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 25-29 in the reply filed on March 31, 2026 is acknowledged.
Status of Claims
Claims 24, 28-29, and 44-60 are currently pending in the instant application. Claims 56-60 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Accordingly, claims 24, 28-29, and 44-55 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 it contains an embedded hyperlink and/or other form of browser-executable code. See the 17th and 60th pages. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 44 is objected to because of the following informalities: “pre-RNA” in line 6 should be “pre-mRNA”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 24, 28-29, and 44-55 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 “substantially complementary” in the instant claims is a relative term which renders the claim indefinite. The term “substantially complementary” is not defined by the claims, nor does the specification provide a standard for ascertaining the requisite degree. Since the word “substantially” itself is relative as the degree of “substantially” is not likely to be the same for one person of ordinary skill in the art (e.g., 80% qualifies as “substantially complementary”) to the next person of ordinary skill in the art (e.g., 95% qualifies as “substantially complementary”), one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Accordingly, the metes and bounds pertaining to the subject matter of claims 24, 28-29, and 44-55 cannot be clearly ascertained.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 48 and 53-54 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Each of claims 48 and 53-54 recites the length range of the SSO of claim 24.
It is noted that the 20-mer length claimed and encompassed by claims 48 and 53-54 appears to provide about 65% sequence complementarity level, and claim 53 recites that the minimum length of the SSO is 9 nucleotides in length, which would therefore result in only about 29% sequence complementarity level against SEQ ID NO:14. As such, it appears that the complementary levels provided by the SSO of claims 48 and 53-54 do not appear to coincide with the art-accepted meaning of “substantially complementary”, which is not clearly defined or re-defined in the instant specification as explained in the §112(b) rejection above. Hence, claims 48 and 53-54 fail to include all structural limitations of claim 24.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 24, 28-29, and 44-55 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.
Claims 24, 28-29, and 45-55 are broadly drawn to an SSO that is complementary or substantially complementary to SEQ ID NO:14, wherein the SSO is “9-31 nucleotides” or “15-31 nucleotides” or “20-31 nucleotides” in length and comprises any type of “artificial nucleotides” or does comprise any modification.
It is noted that the instant specification at best describes a 25-mer SSO that is 100% complementary to 5’-GGCACCAAAGTCTTCCCTGTCCCAT at positions 3-27 of SEQ ID NO:14, wherein the SSO is fully modified with 2’-O-methyl and phosphorothioate, wherein the single SSO species is not a representative number of species within the claimed genus encompassing structural variants as now claimed.
Claim 44 is generically drawn to an SSO that is complementary or substantially complementary to “+9 to +39 downstream to the 5’ splice site” of “a function-disabling pseudoexon” of any pre-mRNA.
It is noted that the instant specification at best discloses 25-mer SSOs fully modified with 2’-O-methyl and phosphorothioate linkages, wherein the 25-mer SSOs are fully complementary to +11 to +35 downstream of a pseudoexon, wherein “52 SSOs had no effect on pseudoexon inclusion” when the instant co-inventors “tested 78 SSOs”, thereby resulting in about 67% failure rate. See page 45. That is, the structure-function correlation for the entire genus is not adequately described by the instant specification, especially in view of the only about 23% success rate in providing NMD by the single structure (length, target site positions, chemical modifications) designed to target various genomic sequences.
