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 .
Information Disclosure Statement
The pre-grant US publications and US Patents cited on one of the information disclosure statements filed 1/17/25 were crossed out because they are duplicates of publications or patents cited on the other IDS filed on the same day.
Specification
The disclosure is objected to because of the following informalities: page 12 discloses that there are color drawings of record. However, it appears to be a typographical error because there is no petition or fee for color drawings of record. The issued was resolved in the parent application 16988391 by canceling the statement on page 12 of the specification.
Appropriate correction is required.
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 15 and 17 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 The claims recite that the modification is immediately next to the SNP or MM, however, the claims depend from claim 12. Claim 12 appears to limit the location of the modification(s) to 2-4 nucleotides from the SNP or MM position nucleotide. Thus, the modification cannot be immediately next to the SNP and MM and 2-4 nucleotides from the SNP or MM. 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 § 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 12-15, 17, and 22-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ISIS Pharmaceuticals (WO2013022990).
‘990 teaches an oligomeric compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides, wherein the modified oligonucleotide has a modification motif comprising:
a 5 '-region consisting of 2-8 linked 5 '-region nucleosides, each independently selected from among a modified nucleoside and an unmodified deoxynucleoside, provided that at least one 5’- region nucleoside is a modified nucleoside and wherein the 3 '-most 5 '-region nucleoside is a modified nucleoside; a 3 '-region consisting of 2-8 linked 3 '-region nucleosides, each independently selected from among a modified nucleoside and an unmodified deoxynucleoside, provided that at least one 3 '- region nucleoside is a modified nucleoside and wherein the 5 '-most 3 '-region nucleoside is a modified nucleoside; and a central region between the 5 '-region and the 3 '-region consisting of 6-12 linked central region nucleosides, each independently selected from among: a modified nucleoside and an unmodified deoxynucleoside, wherein the 5 '-most central region nucleoside is an unmodified; deoxynucleoside and the 3 '-most central region nucleoside is an unmodified deoxynucleoside; wherein the modified oligonucleotide has a nucleobase sequence complementary to the nucleobase sequence of a target region of a nucleic acid associated with a huntingtin transcript, wherein the nucleobase sequence is complementary to a region of the transcript comprising an allelic polymorphism, a nucleotide that is in the nucleotide complementary sequence to the allelic polymorphism is a SNP; a mismatch nucleotide that is a mismatch with a nucleotide in the transcript, wherein at least one nucleotide on either side and within at least four nucleotides from the SNP or mismatch is modified, wherein the modified nucleotide comprises a 2’-substituted sugar moiety comprising F, OCH3, O(CH2)2-OCH3. See for example claims 5-9, 75, and 228-229.
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 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.
Claims 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over ISIS Pharmaceuticals (WO2013022990) as applied to claims 12-15, 17, and 22-23.
‘990 does not specifically teach the limitations in instant claims 19 and 20.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date, to try placing the SNP position from position 2 to position 6 from the 5’ end or the MM position is located 2-11 nucleotides from the SNP position nucleotide. One of ordinary skill in the art would have been motivated to try to an optimize the bioavailability or discrimination between the target and non-target gene. There are a finite number of identifiable and predictable nucleotides in the antisense oligonucleotide to try and optimize the nucleic acid for positioning the X or Y chemical modification(s). See MPEP 2143(I)E.
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.
Claims 12-15, 17, 19-20, 22-23, 40, and 48-49 are rejected under 35 U.S.C. 103 as being unpatentable over Aronin et al. (US 20170051283, of record).
'283 teaches making an siRNA molecule comprising a sense strand having complementarity to a target gene and an antisense strand, wherein the antisense strand comprises a 5' and 3' end; a region that is complementary to a region of a gene (e.g., Huntingtin gene (htt)) comprising an allele polymorphism; a SNP position nucleotide at a position within the region, wherein the SNP position nucleotide is complementary to the allelic polymorphism. See pages 4-7, 11-21, and 56-57 and Figures 8-11 and Table 2. The strands can comprise 16-25 nucleotides. The siRNA molecule can have a mismatch (MM) position nucleotide that is a mismatch with a nucleotide in the gene. The siRNA can have a modification that can be on either side of the SNP position nucleotide, wherein each modification is located within four to two nucleotides from the SNP position nucleotide. The modification can be selected from the group set forth in instant claim 49. The sense and antisense strand can have nucleotides or nucleotide analogs (paragraphs 30 and 62). The siRNA can be asymmetrical wherein one strand is longer than the other strand (pages 3 and 8-9). The sense and/or antisense strand can have a 1-3 nucleotide overhang at the 5' or 3' end (page 12).
‘283 does not specifically teach iRNA molecule on either side of the SNP position nucleotide located within 2-4 nucleotides from the SNP position and/or from the MM position.
It would have been prima facie obvious to a person of ordinary skill in the art before the time the effective filing date to incorporate modifications into the siRNA molecule on either side of the SNP position nucleotide located within 2-4 nucleotides from the SNP position and/or from the MM position, namely to arrive at the claimed invention. The sense strand is designed such that the polymorphism is essentially in the middle of the strand. For example, if a 21-nucleotide siRNA is chosen, the polymorphism is at, for example, a nucleotide 6-16 nucleotides from the 5' end of the sense strand. Then, moving the polymorphism to an off-center position may reduce efficiency of cleavage of siRNA. This movement could be used if desirable for use if off-silencing of the wild-type RNA is detected.
