Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 24, 2025 has been entered.
The Applicants’ Amendment to the Claims filed on July 24, 2025 is entered.
Claim status
Claims 1-102, and 108-110 are cancelled.
Claims 103-107, and 111-115 are pending.
Claim 107 is withdrawn to non-elected invention.
Claims 103-106, and 111-115 are under examination.
Information Disclosure Statement
The IDS filed on 07/24/2025 has been considered by the examiner. Applicants have included a statement that no size fee is required under 37 C.F.R. §1.17(v).
Priority
This US16/934,864 filed on 07/21/2020 which is a CON of 14/866,681 filed on 09/25/2015 (now US Patent 10774330) which is a CON of 14/278,900 filed on 05/15/2014 (now US Patent 9175289) which is a CON of 13/120,342 filed on 10/07/2011 (now US Patent 8796443) which is a 371 of PCT/US2009/005247 filed on 09/22/2009 which claims US priority benefit of US Provisionals 61/224,031 filed on 07/08/2009, 61/149,946 filed on 02/04/2009 and 61/192,954 filed on 09/22/2008.
Response to Amendment
Any/all objections and rejections made in the previous office action and not repeated in this office action are withdrawn in light of the Applicants’ Amendment to the Claims filed on July 24, 2025.
Claim Rejections - 35 USC § 112 – new grounds necessitated by amendment
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.
Currently amended claims 103-106, and 111-115 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.
Base claim 103 is presently amended to recite the limitation "wherein at least 50% of the cytidine (C) and uracil (U) nucleotides in the double stranded region of the nucleic acid molecule are chemically modified " in lines 12-13. There is insufficient antecedent basis for this limitation in the claim because there is no previous reference in the claim to cytidine (C) and uracil (U) nucleotides in the double stranded region of the nucleic acid molecule. Note that it would not be proper to assume inherent presence of cytidine and uracil nucleotides in a double stranded region of the claimed double stranded nucleic acid molecule. For example, uracil nucleotides are found in RNA but the claim is drawn to nucleic acid which includes DNA. Also, cytidines would not be required if the double stranded regions contain only A and U’s, for example. Thus one of ordinary skill in the art would not be able to determine the metes and bounds of the claim as presently written.
Dependent claims 104-106, and 111-115 are indefinite because they depend from claim 103 and are not remedial.
Additionally, claim 111 recites the limitation "wherein the hydrophobic base modification is at position 4 or 5” in line 2. There is insufficient antecedent basis for this limitation in the claim because claim 111 depends from claim 104 which is presently amended to encompass a plurality of hydrophobic base modifications in the phrase: at least one pyrimidine base includes a hydrophobic base modification. Thus it is unclear which pyrimidine base(s) are required to meet the limitation of claim 111 "wherein the hydrophobic base modification is at position 4 or 5”.
Additionally, claim 112 recites the limitation "wherein the hydrophobic base modification” in line 2. There is insufficient antecedent basis for this limitation in the claim because claim 111 depends from claim 104 which is presently amended to encompass a plurality of hydrophobic base modifications in the phrase: at least one pyrimidine base includes a hydrophobic base modification. Thus it is unclear which of the plurality of hydrophobic base modifications referred to in claim 104 are required to meet the limitation of claim 112 regarding the type of hydrophobic base modification.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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.
Claims 103-106, 11-12, and 113-115 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rana (WO 2005/079533; of record), in view of Leake et al (US 2007/0173476; of record).
Claim interpretation: A “blunt” end refers to the end of a double-stranded molecule, indicating that neither strand overhangs the other strand. The currently amended claimed isolated double-stranded nucleic acid molecule (“dsNA”) comprises a guide strand (i.e. antisense strand) of 20-29 nucleotides in length having complementarity to a target gene and a passenger strand (i.e. sense strand) of 10-16 nucleotides in length. Such molecule is construed to require that the passenger/sense strand 3’ end (“SS3”) and the guide/antisense strand 5’-end (“AS5”) form a blunt end (i.e. see just below) and wherein the guide strand 3’-end (“AS3”) overhangs the passenger sense strand 5’-end (“SS5”) by at least 4 nucleotides in length. An exemplary molecule is provided here showing an embodiment having a five nt double strand region shown in bold and underline:
(SS5) 5’ -XXXXXXXXXX-3" (SS3) (10 nt passenger)
(AS3) 3’ -XXXXXXXXXXXXXXXXXXXX-5" (AS5) (20 nt guide with 15 nt 3’ ss)
Regarding claim 103, Rana teach an isolated double stranded nucleic acid molecule comprising: a guide strand (aka “antisense strand”) that is about 19-22 nucleotides which meets the limitation of 20-29 nucleotides in length. (See Ref claims 1-5). Rana et al disclose that the guide/antisense strand has complementarity to a target gene. (See ref claim 1). Rana disclose a passenger strand (aka “sense” strand) of 10-21 nucleotides which meets the limitation of 10-16 nucleotides in length. (See ref claim 1, FIG1A). Rana disclose that the guide strand (aka antisense strand) and the passenger strand form a double stranded nucleic acid molecule having a double stranded region and a single stranded region, wherein the guide strand has a 3' single stranded region of 4-12 nucleotides in length. (See page 7, para 4-5, just below).
