design of the instant invention.
Furthermore, although the prior art does not specifically disclose the ribonucleic acid consisting of 19, 20, or 21 nucleotides in length comprising a sequence selected from SEQ ID NO: 39 and 40, it is clear that for at least SEQ ID NO: 39 and 40, the oligonucleotide SEQ ID NO: 63477 of Cowan differs by a single nucleotide of these sequences. The instantly claimed compounds, are considered to be obvious analogues of the prior art compounds due to the close structural similarity to the prior art compounds, and to the extent that there does not appear to be a critical role for the additionally nucleotide in the prior art compound. It is also noted that both the prior art compound and the instantly claimed compounds are designed to bind nucleic acid encoding human alpha-1-trypsin.
Regarding claim 5, Brown teaches compounds, compositions, and methods useful for reducing α-1 antitrypsin target RNA and protein levels via the use of siRNA (see Example 6, dsRNAs). Additionally, Brown teaches that the nucleic acid molecules of their invention can be inserted into expression constructs, e.g., viral vectors, wherein the expression constructs can be delivered to a subject [0435]. Brown teaches a preference of the dsRNA length to be between 21-23 bps [0113]. Brown also teaches that the dsRNA molecules of their invention may comprise modifications, e.g. 2’-O-methyl nucleosides [0033].
Brown does not teach the sequences of SEQ ID NOs: 39 and 40.
The prior art describes nucleic acid sequences that target and hybridize to the Human alpha-1-antitrypsin gene, having the GenBank Accession number NM_000295.
Cowan teaches genome-targeting RNAs, or guide RNAs for use in genome editing of alpha-1-antitrypsin (SERPINAI), wherein said genome-targeting RN As are useful in a method of treatment of a patient with alpha-I antitrypsin deficiency (Abstract). Cowan teaches “the method further comprises introducing into the cell two guide ribonucleic acid (gRNAs) and a polynucleotide donor template comprising at least a portion of the wild-type SERPINA1 gene, and wherein the one or more DNA endonucleases is two or more Cas9 endonucleases that effect a pair of double-strand breaks (DSBs), the first at a 5′ DSB locus and the second at a 3′ DSB locus, within or near the SERPINA1 gene or other DNA sequences that encode regulatory elements of the SERPINA1 gene, or within or near a safe harbor locus that facilitates insertion of a new sequence from the polynucleotide donor template into the chromosomal DNA between the 5′ DSB locus and the 3′ DSB locus that results in permanent insertion or correction of the chromosomal DNA between the 5′ DSB locus and the 3′ DSB locus within or near the SERPINA1 gene or other DNA sequences that encode regulatory elements of the SERPINA1 gene, or within or near a safe harbor locus and restoration of AAT protein activity, and wherein the first guide RNA comprises a spacer sequence that is complementary to a segment of the 5′ DSB locus and the second guide RNA comprises a spacer sequence that is complementary to a segment of the 3′ DSB locus” [0040]. Cowan teaches SEQ ID NO: 63447, this sequence is 22 nucleotides in length and comprises a spacer sequence that is 100% identical to SEQ ID NO: 40 of the instant invention [0061 and 0169] (See Appendix I). SEQ ID NO: 63447 of Cowan is also the reverse complement of SEQ ID NO: 39 of the instant application (Appendix II). SEQ ID NO: 63447 is described in Cowan as a guide RNA for editing a SERPINA1 (alpha-1-trypsin) gene in a cell from a patient with alpha-1-trypsin deficiency (Page 56, Claim 70). Cowan teaches the single guide nucleic acid (gRNA) has a length from 3 nucleotides to about 100 nucleotides, and comprise a linker that is a simple 4 nucleotide tetraloop [0339]. Cowan teaches pairs of guide strands have been used for deletions and corrections of inversions [0346 and 0348]. Cowan teaches the pairs of gRNAs able to edit the SERPINA1 DNA target region were identified [0626 and 0637].
It would have been obvious to the ordinary skilled artisan at the effective filing date of the instant application to have designed RNA molecules to inhibit the expression of human α-1-trypsin. There is sufficient motivation for the ordinary skilled artisan to design RNA inhibitors of human α-1-trypsin according to the present invention since Brown et al. explicitly describe RNA inhibitors targeting human α-1-trypsin sequence. Moreover, the prior art also discloses multiple sequence structures that comprise the sequences set forth in the instant claims, e.g. Cowan et al. described above, which both disclose a nucleic acid sequence that comprises the entire sequence of SEQ ID NO: 39 of the present invention, and is known in the art to bind nucleic acid encoding human α-1-trypsin. A person skilled in the art seeking alternative nucleic acid structures to be used to inhibit the expression of human α-1-trypsin in an effort to treat conditions associated with the expression of this gene would have been motivated to combine the cited references in the design of the instant invention.
