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 .
Applicant’s election without traverse of group I, SEQ ID NOs: 4205 and 4227 (AD-1318337.1), 2’-O-methyl, and pulmonary fibrosis in the reply filed on 4/22/26 is acknowledged. The sequences of claim 9 have been searched and examined.
Claims 78, 81-84, and 91 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 4/22/26.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 42 is 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.
Claim 42 requires for the moieties to be conjugated to positions selected from 4-8 and 13-18 on the sense strand and positions 6-10 and 15-18 on the antisense strand although each strand can have as little as 15 nucleotides and therefore is not required to have a position 16-18. Therefore, the claim language is not definite.
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, 4, 11, 14, 18, 20, 32, 42, 52, 69, 73, 74, 76, and 96 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 specification does not adequately describe dsRNA agents of any length (i.e. 1000 nt) that comprise sense and antisense strands, wherein the sense strand has at least 12 nt (15 with 3 mismatches) of any portion of SEQ ID NO: 1 (which is 17911 nt in length) and the antisense strand has at least 12 nt of the corresponding portion of SEQ ID NO: 6 that have the structure to function as required by inhibiting expression of MUC5B. Certainly not any dsRNA of any length targeting any 12 nt portion of MUC5B would result in inhibition of expression of MUC5B; and certainly not any dsRNA consisting of the 12-mer duplex would have the required function as it is known that not all dsRNA agents have inhibitory activity against the target (as demonstrated by Table 8 of the specification). The species of specific siRNAs of the specification are not representative of the entire claimed genus.
Not only do the claims encompass dsRNA of any length comprising 12 contiguous nucleotides of any portion of SEQ ID NO: 1 in any region of SEQ ID NO: 1 and the complement thereof, but the claims encompass nucleotide sequences of any length that has at least 90% identity to any portion of the sequences (i.e. a 2-mer that is fully identical to the instantly recited sequences).
Claim 1, part (b) requires for the antisense strand to comprise a region of any length that is complementary to any part of an mRNA encoding SEQ ID NO: 1 (i.e. 14 nucleotides in length comprising a region of 2 nt that is complementary to any part of SEQ ID NO: 1).
Claim 4 requires 12 nucleotides of specific sequences, but these 12 nucleotides can be within a strand that is thousands of nucleotides in length and would therefore not likely have the structure for the required function.
Although instant claim 20 requires for each strand to be no longer than 30 nucleotides in length, the agent comprises (open language) the strands and therefore can comprise additional sequence.
The siRNAs of the specification are species that are not representative of the entire claimed genus.
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 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. With respect to siRNAs, as single species of dsRNA agents, 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 claims encompass very long dsRNA, for example, that can trigger RNAi. Such dsRNA with 12 contiguous nucleotides of SEQ ID NOs: 1 and 6 would not likely function as claimed. For example, Parrish et al. (Molecular Cell, Vol. 6, 1077–1087, November, 2000) teach that sequences of 1000 bp trigger RNAi (page 1078).
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 dsRNA agents within the instant enormous genus that are inhibitory of the target as claimed. 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 § 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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 11, 14, 18, 20, 52, 73, 74, and 76 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Bhat et al. (WO 2021/142245 A1) (support in 62/959,474).
Bhat et al. teach a siRNA for inhibiting expression of MUC5B wherein the sense strand comprises 18 nucleotides of instant SEQ ID NO: 1 and the antisense strand comprises 18 nucleotides of instant SEQ ID NO: 6 (see siRNA No. 3, page 39, SEQ ID NOs: 7 and 8), wherein the siRNA is conjugated to a lipophilic moiety. Bhat et al. teach: In a particular embodiment, the liposomal delivery vehicle is a lipid nanoparticle. A suitable lipid nanoparticle for the present invention comprises one or more of a cationic lipid, a non-cationic lipid, a cholesterol-based lipid, a PEG-modified lipid, an amphiphilic block copolymer and/or a polymer, or a combination thereof. [00020](instant claims 1 and 20).
Bhat et al. teach: [00021] An exemplary lipid nanoparticle may be composed of three lipid components: a cationic lipid ( e.g., a sterol-based cationic lipid), a non-cationic lipid (e.g., DOPE or DEPE) and a PEG-modified lipid (e.g., DMG-PEG2K). In a particular embodiment, a suitable lipid nanoparticle for use with the invention has the following three lipid components: a cationic lipid, DOPE, and DMG-PEG2K. In another particular embodiment, a suitable lipid nanoparticle for use with the invention has the following three lipid components: a cationic lipid, DEPE, and DMG-PEG2K.
Bhat et al. teach incorporation of at least one 2’-O-methyl modification [00019] (instant claims 11 and 14).
