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 .
Application Status
This action is in response to the following:
A. The amendment to claims filed 11/04/2025, in which claim 4 was amended, and no new claims were added; claims 1-3, 5-23, 25-34, 39, 41, 44-50, and 52-90 were previously canceled, and
B. Response to Final Office Action also filed on 11/04/2025 in which Applicant argues that the amendments have overcome the 112(b), the combination of references do not render the invention obvious under 103, and the Double Patenting rejections be held in abeyance until allowable subject matter is found.
The amendments are entered.
C. The 112(b) rejection has been withdrawn.
D. The arguments regarding the 103 and Double Patenting rejections are not persuasive and these rejections have been maintained. Any rejection or objection not reiterated herein has been overcome by amendment.
Claims 4, 24, 35-38, 40, 42-43, and 51 are under prosecution.
Election/Restrictions
The restriction requirement between Groups I and II resulting in the withdrawal without traverse of claims of Group II, as set forth in the Office action mailed on 7/03/2024 was previously made FINAL. The withdrawn claims (claims 54 and 61-65) were previously cancelled in the amendment to claims filed 12/03/2024. The restriction requirement is thus moot.
Claim Objections
Claim 4 is objected to because of the following informalities:
The last wherein clause recites “wherein all thymidines at in the flanking sequences are….”
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
The following rejection is maintained using some of the same references as used in previous office action but using embodiments not previously cited, so as to address amendments.
Claims 4, 24, 35-38, 40, 42, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Grabczyk (US 20170183655, IDS) in view of GenBank (GenBank, Oct 2018 [retrieved on 2024-06-24], retrieved from the Internet: <URL: https://www.ncbi.nlm.nih.gov/nuccore/NM_002439.4>), Williams (US 20050244851), and Khvorova (Khvorova & Watts, Nat Biotechnol. 2017 March ; 35(3): 238–248.).
The phrase, “complementarity to an MSH3 gene” in the recitation of claim 4 is being interpreted as per the instant specification, Pg. 27, to be complementary to at least a part of an mRNA formed in the expression of a MSH3 gene. The term "nucleoside" is being interpreted as per the instant specification, Pg. 12 to mean a monomeric unit of an oligonucleotide. Claims 4 and 24 require any one of four recited sequences. Thus, all sequences recited in the claims are not explicitly discussed as they are recited as optional.
Grabczyk disclose oligonucleotide compositions for the treatment of DNA repeat expansion diseases wherein the oligonucleotides are complementary to subunits of the DNA mismatch repair system such as MSH3 (abstract, paragraph [0008]). Grabczyk’s oligonucleotide is single-stranded, comprised of 15-30 linked nucleotides and have 60%-100% complementary to their target; i.e., at least 10 contiguous nucleobases having at least 90% complementarity to an MSH3 gene (paragraph [0008]; internucleotide linkages, paragraph [0069]). Grabczyk further disclose nucleotide modifications, which in addition to linkages are a means to increase stability, half-life, and affinity for target RNA (RNA modifications, morpholinos, analogs; paragraphs [0070] - [0074]).
With respect to the amendments, Grabczyk teaches embodiments wherein the oligonucleotide comprises 16-20 contiguous nucleotides [030], could be a gapmer or a mixmer [008, 031, 072, 138; a central block of deoxynucleotide monomers sufficiently long to induce RNase H cleavage. The deoxynucleotide block is flanked by ribonucleotide monomers, 0167], all nucleotides are chemically modified [010, 083, 086] and comprise optimally 5-20 phosphorothioated bonds [086]. Grabczyk teaches a particular embodiment, wherein every uridine and cytidine is modified with a 2'-modification [0204]). Grabczyk teaches further exemplary sugar modifications include 5-methyl-cytidine, ribo-thymidine (which is the same as 5-methyl uridine), and 2'-Ome nucleotides (which is the same as O-methoxyethyl) [0204]. Thus, specifically with respect to the gapmer design and combination of modifications of sugar and base, the above citations of Grabczyk read on instant invention’s oligonucleotide comprising: (a) a DNA core positioned between a (b) 5' flanking sequence comprising linked nucleosides; and (c) 3' flanking sequence comprising linked nucleosides, wherein the 5' flanking sequence and the 3' flanking sequence each comprise at least two linked nucleosides; and wherein at least one nucleoside of each flanking sequence comprise an alternative nucleoside and wherein all cytosines within the DNA core can be 5-methyl-2'-O-methoxyethyl-dCytosine, and wherein all thymidines in the flanking sequences can be 5-methyl-2'-O-methoxyethyl-Uracil, and wherein the backbone can be fully phosphorothioate-modified.