The term "non-canonical" siRNA refers to a siRNA having a structure other than that of a classic or canonical siRNA (i.e., a duplex comprising sense and antisense (or guide) strands of about 20-22 nucleotides in length, aligned such that the 3' ends of the strands extend or overhang the 5' ends of the complementary strands. Preferably, the non-canonical siRNAs of the invention include an antisense strand of about 19, 20, 21, or 22 nucleotides in length and a shortened or truncated sense strand (e.g., a sense strand of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 nucleotides in length). The sense strand can be shortened or truncated at the 5' end and aligned such that its 3' end overhangs the 5' end of the antisense strand (e.g., a 2-3 nucleotide overhang (or more), for example a dTdT overhang). The sense strand can be shortened or truncated at the 3' end and aligned such that the 3' end of the antisense strand overhangs its 5' end. The sense strand can be shortened or truncated at the 3' end, the 3' end further comprising 2- 3 non-complementary nucleotides (e.g., dTdT), the sense strand being aligned such that the 3' end of the antisense strand overhangs its 5' end. The sense strand can be shortened or truncated at both ends, the 3' end, optionally, further comprising 2-3 non- complementary nucleotides or more (e.g., dTdT). The above-mentioned shortening / truncations are also contemplated for the antisense strand in relation to a sense strand of about 19, 20, 21, or 22 nucleotides in length.
The term "non-canonical siRNA" can also refer to an siRNA having a non- canonical strand length(s) and/or end(s) or overhang(s). A non-canonical strand length is typically less than 21 nucleotides but at least about 10 nucleotides. The term "non- canonical overhang" refers to the atypical end or overhang formed when the mixed, duplexed, or single stranded nucleic acids of the invention are aligned or annealed (in vitro or in vivo). The end(s) or overhang(s) are distinguished from a "canonical" (or wild type) end or overhang of an siRNA in that the end or overhang lacks a 2-nucleotide overhang (e.g., dTdT) and or one or more nucleotides. Accordingly, non-canonical ends include a 5' ends with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleotide deletions (or truncations) and or no dTdT (also referred to as a 5' non-canonical end) as well as a 3' end with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleotide deletions and/or no dTdT (also referred to as a 3' non-canonical end). Exemplary non-canonical siRNAs are shown in Figs. 3-4.
For example, see embodiment of Rana shown in the Figure just below showing a SS/sense/passenger strand having 1-16 nt, an AS/antisense/guide strand having 4-19 nt, and a blunt 5’end of the duplex.
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Regarding claim 103, Rana disclose that the hydrophobic base modification includes 2’fluor ribonucleotides in the sense and antisense strands, preferably the 2’-fluor modifications are every uridine and cytidine which is construed to includes position 4 or 5. See page 17, lines 19-32, especially last sentence.) and which meets the limitation of at least 50% of the cytidine and uracil nucleotides are chemically modified.
Further, regarding claim 103, Rana disclose that the single stranded region comprises 2-12 phosphorothioate modifications (see page 18, para 2), wherein at least 40% of the nucleotides of the double stranded nucleic acid are modified which meets the limitation of a stretch of four nucleotides. (See page 18, para 1-2, 4).
Also, Rana disclose that at least one modification is a hydrophobic base modification. (See page 9, para 3, which states that a preferred hydrophobic base modification is methylation of one or more bases; page 34, para 1).
Rana meets the limitations of claims 104, 111, and 112 because Rana et al discloses that the hydrophobic base modification comprises a hydrophobic modification of a pyrimidine base, (See “For example, a siRNA molecule can comprise a combination of two sugar-modified nucleotides, wherein the sugar-modified nucleotides are 2 '-fluoro modified ribonucleotides, e.g., 2 '-fluoro uridine or 2 '-fluoro cytidine, and 2'-deoxy ribonucleotides, e.g., 2'-deoxy adenosine or 2'-deoxy guanosine”. (See page 18, para 4).
Regarding claim 111, Rana disclose that the hydrophobic base modification includes 2’fluor ribonucleotides in the sense and antisense strands, preferably the 2’-fluor modifications are every uridine and cytidine which is construed to includes position 4 or 5. See page 17, lines 19-32, especially last sentence.).
