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 1-21 with species election of nucleobase position numbers 13470-13485 of SEQ ID NO:2 in the reply filed on July 16, 2026 is acknowledged.
Status of Claims
Claims 1-23 are currently pending in the instant application. It is noted that 13470-13485 of SEQ ID NO:2 corresponds to 1397-1412 of SEQ ID NO:1 recited in claim 2. Hence, although claim 2 pertains to applicant’s non-elected species, SEQ ID NO:1, claim 2 is deemed to read on applicant’s elected species. Claims 22-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Accordingly, claims 1-21 are under examination on the merits in the instant application.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
The disclosure is objected to because of the following informalities: Tables 1-5 and 14 contain sequence rule non-compliant subject matter as they disclose nucleotide sequences without appropriate SEQ ID NOs. Appropriate correction is required as instructed below.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide sequences appearing in the specification, see Tables 1-5 and 14, are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 6 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 5. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - Improper Markush Grouping
Claim 1-21 are 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 various target portion sequences and that of the antisense oligonucleotide sequences are improper for the following reasons:
The portion sequences recited by the nucleobase position numbers of SEQ ID NO:2 do not all share the same nucleotide sequence. Similarly, the alternatively recited antisense oligonucleotide sequences of SEQ ID NOs:3-123 do not all share a single nucleotide sequence similarity. For instance, applicant’s elected antisense oligonucleotide complementary to positions 13470-13485 of SEQ ID NO:2 shares no sequence homology with that complementary to positions 4817-1832 of SEQ ID NO:2 when the two 16-mer sequences are aligned from positions 1-16.
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 § 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 1-7, 16, and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Blume et al. (US 2005/0244851 A1).
It is noted that SEQ ID NO:82 of the instant application is disclosed as being targeted to nucleotide positions 13470-13485 of SEQ ID NO:2. See Table 7.
Blume discloses a 25-mer oligonucleotide sequence of SEQ ID NO:1635567, which comprises the entire 16-mer sequence of SEQ ID NO:82. See the following nucleotide sequence information pertaining to Blume’s SEQ ID NO:1635567 by accessing https://seqdata.uspto.gov/seqdetail?docId=US20050244851, which is an updated USPTO web site address from that disclosed at page 13, wherein a box has been added for the 16-mer sequence corresponding to SEQ ID NO:82 of the instant application.
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Accordingly, claims 1-7, 16, and 19 are described by Blume et al.
Claims 1-4, 7, 16, and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stevens et al. (WO 03/029404 A2).
Stevens discloses SEQ ID NO:20 (5’-GTAGCGGGCGTAGTTGTTGT) at page 31, which is a 20-mer that is fully complementary to nucleotide positions 11817-11836 of SEQ ID NO:2, thereby comprising at least an 8-mer sequence complementary to the target portion of nucleotide positions “11814 to 11829” of SEQ ID NO:2 or comprising at least an 8-mer sequence of SEQ ID NO:15 claimed in the instant case.
Accordingly, claims 1, 3-4, 7, 16, and 19 are described by Stevens et al.
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.
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 1-21 are rejected under 35 U.S.C. 103 as being unpatentable over Stevens et al. (WO 03/029404 A2) in view of Hashimoto et al. (Arthritis Research & Therapy, 2011, 13:R154), GenBank Accession No. NM_170604.2 (June 24, 2018), Dean et al. (US 2010/0130595 A1), and Masaki et al. (US 2021/0054377 A1).
Stevens teaches that an inhibitor of human RasGPR4 (hRasGRP4) including mutant hRasGRP4 is “an effective amount of an antisense or RNAi molecule to an hRasGRP4 nucleic acid molecule”, wherein the inhibitor is useful for treating a disorder characterized by an increased expression of the hRasGRP4 or characterized by an increased amount of a prostaglandin D2 (PGD2) molecule. See pages 11 and 17-20.
Stevens teaches that the antisense oligonucleotide can be “modified” with “phosphorothioates” and “2’-O-alkylated ribose group” and prepared with “pharmaceutically acceptable carriers”, wherein the antisense oligonucleotide comprises “at least 10 and, more preferably, at least 15 consecutive bases which are complementary to the target” thus “inhibits the transcription of that gene and/or the translation of that mRNA” and that “one of skill in the art can easily choose and synthesize any of a number of appropriate antisense molecules” targeting hRasGRP4 of SEQ ID NO:1 or mutant hRasGRP4 of SEQ ID NO:3 or SEQ ID NO:5 “without undue experimentation.” See pages 35, 43, and 50-51.
Stevens does not expressly teach that the chemically modified antisense oligonucleotide is a gapmer targeted to nucleotide positions 13470-13485 of SEQ ID NO:2.
Hashimoto teaches that human RasGRP4 (hRasGRP4) transcripts have various splicing variants lacking one or more of exons 6, 7, 8, and 9, which all encode and constitute the CDC25-like GEF (CDC25 box) functional, catalytic domain, which comprises exons 6-10. See Figure 3.
It is noted that the nucleotide sequence of exon 10 that is included in all splicing transcripts/isoforms of hRasGRP4 is at positions 1445-1525 of NM_170604.2, which includes positions 1483-1498 of NM_170604.2 (5’-TGAGCTTTCTTATGCC), which is 100% identical to the target sequence elected by applicant in the instant case. See the entire 81-mer exon 10 (see underlined) of NM_170604.2 comprising the elected target sequence (see boxed).
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It is noted that Steven’s SEQ ID NO:1 that is to be targeted by the chemically modified antisense oligonucleotide also comprises the 16-mer target sequence as shown below. See boxed.