Grabczyk does not teach the exact sequences recited by claims 4 and 24 or specifically state that all cytosines within the DNA core are 5-methyl-2'-O-methoxyethyl-dCytosine, and wherein all thymidines in the flanking sequences are 5-methyl-2'-O-methoxyethyl-Uracil and wherein the backbone is fully phosphorothioate-modified.
This deficiency is resolved by Williams, GenBank and Khvorova.
Before the effective filing date, the sequence of MSH3 mRNA was known in GenBank and Williams disclosed a 25-mer exonic sequence bearing SEQ ID NO: 2659730 that by alignment maps to MSH3 mRNA as disclosed in GenBank as shown below wherein Qy is MSH3 mRNA and Db is SEQ ID NO: 2659730 of Williams in reverse.
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Further, Williams disclose that the sequence is specifically complementary to an exon and that this sequence may be further modified to enhance the specificity of hybridization with a complementary nucleic acid sequence as desired (abstract and paragraph [0045]).
The ordinary skilled artisan in the field is familiar with GenBank. An ordinary skilled artisan seeking long-lived pharmacologic activity in vivo for inhibiting the MSH3 transcript in humans (a goal of Grabczyk), would have been motivated to combine the teachings of Genbank with the teachings of Grabczyk using the sequence disclosed by Williams as the latter narrows down an arbitrary region of the MSH3 gene to a particular exon for the advantage of obtaining an oligonucleotide for use in therapeutic approaches. It would have been prima facie obvious for the skilled artisan to have tried to make oligonucleotides with the disclosed exonic sequence of Williams and arrive at sequences that comprise/consist of the claimed sequences such as SEQ ID NO: 1610 or 1606 as shown in the alignment below, wherein 1 is a portion of the MSH3 mRNA, 1610 and 1606 are SEQ ID NO:1610 and SEQ ID NO:1606 of the instant application respectively in reverse, and 2659730_Williams is SEQ ID NO: 2659730 of Williams in reverse:
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Khvorova reviews the state of the art around instant filing date and teaches a combination of modifications are necessary for enhanced ASO activity and stability.
Khvorova teaches modified oligomeric compounds targeted to RNA with various modifications (see whole paper), which can include 2'-methoxyethyl nucleosides (see middle paragraph on page 3). Khvorova teaches all ASOs require chemical modifications to be sufficiently active in vivo (see first line on page 3). Khvorova teaches the most common configurations included modification of terminal nucleotides, of every second sugar with 2′OMe, or of all pyrimidines (see 3rd paragraph on page 7). Khvorova singles out: 5-modified pyrimidine base as a modification that improves ASO specificity (see 2nd to the last paragraph on page 4). Khvorova teaches a fully MOE-modified 18-mer ASO is approved treatment (see middle of page 5). Khvorova teaches that simply phosphorothioating the backbone alone is not sufficient to fully protect ASOs from nucleases as seen from the in vivo efficacy of first-generation ASOs (see third para on page 3). Thus, a combination of modifications is necessary to achieve a fully functional, long-lasting ASO that will recruit RNAse H. Khvorova teaches 2’-methoxyethyl (MOE) is one of the most useful analogs, providing a further increase in nuclease resistance and a jump in binding affinity of ΔTm 0.9°C to 1.7°C per modified nucleotide. The approved antisense drug mipomersen, as well as numerous oligonucleotide drugs currently in clinical trials, carry the 2’-MOE modification (see fourth para on page 3). Thus, Khvorova teaches that it was practiced around the time of instant filing date to modify all nucleotides and to combine modifications of bases, sugars and backbones in arriving at an ASO design.
It would have been obvious to one of ordinary skill in the art to include 2'-methoxyethyl (MOE) modification of the sugar with a 5-modification of the base in the same nucleotide, with a fully phosphorothioated backbone in the ASO, all suggested by Grabczyk, to gain the advantages that similar ASO in the field of approved therapeutics had demonstrated. One of the ordinary skill in the art would be motivated to do so, because Khvorova teaches the advantages of each of these modifications: 2'-methoxyethyl, 5-methyl base modifications, and a fully phosphorothioated backbone. One would have had more than a reasonable expectation of success in improving the ASO capabilities of an oligomeric sequence targeted to MSH with such modifications because these modifications were demonstrated in the prior art to be beneficial in enhancing ASO activity and stability of ASO compounds. See MPEP 2144 II and 2143 I.(A).