Regarding claim 112, Rana disclose that the hydrophobic base modification may be a methyl modification of a uridine or cytidine. (See page 9, para 3, which states that a preferred hydrophobic base modification is methylation of one or more bases; page 18, para 1; page 34, para 1).
However, Rana differs from the presently amended claims because Rana does not explicitly discloses a hydrophobic conjugate which is a small molecule, specifically a cholesterol. Also, Rana discloses hydrophobic modifications to bases but does not explicitly teach a hydrophobic conjugate attached to the siRNA (double-stranded nucleic acid molecule) via a TEG linker.
Regarding claims 103, 105-106, and 113-115, Leake et al discloses a hydrophobic conjugate which is a small molecule, specifically a cholesterol. (See para 0087, 0088, 0236).
Regarding claims 106, and 115, Leake et al discloses a hydrophobic conjugate is attached to a double stranded nucleic acid molecule through a linker, specifically a TEG linker. (See para 0134).
The level of skill in the art was high before the effective filing date of the presently claimed invention.
It would have been prima facie obvious for one of ordinary skill in the art to combine the elements of the Rana reference because these are the preferred embodiments in the Rana disclosure. One of ordinary skill in the art would have been motivated to do such in view of Rana for the rationale of making successful functional RNA small molecules for targeting sequences of interest.
One of ordinary skill in the art would have been motivated to use a hydrophobic conjugate attached to the double stranded nucleic acid molecule through a linker, specifically a cholesterol or TEG linker for the rationale of Leake et al to increase potency (para 0057, Fig11).
It would have been obvious to combine this feature of a cholesterol/TEG linker to the small RNAs of Rana et al because both references are in the same field of making and using siRNAs.
In view of the high skill level in the art it is considered that one of ordinary skill in the art having the Rana et al and Leake references before the effective filing date of the presently claimed invention would have had a reasonable expectation of success to combine the elements of Rana et al and Leake et alto arrive at the presently claimed invention.
Response to Arguments
The Applicants’ Arguments filed on July 24, 2025 have been fully considered but are unpersuasive. The applicants argue that the present claims are amended and that the Rona reference does not teach or disclose all of the features of the rejected claims as amended. Further, the applicants argue that there would not have been a reason to modify the disclosure of the Rona reference to arrive at the claimed invention with a reasonable expectation of success. The applicants argue that:
The claimed invention relates to the development of isolated double stranded nucleic acid molecules that are capable of self-delivery. As explained on pages 40-41 of the application as originally filed, “‘self-delivery’ refers to the ability of a molecule to be delivered into a cell without the need for an additional delivery vehicle such as a transfection reagent.” The application also explains on page 40 that conjugation to a hydrophobic conjugate was a means for optimizing the isolated double stranded nucleic acid molecules for cellular uptake. Page 33 explains that the combination of features recited in claim 1 as amended was important for delivery of the isolated double stranded nucleic acid molecules to cells, stating:
It was also demonstrated experimentally herein that the combination of modifications to RNAi when used together in a polynucleotide results in the achievement of optimal efficacy in passive uptake of the RNAi. Elimination of any of the described components (Guide strand stabilization, phosphorothioate stretch, sense strand stabilization and hydrophobic conjugate) or increase in size results in sub-optimal efficacy and in some instances complete lost [sic] of efficacy. The combination of elements results in development of compound, which is fully active following passive delivery to cells such as HeLa cells. (Figure 23). The degree to which the combination of elements results in efficient self delivery of RNAi molecules was completely unexpected.
Further, the applicants argue:
Rana does not disclose or suggest double stranded nucleic acid molecules that include all of the features recited in claim 103 as amended, including the feature of being linked to a hydrophobic conjugate. Nor would there have been a reason to modify the disclosure of Rana to include such a feature. Rana discloses that delivery can be achieved using, e.g., liposomes, lipophilic carriers, lipid-mediated carrier transport, and chemical-mediated transport (e.g., pages 12 and 21-22). The Examples describe the use of the lipid-based reagent lipofectamine for delivery to cells (e.g., page 29). Based on Rana, one of ordinary skill in the art would have been motivated to use one of the delivery methods disclosed in that reference and would not have a reason to modify double stranded nucleic acid molecules to be linked to a hydrophobic conjugate.
However, this argument is unpersuasive because the rejection is for the combination of Rona and Leake where Leake discloses the element of a hydrophobic conjugate.
