The office action mailed on 12/17/25 has been superceded.
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 .
Applicant’s election without traverse of group I and the species delivery, cholesterol, and intrathecal in the reply filed on 9/6/25 is acknowledged.
Claims 2 and 15-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/6/25.
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 1 and 3-12 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.
The instant claims are directed to any double stranded nucleic acid complex with a first and second strand of any length wherein the first strand comprises a sequence of any length that is capable of hybridizing to at least any part of any target gene or any transcription product thereof. The second strand comprises a base sequence of any length (i.e. 3 nucleotides) that are complementary to the first strand, which would result in annealing. The first strand is not necessarily the same length as the second strand and is annealed at any level (i.e. a single nucleotide).
The specification does not adequately describe the structure required for the complex to have the required function of having an antisense effect on the transcription product. The specification discloses fully annealed dsRNA molecules of a specific length that have inhibitory effects on a target that is fully complementary to the antisense strand, which is not representative of the instantly recited genus that has minimal specificity to any specific target and encompasses various possible configurations of compounds.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being double stranded nucleic acid complexes with minimal specificity to any specific gene and various possible configurations that would function as claimed. In absence of a full length DNA complement to a specific target sequence that has been shown to be reliant for the inhibition, the structure would not meet the function. The specification does not adequately describe the structure within the instantly recited genus that is required for each of the recited functions.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
To achieve the desired function, it appears that the structure is required to be of a shorter length than the claimed genus which has no length limitation; and for the antisense strand and sense strand to be hybridized as a duplex; and for the antisense strand to by fully complementary to a target sequence that its inhibition has been shown to result in the instantly recited outcomes; and for the antisense strand to be DNA. For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888). The instant claim breadth encompasses siRNAs.
For example, the instant claim language encompasses other possible structures including ribozyme, which have not been described by the instant specification. Ribozymes meet the instant limitation of have a first and second strand, wherein the first strand is capable of hybridizing to a part of a target gene or transcription product, and the first and second strand have a region of complementarity and anneal to each other, as evidenced by Doherty et al. (Annu. Rev. Biochem. 2000. 69:597–615).
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for possible double stranded nucleic acid complexes with varying levels of complementarity between each strand and between the antisense strand and the target within the instant enormous genus that would have the required function of an antisense effect. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
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.
Claim(s) 1 and 3-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yokota et al. (WO 2014/203518 A1), in view of Eldar-Finkelman (WO 2005/000192 A2).
Yokota et al. teach: double-stranded antisense nucleic acid complexes that can efficiently alter the processing of RNA in a cell via an antisense effect, and methods for using the same. One method comprises contacting with the cell a double-stranded nucleic acid complex comprising: a first nucleic acid strand annealed to a second nucleic acid strand, wherein: the first nucleic acid strand comprises (i) nucleotides independently selected from natural DNA nucleotides, modified DNA nucleotides, and nucleotide analogs, (ii) no regions that have 4 or more consecutive natural DNA nucleotides, (iii) the total number of natural DNA nucleotides, modified DNA nucleotides, and nucleotide analogs in the first nucleic acid strand is from 8 to 100, and (iv) the first nucleic acid strand is capable of hybridizing to RNA inside of the cell; and the second nucleic acid strand comprises nucleotides independently selected from natural RNA nucleotides, modified RNA nucleotides, and nucleotide analogs (abstract).
Yokota et al. teach: The antisense method is a method of selectively altering the expression of a protein that is encoded by a target gene, by introducing into a cell an oligonucleotide (antisense oligonucleotide (ASO)) which is complementary to a partial sequence of the mRNA (sense strand) of a target gene (page 1) (instant claim 1).
Yokota et al. teach: In some other embodiments, the first nucleic acid strand is (i) selected from a morpholino oligonucleotide, a 2'-O-methyl modified oligonucleotide, a 2'-O-(2-methoxyethyl) modified oligonucleotide, or a bridged nucleotide oligonucleotide, (ii) the total number of nucleotides in the first nucleic acid strand is from 8 to 100, and (iv) the first nucleic acid strand is capable of hybridizing to RNA inside of the cell; and the second nucleic acid strand comprises nucleotides independently selected from natural RNA nucleotides, modified RNA nucleotides, and nucleotide analogs (pages 10 and 11) (instant claims 1 and 3-5).