Regarding claim 35, Grabczyk further teach wherein the oligonucleotide comprises at least one alternative internucleoside linkage (internucleotide linkages, paragraph [0069]).
Regarding claim 36, Grabczyk further teach wherein the at least one alternative internucleoside linkage is a phosphorothioate internucleoside linkage (phosphorothioate backbone, paragraph [0010]).
Regarding claim 37, Grabczyk further teach wherein the at least one alternative internucleoside linkage is a 2'-alkoxy internucleoside linkage (2′-O-methoxyethyl (MOE), paragraph [0074]).
Regarding claim 38, Grabczyk further teach wherein the at least one alternative internucleoside linkage is an alkyl phosphate internucleoside linkage (alkylphosphate, paragraph [0069]).
Regarding claim 40, Grabczyk further teach wherein the alternative nucleobase is 5'- methylcytosine, pseudouridine, or 5-methoxyuridine (5-methylcytosine, paragraph [0010]).
Regarding claim 42, Grabczyk further teach wherein the oligonucleotide comprises an alternative sugar moiety which is 2'-OMe or a bicyclic nucleic acid (2-O-methyl moieties, claim 24).
Regarding claim 51, Grabczyk further teach a pharmaceutical composition comprising one or more of the oligonucleotides of claim 4 (paragraph [0107]).
Thus, Grabczyk in view GenBank, Williams, and Khvorova make obvious instant claims 4, 24, 35-38, 40, 42, and 51.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Grabczyk (US 20170183655, IDS) in view of GenBank (GenBank, Oct 2018 [retrieved on 2024-06-24], retrieved from the Internet: <URL: https://www.ncbi.nlm.nih.gov/nuccore/NM_002439.4>)), Williams (US 20050244851), and Khvorova (Khvorova & Watts, Nat Biotechnol. 2017 March ; 35(3): 238–248.) as applied to claims 4, 24, 35-38, 40, 42, and 51 above and further in view of O'Dea (O'Dea T and McLaughlin LW, Curr Protoc Nucleic Acid Chem. 2001 May; Chapter 5:Unit 5.3.).
Regarding claim 43, the teachings of Grabczyk, GenBank, Williams, and Khvorova have been discussed in the rejection for claim 4 above. Grabczyk further disclose wherein the oligonucleotide comprises a ligand conjugated to the 5' end or the 3' end of the oligonucleotide (3′-C-linked, linking one or more moieties or conjugates to the oligonucleotide; paragraphs [0066] and [0081]). Grabczyk disclose that such a ligand positioned in a region of the oligonucleotide, enhances the in vivo properties of the oligonucleotide (enhances the activity, cellular distribution, or cellular uptake of the oligonucleotide paragraph [0081]).
Neither Grabczyk nor GenBank, Williams, nor Khvorova teach wherein a ligand conjugated to the 5' end or the 3' end of the oligonucleotide is through a monovalent or branched bivalent or trivalent linker.
However, at the time of the effective filing date, O'Dea teach a method wherein linkers of various sizes and shapes can be engineered in between nucleotides (title). O'Dea disclose a basic protocol for conjugating hexa(ethylene glycol) but caveat that by disclosing that the protocol for making linkers of any size; i.e., monovalent or branched bivalent or trivalent linker of the instant claim are encompassed, are the same (Protocol 1, paragraph [0004]).
The ordinary skilled artisan, seeking to link a ligand with a therapeutic oligonucleotide to impart further good, in vivo properties (a goal of Grabczyk), and further making the oligonucleotide long-lasting for increased time-periods (a goal of Khvorova) would have been motivated to utilize the teachings of O’Dea in utilizing linkers in conjugating a ligand to the oligonucleotide of Grabczyk, GenBank, Williams, and Khvorova because O’Dea provide the teachings to do so. The skilled artisan would be motivated to do so because of the ready availability of a protocol to use a linker of suitable length and structure such as a monovalent or branched bivalent or trivalent linker to arrive at an improved therapeutic oligonucleotide. Given the teachings of the cited references and the level of skill of the ordinary skilled artisan, it must be considered, absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention reached when combining the cited references. See MPEP 2143 I.(A) and (G).
