DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of claims 185, 187-188, 191, and 196-201 with species election of SEQ ID NO:68 in the reply filed on May 28, 2026 is acknowledged.
Status of Claims
Claims 78 and 186-203 are currently pending in the instant application. Claims 186, 189-190, 192-195, and 202-203 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Accordingly, claims 78, 187-188, 191, and 196-201 are under examination on the merits in the instant application.
Specification
The disclosure is objected to because of the following informalities: Page 27 contains a large blank area with only 7 lines of disclosure. It is unclear whether a piece of disclosure is missing. Clarification is required.
Claim Rejections - Improper Markush Grouping
Claim 197 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination of process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP §706.03(y).
The Markush grouping of SEQ ID NOs:1-226 is improper because the different nucleotide sequence species are targeted to different sites/regions of the target sequence of about 30,000 nucleotides in length. As such, it is prima facie evident that the alternatively recited SEQ ID NOs do not all share a common nucleotide sequence, nor do they share a common function flowing from a commonly shared nucleotide sequence.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternatives within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 78, 187-188, 191, and 196-201 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are broadly drawn to any type of agent including but not limited to an antisense oligomer that binds to a PKD2 pre-mRNA comprising an NMD exon, wherein the agent is required to modulate splicing of the NMD exon, thereby modulating (both increasing and decreasing) expression of PKD2 protein.
Regarding the broad genus of “agent”, it is noted that the term “agent” is expressly disclosed as encompassing “a small molecule” and “a polypeptide”. See paragraphs 0084-0085. Contrary to the different types of agents that embrace non-nucleotide molecules as defined by the specification, it appears that the instant specification at best describes antisense DNA oligomers that are uniformly 18 nucleotides in length. This single agent species within the broad genus of any agents is not a representative number of species reflecting structural variants within the agents that include “a small molecule” and “a polypeptide”. In addition, even within the claimed ASO agents designed to bind to an NMD exon-containing PKD2 pre-mRNA, wherein the ASO agents comprise “8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NOs: 1-226”, the instant specification fails to describe the requisite structure-function correlation for all of ASO agents comprising 8-18 nucleotides of SEQ ID NOs:1-226. For instance, SEQ ID NOs:41, 44, 54, and 62 had little or no effect in increasing productive PKD2 mRNA and decreasing non-productive PKD2 mRNA as evidenced by FIG.7A-8B. In fact, more than 50% of SEQ ID NOs:1-99 failed to increase productive PKD2 mRNA as evidenced by FIG. 7A-8B. Furthermore, the mRNA expression in FIG. 7A-8B does not represent the PKD2 “protein” expression that is modulated as required and claimed in the instant case. It is noted that the increased PDK2 protein expression is at best shown to be assayed with a combination of ASO 21 with 67 or 68 or a combination of ASO 22 with 67 or 68. See FIG. 9E. In addition, “21+67” at 40 nM did not provide any statistically significant increase in PKD2 protein expression compared to “NTC” at 40 nM. Taken together, the instant specification itself demonstrates a high level of unpredictability pertaining to the actual functionality of modulating (both increasing and decreasing) PKD2 protein expression by any selected 18-mer sequence of SEQ ID NOs:1-226 or 8-17 fragments thereof, let alone the entire genus of agents encompassing any nucleic acid agents, any small molecule agents, any polypeptide agents, and so forth. Therefore, the combination species in FIG. 9E are not a representative number of the claimed genus as they do not reflect the requisite structure-function correlation for the myriad structural variants within the entire genus of agents as now claimed.
In view of the foregoing, it is concluded that the instant specification fails to reasonably convey that the instant co-inventors had possession of the entire genus as of the filing date sought in the instant application.
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.
Claims 78, 187, 196, and 198-201 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aznarez et al. (US 2019/0070213 A1, applicant’s citation).
Aznarez discloses a composition for increasing the expression of “a fully processed PKD2 mRNA” encoding “a functional form of a PC-2 protein”, wherein the composition comprises a pharmaceutically acceptable excipient and “an antisense oligomer that hybridizes to a target sequence of a deficient PKD2 mRNA transcript, wherein the deficient PKD2 mRNA transcript comprises a retained intron”, wherein the oligomer is an “18-mer” that is designed to target “immediately downstream of the 5’ splice site or upstream of the 3’ splice site” or the “retained-intron-containing pre-mRNA (RIC pre-mRNA) transcribed from the PKD2 gene” and comprises a phosphorothioate linkage and 2’-O-methyl modifications. See paragraphs 0056-0057, 0409, 0845, and 2009.
Aznarez teaches that the antisense oligomer targeting the retained intron of the PKD2 pre-mRNA can be designed as provided in “WO 2015/035091, titled “Reducing Nonsense-Mediated mRNA Decay,” and “the antisense oligonucleotide is linked with a viral vector”. See paragraphs 0896 and 0926.