Bhat et al. teach incorporation of phosphorothioate modifications [000258] (instant claim 18).
Bhat et al. teach: [000304] Other suitable cationic lipids for use in the pharmaceutical compositions and methods of the present invention include ionizable cationic lipids as described in International Patent Publication WO 2013/149140, which is incorporated herein by reference. In some embodiments, the pharmaceutical compositions and methods of the present invention include a cationic lipid of one of the following formulas: (page 74) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from the group consisting of hydrogen, an optionally substituted, variably saturated or unsaturated C1-C20 alkyl and an optionally substituted, variably saturated or unsaturated C6-C20 acyl; wherein Li and L2 are each independently selected from the group consisting of hydrogen, an optionally substituted C1-C30 alkyl, an optionally substituted variably unsaturated C1-C30 alkenyl, and an optionally substituted C1-C30 alkynyl; wherein m and o are each independently selected from the group consisting of zero and any positive integer (e.g., where m is three); and wherein n is zero or any positive integer (e.g., where n is one). In some embodiments, the pharmaceutical compositions and methods of the present invention include the cationic lipid (15Z, 18Z)-N,N-dimethyl-6-(9Z,12Z)-octadeca-9,12-dien-l-yl) tetracosa-15,18-dien-l-amine (“HGT5000”), having a compound structure of: (page 74) and pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions and methods of the present invention include the cationic lipid (15Z, 18Z)-N,N- dimethyl-6-((9Z, 12Z)-octadeca-9, 12-dien- 1-yl) tetracosa-4, 15, 18-trien-l -amine (“HGT5001”), having a compound structure of: (page 75) and pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions and methods of the present invention include the cationic lipid and (15Z,18Z)- N,N-dimethyl-6-((9Z,12Z)-octadeca-9,12-dien-l-yl) tetracosa-5,15,18-trien- 1 -amine (“HGT5002”), having a compound structure of: (page 75) and pharmaceutically acceptable salts thereof. (instant claim 52).
Bhat et al. teach cells comprising the siRNA (abstract, [00030]) (instant claim 73); and pharmaceutical compositions comprising the siRNA (abstract, [00010]) (instant claim 74).
Bhat et al. teach delivery via oral aspiration, meeting the instant limitation of any device for oral administration [00032]. Bhat et al. teach delivery via nebulization [000380] and teach delivery via a nebulizer device [000130][000438](instant claim 76),.
Therefore, the claims are anticipated by Bhat et al.
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) 32, 42, and 69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bhat et al. (WO 2021/142245 A1) as applied to claims 1, 11, 14, 18, 20, 52, 73, 74, and 76 above, and further in view of Ladine et al. (US 2010/0173359 A1), Osborn et al. (Nucleic Acids Research, 2019, Vol. 47, No. 3, 1070-1081), and Jalkanen et al. (US 2012/0027770 A1).
Bhat et al. do not teach incorporation of lipophilic moieties at internal positions (instant claims 32 and 42). However, the properties of such lipophilic moieties for siRNAs were known in the art, as evidenced by Bhat et al. It would have been obvious as a matter of design choice to conjugate the lipophilic moiety at various internal positions with a reasonable expectation of success. The claims are not limited to any specific lipophilic moiety at any specific position that has demonstrated an unexpected result.
Ladine et al. teach conjugation of siRNAs to lipophilic moieties including cholesterol to facilitate delivery, wherein the conjugate can be at internal positions [0131].
Osborn et al. teach that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation (abstract). Osborn et al. teach extensive internal modification of siRNA with cholesterol conjugates (Figure 1B) with resultant liver delivery (page 1077). Therefore, there was motivation in the art to incorporate internal lipophilic conjugates with the motivation and expectation of facilitation of delivery to the liver.
Bhat et al. does not teach a phosphate at the 5’ end of the antisense strand. However, Jalkanen et al. teach: The 5'-terminal of the antisense is typically a phosphate group (P). The siRNA duplexes having terminal phosphate groups (P) are easier to administrate into the cell than a single stranded antisense. In the cell, an active siRNA antisense strand is formed and it recognizes a target region of the target mRNA. This in turn leads to cleaving of the target RNA by the RISC endonuclease complex (RISC=RNA-induced silencing complex) and also in the synthesis of additional RNA by RNA dependent RNA polymerase (RdRP), which can activate DICER and result in additional siRNA duplex molecules, thereby amplifying the response [0041].
Therefore, it would have been obvious to incorporate a 5’ terminal phosphate on the antisense strand with the expectation of amplifying the response as taught by Jalkanen et al. (instant claim 69).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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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.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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