Thus, Grabczyk, GenBank, Williams, and Khvorova in view of O’Dea make obvious instant claim 43.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments regarding 103 rejection, filed 11/04/2025, have been fully considered but they are not persuasive as discussed below.
On pg. 6, the response summarizes the rejection of claims under 103. Bridging pgs. 6-7, Applicant states, a POSA must have motivation and reasonable expectation of success in combining references and cite: Pfizer Inc. v. Sanofi Pasteur Inc., 94 F.4th 1341, 1346 (Fed. Cir. 2024). On pg. 7, specifically, Applicants argue that i) the references do not motivate a POSA to modify all core cytosines, all flanking uracils, and fully phosphorothioating the whole backbone. Applicants continue to argue that ii) the art taught that modifications would allegedly have resisted degradation by RNase H. This is the opposite of the intended "inhibition of gene expression via an RNase H-mediated pathway." And iii) there is no reasonable expectation of success. Applicants continue to show on pg. 8, a table from specification that shows surprising results of claimed oligonucleotides.
In response to applicant’s argument that i) 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, Khvorova had reviewed the ASO designs around the time of filing of instant application. Khvorova taught the success of ASO with cited modifications. Commercial success is a motivator for combining prior art references.
In response to applicant’s argument that ii) the art taught that modifications would allegedly have resisted degradation by RNase H, Applicants have not cited any reference where this might be true. On the contrary, the same art of Khvorova discussed above taught that such modifications enabled RNAse H mediated degradation of target (also discussed in OA above).
In response to applicant’s argument that iii) there is no reasonable expectation of success and their results show surprising results of claimed oligonucleotides:
Pfizer Inc. v. Sanofi Pasteur Inc., 94 F.4th 1341, 1346 (Fed. Cir. 2024), as Applicants have cited, states that a reasonable expectation of success is sufficient for a 103 rejection. Applicants arguments are not persuasive because Applicants do not state why there would be no reasonable expectation of success in combining known prior art variables.
With respect to, showing of surprising results, it is understood that such surprising results must be viewed in context of what was expected when combining references. "Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected." (emphasis added). See MPEP §716.02. "It is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference". ( original emphasis). In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972). In the instant case, Khvorova had taught that claimed modifications would render an ASO into a successful inhibitory agent. Therefore, Applicants table demonstrates results that were expected, as per Khvorova’s teachings, and contrary to Applicants’ assertion, are not surprising results.
In view of the foregoing, the 103 rejection of claims 4, 24, 35-38, 40, 42 -43, and 51 is maintained.
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 4, 24, 35-38, 40, 42-43, and 51 remain provisionally rejected under 35 U.S.C. 101, for claiming the same invention as that of claims 1, 5, 146-148, 151-154, 262, 338, 341, 346, 348-354, and 362 of copending Application No. 18/566,561 (reference application) for reasons of record set forth in the office action of 06-05-2025, and reiterated below.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims of the aforementioned co-pending application are also drawn to a composition comprising an oligonucleotide of 15-30 linked nucleosides in length which causes a reduction in MSH3 mRNA expression, wherein the MSH3 transcript sequence, SEQ ID NO: 5151, is 100% identical to SEQ ID NO: 1 disclosed in the instant application; and method of using the same to treat or delay the progression a nucleotide repeat expansion disorder in a subject. In addition, when a person of ordinary skill in the art looks for antisense oligonucleotides that are embraced by the claims 1, 5, and 146 of ‘561, several antisense oligonucleotides in table 3 on pages 134-234 of the disclosure of ‘561 would read on the antisense oligonucleotide (SEQ ID NO: 1606) recited in instant claim 4. For example, see SEQ ID NOs: 3736, 3731, 3792, 3760, 3756, 3796, 3782, 3785, 3991, 3835, and 4041. Any additional limitations of the ‘561 claims are encompassed by the open language “comprising” found in the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
It is noted that Applicant submits that the rejection of copending Application No. 18/566,561 be held in abeyance until allowable subject matter is found because of the date of filing of the instant application is before the filing date of ‘561.
This is not found persuasive. The provisional NSDP rejection over copending Application No. 18/566,561 is not withdrawn because even though the filing date (7/22/19) of the instant application is before the filing date of ‘561 (6/4/21), this is not the only rejection remaining of record. See MPEP 804 (I)(B)(1)(b)(i).
Conclusion
Claims 4, 24, 35-38, 40, 42-43, and 51 are rejected.
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 SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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/SHABANA S MEYERING/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635