Accordingly, claims 78, 187, 196, and 198-201 are described by Aznarez et al.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 78, 187-188, 191, 196-197, and 201 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claims recite a fragment of a nucleic acid that occurs naturally as evidenced by the fact that a 16-mer DNA fragment of applicant’s elected SEQ ID NO:68 (see positions 3-18) occurs in human PAX5 DNA genomic sequence as evidenced by NM_016734.3 containing the 16-mer sequence at positions 3354-3369. Further, a 15-mer DNA fragment of SEQ ID NO:68 (see positions 3-17) is found in human ZFN208 DNA genomic sequence as evidenced by NM_007153.3 containing the same 15-mer sequence at positions 7060-7074.
The product of nature judicial exception claimed in the instant case is not integrated into a practical application because there is no additional structural limitation that alters the naturally occurring nucleotide sequence into a non-naturally occurring sequence. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional non-naturally occurring structural limitations that are sufficient to amount to significantly more than a fragment of a naturally occurring nucleic acid.
Note that isolated DNA was deemed patent ineligible under §101 in Association for Molecular Pathology v. Myriad Genetics, Inc., 106 USPQ2d 1972 (June 13, 2013), wherein the Supreme Court held that “Myriad found the location of the BRCA1 and BRCA2 genes, but that discovery, by itself, does not render the BRCA gene “new…composition(s) of matter,” §101, that are patent eligible.” Also note that synthetic primers do not have a different structure from naturally occurring nucleic acids thus were deemed patent ineligible under §101. See Univ. Of Utah Research Found. v. Ambry Genetics Corp., 113 USPQ2d 1241 (Fed. Cir. 2014).
Regarding claim 201, although the claim recites an additional element “a pharmaceutically acceptable excipient and/or a delivery vehicle” and the intended functional use of “pharmaceutical composition”, this additional element and the intended use recitation amount to mere generic instructions to use the naturally occurring genomic fragment, thereby merely adding insignificant extra-solution activity to the judicial exception without any inventive concept.
In view of the foregoing, it is concluded that claims 78, 187-188, 191, 196-197, and 201 are not patent eligible under §101.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 78, 187, 196, and 198-201 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-23, and 27-42 of U.S. Patent No. 9,976,143 B2 in view of Aznarez et al. (US 2019/0070213 A1, applicant’s citation).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are encompassed and/or rendered obvious by the ‘143 patent claims that require a chemically modified “antisense oligomer” targeting a “retained-intron-containing pre-mRNA” that causes “polycystic kidney disease”. It would have been obvious for one of ordinary skill in the art to reasonably envisage that the “antisense oligomer” claimed in the ‘143 patent claims fully encompass the instantly claimed agent in view of the scientific knowledge and teachings disclosed in Aznarez, which are set forth in the §102(a)(1) rejection above and fully incorporated by reference herein.
Claims 78, 187, 196, and 198-201 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 15-21 of U.S. Patent No. 10,696,969 B2 in view of Aznarez et al. (US 2019/0070213 A1, applicant’s citation).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are encompassed and/or rendered obvious by the ‘969 patent claims that are drawn to and require a chemically modified “antisense oligomer” targeting a “retained-intron-containing pre-mRNA” that causes “polycystic kidney disease”. It would have been obvious for one of ordinary skill in the art to reasonably envisage that the “antisense oligomer” claimed in the ‘143 patent claims fully encompass the instantly claimed agent in view of the scientific knowledge and teachings disclosed in Aznarez, which are set forth in the §102(a)(1) rejection above and fully incorporated by reference herein.
Claims 78, 187, 196, and 198-201 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-8, 17-23, and 67-68 of copending Application No. 19/187,338 in view of Aznarez et al. (US 2019/0070213 A1, applicant’s citation).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are encompassed and/or rendered obvious by the ‘338 claims that require an antisense oligomer that promotes inclusion of “an alternatively-spliced coding exon (ASCE)”, which is spliced out when undergoing “non-sense mediated RNA decay”, wherein the antisense oligomer increases the target protein expression. It would have been obvious for one of ordinary skill in the art to reasonably envisage that the “antisense oligomer” claimed in the ‘143 patent claims fully encompass the instantly claimed agent in view of the scientific knowledge and teachings disclosed in Aznarez, which are set forth in the §102(a)(1) rejection above and fully incorporated by reference herein.
Claims 78, 187, 196, and 198-201 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 33, 35-39, 41, 43, and 46-50 of copending Application No. 19/542,296 in view of Aznarez et al. (US 2019/0070213 A1, applicant’s citation).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are encompassed and/or rendered obvious by the ‘296 claims drawn to an antisense oligomer that “binds to a targeted portion of a pre-mRNA that contains a nonsense mediated RNA decay-inducing exon (NMD exon)”. It would have been obvious for one of ordinary skill in the art to reasonably envisage that the “antisense oligomer” claimed in the ‘143 patent claims fully encompass the instantly claimed agent in view of the scientific knowledge and teachings disclosed in Aznarez, which are set forth in the §102(a)(1) rejection above and fully incorporated by reference herein.
Conclusion
No claim is allowed.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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