Therefore, Yokota et al. teach a double-stranded complex comprising a first and second nucleic acid strand, wherein the strands are complementary to each other and the one strand is complementary to mRNA of a target gene, wherein the one strand is a morpholino oligonucleotide and the other strand comprises nucleotide analogs, meeting the instant limitation of claim 3 that the complex does not comprise four consecutive natural ribonucleosides; and the limitations of claims 4 and 5 because each nucleotide is a morpholino in the first strand.
Yokota et al. teach: The bonding between the nucleic acid strand and the functional moiety may be direct bonding, or may be indirect bonding mediated by another material. However, in certain embodiments, it is preferable that a functional moiety be directly bonded to the second nucleic acid strand via covalent bonding, ionic bonding, hydrogen bonding or the like, and from the viewpoint that more stable bonding may be obtained, covalent bonding is more preferred (page 20).
Yokota et al. teach: The moiety having a "targeted delivery function" may be, for example, a lipid, from the viewpoint of being capable of delivering the double-stranded nucleic acid complex of certain embodiments to the liver or the like with high specificity and high efficiency. Examples of such a lipid include lipids such as cholesterol and fatty acids (for example, vitamin E (tocopherols, tocotrienols), vitamin A, and vitamin D); lipid-soluble vitamins such as vitamin K (for example, acylcarnitine); intermediate metabolites such as acyl-CoA; glycolipids, glycerides, and derivatives thereof. However, among these, from the viewpoint of having higher safety, in certain embodiments, cholesterol and vitamin E (tocopherols and tocotrienols) are used (page 20) (instant claims 6-8).
Yokota et al. teach that the functional moiety is bonded to the 5’ end of the second strand (page 20 and Figures 6-7) (instant claim 9).
Yokota et al. teaches incorporation of cleavable BNAs, meeting the instant limitation of a cleavable linker (page 15) (instant claim 10).
Yokota et al. teach that the method is for suppressing the expression level of a product. However, it is noted that instant claims 11 and 12 recite intended uses rather than method steps and the intended uses would necessarily flow from the recited method steps.
Yokota et al. does not teach that the method is in the regulation of a target gene is in central nervous system or that delivery is via intrathecal or intraventricular administration.
However, the route of administration is a matter of design choice depending upon the location of the desired target.
Yokota et al. teaches: There are no particular limitations on the preferred form of administration of the composition of some embodiments, and examples thereof include enteral (peroral or the like) or non-enteral administration, more specifically, intravenous administration, intraarterial administration, intraperitoneal administration, subcutaneous administration, intracutaneous administration, tracheobronchial administration, rectal administration, and intramuscular administration, and administration by transfusion.
Yokota et al. teaches: The composition of some embodiments can be used for animals including human beings as subjects. However, there are no particular limitations on the animals excluding human beings, and various domestic animals, domestic fowls, pets, experimental animals and the like can be the subjects of some embodiments.
Yokota et al. teaches: The double-stranded nucleic acid complex can be delivered to a target site with high specificity and high efficiency, and can suppress the expression of a target gene or the level of a transcription product very effectively.
Therefore, when utilizing the method of Yokota et al. to suppress a target in the CNS of a subject, it would have been obvious to select intrathecal or intraventricular administration as a matter of design choice with a reasonable expectation of success given that Yokota et al. teaches that the method does not have any particular limitations on the mode of delivery and that the complex can be delivered to a target site with high specificity and high efficiency, and can suppress the expression of a target gene or the level of a transcription product very effectively.
For example, Eldar-Finkelman teach a method of inhibiting GSK-3 and methods of treating GSK-3 mediated conditions (abstract) via delivery of GSK-3 inhibitors (page 5), wherein the inhibitor can be siRNA or antisense oligonucleotides (page 36).