In fact, it is found that the state of the prior art pertaining to obtaining a functional SSO useful for promoting inclusion of a pseudoexon and providing NMD was almost non-existent or at its infancy as evidenced by the post-filing reference that reflects the state of the prior art pertaining to the claimed subject matter. See for instance the Petersen reference (Ph.D. thesis, 2023, applicant’s citation), which reports that “none of the SSOs targeting the region from +9, +11, +13, or +15 downstream from the [LRRK2] PE6 pseudoexon 5’ss efficiently activates its inclusion.” (emphasis added). See page 35 of 71. The reference also reports that the activity/function of the SSOs highly depend on the type of chemical modifications. See for instance page 39 of 71 for the following: “Transfection of the +11 SSO-T with UNA introduced at different single and double positions was inefficient to activate the endogenous [LRRK2] PE1/2 pseudoexons in SH-SY5Y cells” (emphasis added). See also page 4 of 25 for the following: “We tested the 22- and 25-mer 2’-MOE+11 SSOs relative to the 25-mer 2’-OMe +11 SSO and verifies that the 2’-MOE SSOs are more efficient, probably due to stronger complementary base-pairing” (emphasis added). Hence, the entire genus of modifications or the absence of modifications (e.g., claim 49) as broadly and generically claimed for the SSO in the instant case is not supported by either the prior art knowledge reflected by the Petersen reference or the 2’-O-methyl/phosphorothioate-modified SSOs disclosed in the instant specification.
Now, it is noted that the post-filing Petersen reference does speculate that the 2’-MOE SSO provides “more efficient” psuedoexon inclusion “probably due to stronger complementary base-pairing”. As such, an SSO without any mismatches or base substitutions, thereby providing a “stronger complementary base-paring” with the target sequence appears to have been deemed preferable over the instantly claimed SSO having “1 or 2 or 3 substitutions” or “having at least 90% sequence identity” relative to a complementary sequence of positions 3-27 of SEQ ID NO:14. Again, regarding targeting SEQ ID NO:14, the instant specification discloses only a single species of a 25-mer 2’-O-methyl/phosphorothioate-modified SSO that is 100% complementary to positions 3-27 of SEQ ID NO:14, which is far from representing other SSO sequence/modification variants encompassed by the claimed genus, especially in view of the complete lack of relevant prior art knowledge pertaining to the claimed SSO targeting SEQ ID NO:14 as of the filing date sought in the instant application.
In view of the foregoing, it is concluded that the instant specification fails to adequately describe the entire genus of claims 24, 28-29, and 44-55 in such a manner to reasonably convey that the instant co-inventors had possession of the entire genus as of the filing date sought in the instant case.
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 24, 29, 44-45, and 53-55 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 an oligonucleotide that is complementary or substantially complementary to a region within SEQ ID NO:14.
It is noted that the claimed oligonucleotide reads on a 15-mer that is 100% complementary to the 15-mer region within SEQ ID NO:14 at positions 2-16 (5’-GGGCACCAAAGTCTT), wherein such oligonucleotide (5’-AAGACTTTGGTGCCC) is found in the naturally occurring human TTLL11 (NM_001386832). See the boxed nucleotide sequence at positions 512-526.
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In addition, a 16-mer (5’-TGGGACAGGGAAGACT) that is 100% complementary to the 16-mer region within SEQ ID NO:14 at positions 11-26 (5’-AGTCTTCCCTGTCCCA) is found in the naturally occurring human ORC1 (NM_004153). See the boxed nucleotide sequence at positions 1791-1806.
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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).
In view of the foregoing, it is concluded that claims 24, 29, 44-45, and 53-55 are not patent eligible under §101.
Relevant Art
The following references are made of record as they are considered pertinent to applicant's disclosure:
1. Beibel et al. (WO 2022/208170 A1) teach that one can make and use “antisense oligonucleotides and splice-switching oligonucleotides (SSOs)” that can promote the inclusion of a pseudoexon such as “a novel, 115-bp exon containing an in-frame stop codon (55bp from the 3’ end of the novel exon) between exons 49 and 50 of the HTT mRNA”, wherein the inclusion of the novel exon helps “trigger nonsense-mediated decay”, “thereby lowering HTT transcript and protein levels.” See pages 15, 33, and 46.
2. Bhattacharyya et al. (Nature Communications, 2021, 12:7299) report “promoting the inclusion of a pseudoexon containing a premature termination codon” is capable of “leading to HTT mRNA degradation and reduction of HTT levels.” See abstract.
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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