Further, the applicants argue the combination of references of Rona and Leake et al. The applicants argue that the present claims are amended and that the Rona and Leake et al references does not teach or disclose all of the features of the rejected claims as amended. Further, the applicants argue that there would not have been a reason to modify the disclosure of the Rona reference to arrive at the claimed invention with a reasonable expectation of success. Specifically, the applicants argue the following:
On pages 10-11 of the Office Action, the Examiner acknowledges that Rana “does not explicitly recite [the claim] limitations in a single embodiment,” but argues that it would have been obvious to select such features “because these are the preferred embodiments in the Rana disclosure.” However, Rana does not disclose the specific combination of features recited in the rejected claims as amended, let alone disclose such a combination as being preferred.
Moreover, while acknowledging that Rana does not disclose linking a double stranded nucleic acid molecule to a hydrophobic conjugate, the Examiner contends that one of ordinary skill in the art would have selected that one feature from Leake to combine with Rana. However, Leake discloses numerous features of double stranded nucleic acid molecules, including features which would have led one of ordinary skill in the art away from pursuing features recited in the rejected claims. For example, Leake discloses multiple times that the double stranded nucleic acid molecules disclosed in that reference are 18-30 base pairs long, with preferred embodiments being 18-19, 19-25, 19-23, or 19 base pairs (e.g., paragraphs [0202], [0216], [0220], [0230], [0239], and [0286]), none of which would be encompassed by the rejected claims. When Leake deviates from these lengths, it is within the context of disclosing a double stranded nucleic acid molecule “not used for silencing of genes,” which Leake discloses could be 16-28 base pairs in length although still preferably 18-30 base pairs (e.g., [(0252]). Further, Leake discloses that in some embodiments a naked or unmodified antisense strand is preferred (e.g., [0209]) and that in some embodiments, “[o]verhangs of two nucleotides are most preferred” (e.g., [0203]). Leake also discloses that certain chemical modification patterns were “very effective for stabilization of some sequences but not for others” (e.g., [0234]). The Examiner has not explained why, in the absence of impermissible hindsight, one of ordinary skill in the art would have selected one feature from Leake while ignoring numerous features that are inconsistent with the rejected claims. When faced with the extensive and sometimes contradictory options disclosed in Rana and Leake for double stranded nucleic acid molecules, one of ordinary skill in the art would not have had a reason to specifically choose the features recited in the rejected claims and combine them as recited in the rejected claims.
“An obviousness determination requires finding both ‘that a skilled artisan would have been motivated to combine the teachings of the prior art . . . and that the skilled artisan would have had a reasonable expectation of success in doing so.’ Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367-68 (Fed. Cir. 2016).” In re Stepan Co., 868 F.3d 1342, 1345-1346 (Fed. Cir. Aug. 25, 2017). “[T]o have a reasonable expectation of success, one must be motivated to do more than merely to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1365 (Fed. Cir. 2007) (quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006)). Here, the Examiner has not provided any explanation for why one of ordinary skill in the art would have been motivated to do more than merely vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result.
The applicants’ arguments have been fully considered but are unpersuasive. First, it is noted that the claims are drawn to a product rather than to a method. The claims do not require a successful result to method steps. The successful result for the product is simply that the product has the required structure as claimed. Present claims do not contain functional language which requires particular properties of the claimed product.
Secondly, the argument that the Rona reference does not disclose wherein the double stranded nucleic acid molecule is linked to a hydrophobic conjugate is unpersuasive because the Leake et al reference is relied on for this feature.
Further, the applicants argument is unpersuasive because while Rana disclose that a dTdT 3’-end overhang on the sense strand is preferred, such a disclosure does not teach away from other alternative embodiments of Rana’s invention. Rana clearly teach that the siRNAs of their invention may comprise a guide strand having a 3’ single stranded region of 4-12 nucleotides in length and a guide strand having a 5’end that is blunt.
Note that the embodiment shown in the Fig above and just below showing the blunt end. The length of the antisense and sense strands are disclosed throughout Rana: “Preferably, the non-canonical siRNAs of the invention include an antisense strand of about 19, 20, 21, or 22 nucleotides in length and a shortened or truncated sense strand (e.g., a sense strand of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 nucleotides in length).”
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Thus it is considered that Claims 103-106, 11-12, and 113-115, as a whole, are rendered obvious over Rana, in view of Leake et al).
Conclusion
No claim is allowed.
Note that a terminal disclaimer for each of US Patent 8,796,443 and US Patent 9,175,289 are of record.
Zheng et al, (RNA 2004 Vol 10, pages 1934-1945; of record);
Corey “Chemical modification: the key to clinical application of RNA interference? (J Clin Invest Vol 117, pages 3615-3622; of record);
Gregory et al (Cell 2005 Vol 123, pages 631-640; of record);
MacRae et al (Science 2006 Vol 311, pages 195-198; of record);
Rana, “Illuminating the silence: understanding the structure and function of small RNAs” (Nat Rev Mol Cell Biol 2007 Vol 8, pages 23-36; of record).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658