Eldar-Finkelman teach that GSK-3 can be inhibited with siRNA or antisense oligonucleotides via intraventricular or intrathecal administration (page 30) and that GSK-3 activity is implicated in various central nervous system disorders. the method according to this aspect of the present invention can be used to treat various chronic neurodegenerative diseases such as, but not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS associated dementia, amyotrophic lateral sclerosis (AML) and multiple sclerosis. As is discussed hereinabove, GSK-3 activity has particularly been implicated in the pathogenesis of Alzheimer's disease (pages 10, 28, and 34).
It would have been obvious to practice the method of Yokota et al. wherein the double-stranded nucleic acid complex is targeted to GSK-3 in the CNS via intrathecal or intraventricular delivery because Eldar-Finkelman offers motivation to inhibit GSK-3 in this manner with antisense oligonucleotides or siRNAs for the treatment of CNS diseases.
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 1 and 3-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 13-21, 34-36, and 38-40 of copending Application No. 17/602,035 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of application ‘035 are directed to a method of suppressing or increasing the expression of a transcription product in skeletal or heart muscle via delivery of a double-stranded nucleic acid complex comprising a first nucleic acid strand and a second nucleic acid strand, wherein said first nucleic acid strand comprises a base sequence that is capable of hybridizing to all or part of said transcription product of the target gene, and has an antisense effect on said transcription product, said second nucleic acid strand comprises a base sequence complementary to said first nucleic acid strand, and is bound to cholesterol or analog thereof, and said first nucleic acid strand is annealed to said second nucleic acid strand.
Application ‘035 recites (claim 7) that the nucleic acid consists of sugar-modified nucleosides. Although application ‘035 does not recite that the sugar-modified nucleosides are morpholinos, the specification defines the sugar-modified nucleosides as including morpholinos. The incorporation of at least 2 morpholinos or wherein the double stranded complex does not comprise four consecutive natural ribonucleosides are obvious variations of the claims of application ‘035 which recite full modification with sugar-modified nucleosides. Application ‘035 recites that the nucleic acid does not comprise a natural ribonucleoside (claim 6).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 9,816,089 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US ‘089 are directed to a method of reducing the level of a transcription product in a cell comprising contacting the cell with a composition comprising: a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, wherein: (i) the first nucleic acid strand is 8 to 100 nucleotides in length and hybridizes to the transcription product, comprises (a) a region consisting of at least 4 consecutive DNA nucleotides that are recognized by RNase H when the strand is hybridized to the transcription product, wherein the at least 4 consecutive DNA nucleotides may be modified or unmodified, and further comprises (b) one or more nucleotide analogs located on 5′ terminal side of the region, and (c) one or more nucleotide analogs located on 3′ terminal side of the region; and (ii) the second nucleic acid strand (a) comprises at least 4 consecutive RNA nucleotides, and (b) further comprises a 5′ wing region of one or more modified nucleotides, nucleotide analogs and/or modified nucleotide analogs located 5′ to the at least 4 consecutive RNA nucleotides, and/or a 3′ wing region of one or more modified nucleotides, nucleotide analogs and/or modified nucleotide analogs located 3′ to the at least 4 consecutive RNA nucleotides, wherein the at least 4 consecutive RNA nucleotides can be cleaved by RNase H when the second nucleic acid strand is annealed with the first nucleic acid strand, and wherein the second nucleic acid strand further comprises a functional moiety having a function selected from a labeling function, a purification function, and a targeted delivery function.
The double-stranded nucleic acid of the method US ‘089 is a species of the instant genus of complexes of the instant method. US ‘089 recites incorporation of one or more nucleotide analogs, which meets the instant requirement of two. US ‘089 recites various modifications (claims 10 and 11) and the specification defines the sugar-modified nucleosides as including morpholinos. The incorporation of at least 2 morpholinos is an obvious variation of the claims of US ‘089 which recites incorporation of sugar-modified nucleosides.
US ‘089 discloses the method as being in the nervous system and via intrathecal administration (Example 13). The claims are obvious variations.
Conclusion
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636