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It is noted that Steven’s SEQ ID NO:3 that is to be targeted by the chemically modified antisense oligonucleotide also comprises the 16-mer target sequence as shown below. See boxed.
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It is noted that Steven’s SEQ ID NO:5 that is to be targeted by the chemically modified antisense oligonucleotide also comprises the 16-mer target sequence as shown below. See boxed.
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Dean teaches that one of ordinary skill in the art can design and synthesize antisense oligonucleotides targeted to a desired region of a target sequence, wherein the antisense oligonucleotides are at least 14 nucleotides in length and have a gapmer modification motif such as “4-8-4”, wherein the gapmer modification motif helps “enhance the inhibitory activity, increase binding affinity for a target nucleic acid, or increase resistance to degradation by in vivo nucleases”, wherein the wing segments comprise modified sugars including “2’-O-methoxyethyl sugar” (“2-MOE”) or “bicyclic sugar modified nucleosides” having a 4’-(CH2)n-O-2’ bridge, wherein the antisense oligonucleotides are conjugated to cholesterols to “enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.” See paragraphs 0076-0077, 0142, 0145-0146, and 0153-0154; Table 1; Figures 1-8.
Dean teaches that the antisense oligonucleotide comprises “a modified nucleotide such as a 5-methylcytosine”, which is “particularly useful for increasing the binding affinity of an antisense compound for a target nucleic acid.” See paragraphs 0105 and 0134.
Masaki teaches that a gapmer antisense oligonucleotide can comprise “2’-O-methoxyethyl (MOE)” and/or “2’-O-methylcarbamoylethyl (MCE) nucleotide” in the 5’ wing and the 3’ wing segments and that the gapmer can be 16 nucleotides in length. See paragraphs 0044-0045; Table 1; claims 12-13.
Masaki teaches that the antisense oligonucleotide “can also be converted to a pharmaceutically acceptable salt or released from a formed salt”, wherein the salt is “formed with an alkali metal (such as lithium, sodium and potassium)”. See paragraph 0295.
It would have been obvious to one of ordinary skill in the art before the effective filing date to follow the teachings of Stevens and make a chemically modified 16-mer gapmer antisense oligonucleotide targeting exon 10 that is present in various hRasGRP4 transcripts. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to make a widely useful hRasGRP4 inhibitor that is effective for inhibiting the expression/activity of various hRasGRP4 splicing transcript variants because making a chemically modified antisense oligonucleotide targeting hRasGRP4 sequence variants such as Stevens’ SEQ ID NOs:1, 3, and 5 was an art-recognized goal as evidenced by Stevens, and because hRasGRP4 splicing variants were known to retain exon 10 encoding/constituting the functional catalytic domain of CDC25 box as evidenced by Hashimoto, thereby providing a reasonable expectation of success for one of ordinary skill in the art to inhibit the expression/activity of all splicing isoforms having exon 10, which is only 81 nucleotides in length as disclosed in the information provided in NM_170604.2. Since the skills of designing and synthesizing antisense oligonucleotides against a given target region were within the technical grasp of one of ordinary skill in the art as evidenced by the teachings of Stevens (“one of skill in the art can easily choose and synthesize any of a number of appropriate antisense molecules” “without undue experimentation”) and Dean’s design and synthesis of multiple antisense oligonucleotides against a given target sequence, and since a 16-mer gapmer antisense oligonucleotide was an art-recognized design choice as evidenced by Dean (“4-8-4” motif) and Masaki (see Table 1), wherein the chemically modified gapmer was deemed desirable as it enhances properties of the antisense oligonucleotide as taught by Dean, and wherein 2’-O-MOE, 2’-O-MCE, 4’-(CH2)n-O-2’ bridge, 5-methylcytosine, and phosphorothioate linkages were all art-recognized modifications known for a gapmer antisense oligonucleotide as evidenced by Dean and Masaki, one of ordinary skill in the art would have had a reasonable expectation of success in making a 16-mer sequence targeted to a 16-mer portion of exon 10 of various hRasGRP4 splicing variants, thereby obtaining SEQ ID NO:82 claimed in the instant case. It would also have been obvious for one of ordinary skill in the art to further conjugate the gapmer with a delivery excipient such as a cholesterol moiety with a reasonable expectation of success so as to “enhance the activity, cellular distribution or cellular uptake of the oligonucleotide” as taught by Dean and to formulate the gapmer as “a pharmaceutically acceptable salt” formed with “sodium” as converting the gapmer to a pharmaceutically acceptable salt formed with sodium was an art-recognized practice/methodology as evidenced by Masaki.
Accordingly, claims 1-21 taken as a whole would have been prima facie obvious before the effective filing date.
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 1-7, 16, 19, and 21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
The instant claims recite an oligonucleotide of at least 8 nucleotides of SEQ ID NO:82, wherein such oligonucleotide is a fragment of naturally occurring human sequences. See for instance, positions 2144-2157 of human TADA2A mRNA (NM_001488.5) that are fully homologous to positions 2-15 of SEQ ID NO:82. See also nucleobase positions 24844434-24844449 of human chromosome 5, GRCh38.p14 Primary Assembly (NC_000005.10) comprising the entire 16-mer sequence of SEQ ID NO:82 or nucleobase positions 93649055-93649068 of human chromosome 1, GRCh38.p14 Primary Assembly (NC_000001.11) comprising nucleotide positions 2-15 of SEQ ID NO:82. Note that due to the extremely large size of the human genomic nucleotide sequences of NC_000005.10 and NC_000001.11, the nucleotide sequence citations are not attached herewith.
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 genomic or messenger RNA 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 21, although the claim recites an additional element “a pharmaceutically acceptable carrier” 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 or mRNA 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 1-7, 16, 19, and 21 are not patent eligible under §101.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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