In addition, there can be mismatch base pair between the 5' end of the first or antisense strand and the 3' end of the second or sense strand. One of ordinary skill in the art would have been motivated to make the siRNA for the selective destruction of mutant mRNA transcribed from mutant genes thus preventing the production of the mutant proteins encoded by said genes and avoiding targeting non-allele specific sites that would result in loss of both normal and mutant genes. A person of ordinary skill in the art would have been motivated to insert a mismatch to enhance single nucleotide specificity (paged 16-17). A mismatch can also be used to mediate RNAi or translational suppression (pages 19-20). The sense and antisense strand can have nucleotides or nucleotide analogs and be 16-30 nucleotides in length (pages 16- 20). The siRNA can have at modification within 5 nucleotides from a specificity-determining nucleotide (the nucleotide which recognizes the disease-related polymorphism. See pages 12-21.
Thus, '283 makes obvious the limitations in the instant claims to enhance target discrimination, to enhance stability of the siRNA, to enhance the target efficiency, to improve efficacy in binding and/or to reduce toxicity. The modifications recited in the instant claims are suggested on pages 20-22 and can be used to increase the bioavailability of the siRNA. It would have been obvious for one of ordinary skill int the art try these chemical modification(s) (not including 2’ fluoro or 2-OMe) in the claimed nucleic acid. See MPEP 2143(I)A, B and E.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the time of the effective filing date.
NOTE: The prior art does not suggest or make obvious a sub-species recited in instant claims 24, 25, 27, 29-30 and 49 because the prior art does not teach using the specific sugar modification(s) (2’ fluoro and 2’-O-methyl) at these positions near the MM and/or SNP position on the nucleotide sequence. Example 14 (page 112, Figs 48A-48D) of the as-filed specification teaches an unexpected result when using these specific sugar modification(s) on either side of the SNP and/or MM position nucleotide within four nucleotides from the SNP or MM position. However, there appears to be nothing of record for one of ordinary skill in the art to extrapolate from the results observed for these two specific chemical modifications in example 14 to the other chemical modifications recited in the instant claims. “even after decades of research and the development of potent, relatively generalizable designs, it is not well understood how different chemical substitutions at each of the positions in the passenger and guide strands affect the intrinsic activity, i.e., ability of the siRNA strands to engage with RISC during the loading process and subsequent cleavage of its target mRNA.” “Specifically, the factors governing the interplay between sequence and chemistry of the siRNA and the resulting sequence-dependent tolerance for chemical modifications, remain poorly understood.” See Kliuchnikov et al. Molecular Therapy Nucleic Acids, pages 1-12, 2025.
Subject matter taught in US20200087663 (cited on an IDS) teaches or makes obvious the claimed invention, but the subject matter taught in ‘663 reading on the claimed invention does not enjoy a priority date before instant application because the subject matter (a SNP position nucleotide at a position within the seed region, wherein the SNP is complementary to the allelic polymorphism) was added to ‘663 and not disclosed in the provisional for ‘663. The filing or publication date of ‘663 is after the effective filing date of the instant application (8/23/2019).
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 12-15, 17, 19, 20, 22-25, 27, 29, 30, 40, 45, 48, 49, and 61-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12024706, cited on an IDS. Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a siRNA comprising an oligonucleotide comprising a sequence that is complementary to a gene comprising an allelic polymorphism; a single nucleotide polymorphism (SNP) nucleotide at a position within the oligonucleotide; a mismatch (MM) to a position in the gene; and at least one sugar modified nucleotide on either site of the SNP position, wherein the modification is within four nucleotides from the SNP position or at least one modified nucleotide on either side of the MM position, wherein the modification is within four nucleotides from the MM position, wherein the modification can be a 2’-O-methyl, a 2’-methoxy or a 2’-fluoro (see claim 10 of ‘706). The claims of ‘706 make obvious the limitations in instant claims 15, 17, 19- 20, 22-23, 25, 27, 29, 30 (see claims 11-14 of ‘706). It would have been obvious for one of ordinary skill in the art to combine the modification at the SNP and MM position to study bioavailability of the siRNA in a cell. In addition, both claims recite a branched oligonucleotide comprising at least two of the siRNA. Claim 20 of ‘706 discloses using a linker to connect the siRNA in the branched oligonucleotide.
Claims 12-15, 17, 19-20, 22-25, 27, 29, 30, 40, and 48-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of US 12692498. Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a siRNA comprising an oligonucleotide comprising a sequence that is complementary to a gene comprising an allelic polymorphism; a SNP nucleotide at a position within the oligonucleotide; a MM to a position in the gene; and at least one sugar modified nucleotide on either site of the SNP position, wherein the modification is within four nucleotides from the SNP position or at least one modified nucleotide on either side of the MM position, wherein the modification is within four nucleotides from the MM position. Thus, claims from ‘498 make obvious instant claims 12, 15, 17, 19-20, 22, 23, 40, and 48.
The claims from ‘498 do not specifically embrace a sugar modification for a nucleotide by the SNP or MM position. However, when one of ordinary skill in the art looks at the disclosure of ‘498 for a definition of the modified nucleotide, pages 12-13 and 43 and Figure 15 disclose the sugar modifications set forth in instant clams 13, 14, 24, 25, 27, 29, 30, and 49. See also MPEP 804(II)(B)1: The portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. Thus, in view of the definition of the modification recited in the claims of ‘498, the instant claims would have been obvious to one of ordinary skill in the art as an obvious variant to use the sugar modification in the positions.
Conclusion
See attached PTO-326 for disposition of claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571)-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
Prosecution Insights