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 .
DETAILED ACTION
Applicant's amendments and remarks filed on February 19, 2026 are acknowledged. Claims 2-9, 11-14, 16-19, 21-27, 29, 34-43, 46-50, 52-56, 58, and 60-73 have been canceled. Claims 1, 10, 15, 31, 32, 74, 82, and 83 were amended. Claims 1, 10, 15, 20, 28, 30-33, 44, 45, 51, 57, 59, and 74-83 are pending.
Election/Restrictions
Claims 1, 10, 15, 20, 28, 30-33, 44, 45, and 74-83 are allowable. Claims 51, 57, and 59, previously withdrawn from consideration as a result of a restriction requirement, require all the limitations of an allowable claim. Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement among inventions I through III, as set forth in the Office action mailed on June 20, 2025, is hereby withdrawn and claims 51, 57, and 59 are hereby rejoined and fully examined for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 1, 10, 15, 20, 28, 30-33, 44, 45, 51, 57, 59, and 74-83 are examined on the merits herein.
Priority
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Withdrawn Objections
In view of Applicant’s amendments and response, the objections to the drawings and specification are withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b) and 35 U.S.C 103 rejections are withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 19, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings were received on February 19, 2026. These drawings are found acceptable by the examiner.
Specification
The disclosure filed on 06/07/2023 is objected to because of the following informalities:
Page 9, lines 26 and 32 reads “associate” and should read “associated”.
Page 115, lines 27 and 33 reads “associate” and should read “associated”.
Page 115, line 32 is missing a period at the end of the paragraph.
Page 166, line 27 reads “sligntly” and should read “slightly”.
Page 167, line 7 reads “taregting” and should read “targeting”.
Appropriate correction is required.
Claim Objections
Claims 32, 82, and 83 are objected to because of the following informalities:
The structure in claims 32, 82, and 83 (reproduced below) appears to be cut off (designated by arrows).
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Appropriate correction is required.
Response to Arguments
Applicant's arguments filed February 19, 2026 have been fully considered but they are not persuasive.
Applicant asserts that the structure in claims 32, 82, and 83 have been replaced rendering the objection to these claims moot. Contrary to Applicant’s assertions, the structure in these claims still appear to be cut off as shown in the image above designated by arrows.
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 57 and 59 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is
sufficient evidence to support a determination that a disclosure does not satisfy the
enablement requirement and whether any necessary experimentation is "undue".
These factors include, but are not limited to: (A) The breadth of the claims; (B) The
nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary
skill; (E) The level of predictability in the art; (F) The amount of direction provided by the
inventor; (G) The existence of working examples; and (H) The quantity of
experimentation needed to make or use the invention based on the content of the
disclosure. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of claims:
Claim 57 is drawn to a method of treating a subject having a disorder that would benefit from reduction in complement factor B expression, comprising administering to the subject a therapeutically effective amount of the dsRNA agent, or a salt thereof, of claim 1, thereby treating the subject having the disorder that would benefit from reduction in complement factor B expression. Claim 59 further limits the disorder to a complement factor B-associated disorder.
The broadest reasonable interpretation of claim 57 is that the method encompasses treating a subject having any disorder that would benefit from reduction in complement factor B expression comprising administering to the subject a therapeutically effective amount of the dsRNA agent, or a salt thereof, of claim 1. The broadest reasonable interpretation of claim 59 is that the disorder is any complement factor B-associated disorder.
Nature of the invention:
The specification filed on June 7, 2023 envisions that the invention provides a method of treating a subject having a disorder that would benefit from reduction in complement factor B (CFB) expression [page 10, first paragraph]. In one embodiment, the disorder is a complement factor B-(CFB)-associated disorder [page 10, line 13]. The specification further discloses that the term "complement factor B disease" or "CFB-associated disease," is a disease or disorder that is caused by, or associated with, complement activation [page 27, lines 33-34]. The specification also discloses that complement factor B-associated disorders are typically associated with inflammation or immune system activation, e.g., membrane attack complex-mediated lysis, anaphylaxis, or hemolysis.
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[page 8, last paragraph bridging to page 9].
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[page 9, first and second full paragraphs].
Amount of direction provided by the inventor and existence of working
examples:
Working example 2 discloses in vitro single dose screens of dsRNA agents in Hep3B cells and primary mouse hepatocytes (PMH). The results of the single dose screens in Hep3B cells are shown in Tables 8, 9, and 12. The results of the single dose screens in PMH cells are shown in Tables 10 and 11.
Working examples 3 and 4 discloses in vivo screening of dsRNA duplexes in mice wherein mice were administered an AAV8 vector encoding human complement factor B by intravenous tail vein injection. The results demonstrated that human CFB mRNA levels were reduced upon treatment with a single dose of siRNA targeting hCFB at 2 mg/kg.
Working example 6 evaluated whether hemolytic activity could be strongly suppressed using a combination of a dsRNA agent targeting complement component C3 and a dsRNA agent targeting complement component C5 or a dsRNA agent targeting complement component factor B as compared to use of a single dsRNA targeting C3, C5, or CFB alone. The results demonstrated that the combination of a dsRNA agent targeting C3 and a dsRNA agent targeting CFB effectively suppressed alternative hemolysis activity to less than about 10% while the combination of a dsRNA agent targeting C3 and a dsRNA agent targeting C5 effectively suppresses classical hemolysis activity.