Furthermore, although the prior art does not specifically disclose the ribonucleic acid consisting of 19, 20, or 21 nucleotides in length comprising a sequence selected from SEQ ID NO: 39 and 40, it is clear that for at least SEQ ID NO: 39 and 40, the oligonucleotide SEQ ID NO: 63477 of Cowan et al. differs by a single nucleotide of these sequences. The instantly claimed compounds, are considered to be obvious analogues of the prior art compounds due to the close structural similarity to the prior art compounds, and to the extent that there does not appear to be a critical role for the additionally nucleotide in the prior art compound. It is also noted that both the prior art compound and the instantly claimed compounds are designed to bind nucleic acid encoding human alpha-1-trypsin.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claims 1-5 under 35 U.S.C 103 over Brown (US 2015/0011607) in view of GenBank Accession No. NM_000295 (April 23rd, 2019) and Cowan et al (US 2019/0010490 A1; Jan. 10, 2019) has been maintained in view of Applicant’s Amendments and arguments filed on 08/29/2025. Applicant’s arguments have been considered but have not been found persuasive.
Applicant argues this combination of references does not provide that a person of ordinary skill in the art (POSA) would have been motivated to combine their teachings with a reasonable expectation of success to arrive at the claimed invention. Applicant agrees that Brown teaches a general concept but argues that this combination provides nothing more than a research goal to silence the AAT gene-without providing any guidance as to how one might successfully achieve that goal. Applicant continues the argument stating that the GenBank reference discloses that the AAT gene transcript (NM_000295) is over 1256 base pairs long and this presents a person of ordinary skill with at least 1236 potential siRNA target sites. Applicant argues the selection of an effective siRNA sequence from this vast number of candidates is a notoriously empirical and unpredictable process and therefore a POSA would understand that many factors, such as the secondary structure of the target mRNA and potential off-target hybridization events, can disrupt the RISC complex and lead to ineffective gene knockdown.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes 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 this case, the Examiner asserts that the obviousness to try rationale is utilized. Where MPEP § 2143 (I)(E) states:
“To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness”
In context of (I), Brown teaches compounds, compositions, and methods useful for reducing α-1 antitrypsin target RNA and protein levels via the use of siRNA (see Example 6, dsRNAs).
In the context of (II), Applicant’s argument states that the GenBank reference discloses that the AAT gene transcript (NM_000295) is over 1256 base pairs long and this presents a person of ordinary skill with at least 1236 potential siRNA target sites. Showing a finite number of potential siRNA target sites.
In the context of (III), Brown teaches that the nucleic acid molecules of their invention can be inserted into expression constructs, e.g., viral vectors, wherein the expression constructs can be delivered to a subject [0435]. Brown teaches a preference of the dsRNA length to be between 21-23 bps [0113]. Brown also teaches that the dsRNA molecules of their invention may comprise modifications, e.g. 2’-Omethyl nucleosides [0033]. Brown describes nucleic acid sequences that target and hybridize to the Human alpha-1-antitrypsin gene, having the GenBank Accession number NM_000295.4 [0026].
It should also be noted that the Applicant’s argument is reliant on the function of the claims whereas the claims are drawn to a product. Specifically, the independent claim recites, “a chemically modified ribonucleic acid consisting of 19, 20, or 21 nucleotides and having a sequence selected from according to SEQ ID NO: 39 or 40” which is a product. None of the dependent claims outline a functional limitation of the independent claim.
Applicant argues a prima facie case of obviousness requires not only a motivation to combine prior art references, but also a reasonable expectation of success in achieving the claimed invention. Applicant continues to argue that the Examiner's rationale suggests that because the elements were known but does not suggest a motivation or a reasonable expectation of success in producing an effective RNAi agent.
Applicant’s arguments are not persuasive because motivation as well as a reasonable expectation of success by has been established and stated above wherein Brown and Cowan provide motivation as well as reasonable expectation of success to combine the teachings to reach the product as claimed in the instant invention. 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).
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/ Examiner, Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637