State of the prior art, level of predictability in the art, and level of one of
ordinary skill:
Morgan et al. (Nature Reviews Drug Discovery 2015) discloses that the complement system is a key innate immune defense against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease [abstract]. Further, as the field has grown, it has become increasingly clear that there will be no ‘one size fits all’ solution to complement therapies; agents that are effective in one disease might do nothing in, or even exacerbate, another. Rational design and selection of therapies will require in-depth understanding of the way complement works in each disease [page 859, left column, third full paragraph]. Morgan et al. also discloses that hurdles to the commercialization of complement therapeutics still exist, including cost, routes of administration and infection risk [page 873, right column, second full paragraph].
Schubart et al. (PNAS 2019) discloses that dysregulation of the alternative complement pathway (AP) predisposes individuals to a number of diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy [abstract]. In addition, recent studies have revealed that the AP may also contribute to a number of Ig-mediated kidney pathologies [page 7926, left column, first paragraph].
Quantity of experimentation:
In view of the breadth of the claims which embrace treating a subject having any complement factor B-associated disorder that would benefit from reduction in complement factor B expression comprising administering to the subject a therapeutically effective amount of the dsRNA agent, or a salt thereof, of claim 1, the state and level of predictability in the art, the lack of working examples to show treating a subject having any disorder that would benefit from reduction in complement factor B expression wherein the disorder is any complement factor B-associated disorder, and the failure to provide adequate guidance to overcome the state and level of predictability of the art, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims.
Allowable Subject Matter
Claims 1, 10, 15, 20, 28, 30-33, 44, 45, 51, and 74-83 are allowed.
The following is a statement of reasons for the indication of allowable subject matter:
The closest prior art is Borodovsky et al. (US 2016/0298124, reference of
record). Borodovsky et al. teaches iRNA, e.g., double-stranded ribonucleic acid (dsRNA) and compositions targeting the complement factor B (CFB) gene [abstract]. Further, Borodovsky et al. teaches double-stranded ribonucleic acids (dsRNA) comprising a sense strand and an antisense strand for inhibiting expression of complement factor B (CFB) in a cell, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequence of SEQ ID NOS: 12-16, 33, and 36 [0014]. Borodovsky et al. teaches SEQ ID NO: 12 (designated as Db) which is an antisense sequence of a CFB nucleotide sequence [0343]. SEQ ID NO: 12 is the reverse complement of NM_001710.5. The closest prior art oligonucleotide is designated as AD-60309.1 [Table 3]. The sense sequence of this duplex targeted positions 2393-2413 and the antisense sequence of this duplex targeted positions 2391-2413 of NM_001710.5. The sense sequence of AD-560018.1 (instant SEQ ID NO: 450) targeted positions 2397-2417 and the antisense sequence of AD-560018.1 (instant SEQ ID NO: 521) targeted positions 2395-2417 of NM_001710.5. Therefore, the positions targeted by the closest prior art oligonucleotide overlap with the positions targeted by the claimed oligonucleotide.
Duplex ID Sense ID Sense sequence Antisense ID Antisense seq
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A single dose screen in primary mouse hepatocytes transfected with AD-60309.1 was performed at 10 nM and 0.1 nM. The results indicate that at 10 nM, 100.72% of message remained relative to untreated cells and at 0.1 nM 112.85% of message remained relative to untreated cells [0886] and [Table 10].
In the instant specification, Table 4 (reproduced below) shows unmodified sense and antisense strand sequences of Complement Factor B dsRNA agents. Specifically, Table 4 shows that AD-560016, AD-560017, AD-560019, and AD-560021 all target the same region of the CFB gene as AD-560018. Furthermore, the table demonstrates that the duplexes designated as AD-560016, AD-560017, AD-560018, AD-560019, and AD-560021 all target the same region as Borodovsky et al. AD-60309.1.
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As evidenced by Table 5 of the specification filed on June 7, 2023, AD-560016, AD-560017, AD-560019, and AD-560021 have the same modification pattern as AD-560018 (reproduced below).
Duplex Sense sequence SID Antisense sequence SID mRNA target sequence SID
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According to Tables 9 and 10 (reproduced below), the specific structural features and modification pattern of AD-560018 does demonstrate superior ability to inhibit expression of CFB and provides unexpected and improved results compared to other oligonucleotides that target other regions of the CFB gene.
Table 9: Complement Factor B In Vitro Single Dose Screens in Hep3B cells
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Table 10: Complement Factor B In Vitro Single Dose Screens in Primary Mouse Hepatocytes
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Comparing instant AD-560018.1 to the closest prior art oligonucleotide (AD-60309.1), it is unexpected that AD-560018.1 only had 13.28% of message remaining compared to AD-60309.1 which had 100.72% of message remaining when the primary mouse hepatocytes were transfected with the oligonucleotide at 10nM dose.
Therefore, claims 1, 10, 15, 20, 28, 30-33, 44, 45, 51, and 74-83 are allowable.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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