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 .
Claim Status
Claims 75-101 are pending in the application.
Priority
This application has PRO of 63434915 12/22/2022, PRO of 63428348 11/28/2022, and PRO of 63416416 10/14/2022.
Claim Objections
Claim 75 is objected to because of the following informalities: "the Appropriate correction is required.
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.
Claims 89 and 99 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.
Claims 89 and 99 depend on claims 84 and 90 respectively and recite the method of treating a neonatal subject that has Type 0 spinal muscular atrophy (SMA). It is unclear what the metes and bounds of these claims are because the specification defines neonatal as "a human subject once it is delivered from a carrier” and type 0 SMA as occurring in utero. As such the claims require the mutually exclusive conditions of a delivered neonatal subject with an in utero form of SMA, rendering the scope of these claims indefinite.
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 75-101 are rejected under 35 U.S.C. 103 as being unpatentable over Ratni et al. (US 2021/0147447 A1, published on May 20, 2021), in view of Baptiste et al. (2021, Clinical Obstetrics and Gynecology, 64.4), McCampbell (US 2022/0280548 Al, published Sep. 8, 2022), and Pfefen et al. (US 2020/0375993 A1, published Dec. 3, 2020),
Regarding claims 75, 76, 79, 88, 89, 91 and 98 – 101 Ratni et al. teaches a method for the treatment of spinal muscular atrophy (SMA) in a human in need thereof, with said method comprising administering to said human a therapeutically effective amount of
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(Risdiplam) or a pharmaceutically acceptable salt thereof (pg. 5 paragraphs [0062] and [0065], and pg. 30, claim 57). They also claimed a composition of Risdiplam that can be administered as an oral solution (pg. 12 paragraph [0241], and pg. 30 claim 78). The instant application describes fetal and neonatal subjects which the Applicant’s specification defines as “human subjects” prior to and following delivery (pg. 11 paragraph [0081], and pg. 12 paragraph [0082]. Therefore, the teaching of SMA treatment in human subjects by Ratni et al. encompasses treatment of the subject populations in the instant application. Furthermore, the claimed method described by Ratni et al. can be used to treat SMA Type 0, 1, 2, 3, or 4 (pg. 30, claims 58-62) and further discloses treatment of infants and toddlers (pg. 30, claims 63 and 64). Ratni et al. defines types 0 and 1, stating: “Type 0 SMA (In Utero SMA) is the most severe form of the disease and begins before birth. Usually, the first symptom of Type 0 SMA is reduced movement of the fetus that can first be observed between 30 and 36 weeks of pregnancy” and “Type 1 SMA (Infantile SMA or Werdnig Hoffmann disease) presents symptoms between 0 and 6 months, form of SMA is also very severe” (pg. 1 paragraphs [0008] – [0012]). Thus, since Ratni et al. describes Type 0 SMA as in utero and Type 1 as infantile their claims suggest treatment of SMA in fetal and neonatal subjects.
Ratni et al. differs from the claimed invention in (A) the teaching of Risdiplam administration to a carrier for in utero SMA treatment with associated SMN2 copy numbers disclosed by claims 75 - 83, 87, 91, 92, 97 and 100, (B) the treatment of a fetus for SMA followed by the continuation as a neonate as required by claims 83, 84, 90, 91, and 96, (C) the dosages utilized as required by claims 80, 81, 85, 86, 92, 93, and 96, and (D) measurement of Risdiplam in blood with treatment initiation as required by claims 94 and 95.
With regard to the limitations of (A) Baptiste et al. (2021) teaches that patients with 2
copies or less of SMN2 tend to have clinical onset of symptoms early in infancy with a more severe phenotype (pg. 918, right column, lines 15 – 18) and “fetuses with ≤ 2 copies of SMN2 may benefit from in utero treatment” (pg. 923, left column, lines 42 – 43). They also teach that Risdiplam is given orally and dosing is weight-based (pg. 923, left column, lines 30 and 31). Furthermore, they suggest that Risdiplam “could potentially be given to the mother orally if it crosses the placenta, or could be administered directly into the amniotic fluid for the fetus to swallow” (pg. 923, right column, lines 41 – 46).
With regard to the limitations of (B) McCampbell suggests that in some instances, SMA is detected in a fetus at around 30 to 36 weeks of pregnancy (corresponding to the third trimester) and it “may be desirable to treat the fetus in utero” (pg. 39, paragraph [0443]). They also disclose “a method of rescuing and/or treating a neonatal subject having SMA … comprising the step of administering (e.g., concurrently and sequentially), a small molecule for increasing SMN function (e.g., Risdiplam or Branaplam) and a recombinant SMN1 gene (e.g., in a rAAV) … to the neuronal cells of a fetus and/or a newborn subject (e.g., a human fetus and/or newborn)” (pg. 39, paragraph [0443]). They additionally describe neonatal treatment, with the method disclosed above, after delivery (pg. 40, paragraph [0444]).
With regard to the limitations of (C) Pfefen et al. teaches the dosages of Risdiplam (7-(4, 7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one) for the treatment of SMA (pg. 2 paragraph [0017], and pg. 30 claim 23) as required by Applicant’s claims 80, 81, 85, 86, 92, 93, and 96. Pfefen et al. discloses the oral administration of a 5 mg daily dose of Risdiplam in treatment to a subject with a body weight of more than or equal to 20 kg (pg. 2 paragraph [0017], pg. 30 claim 23b) and 0.25 mg/kg for a subject with a body weight less than 20 kg (pg. 2 paragraph [0017], pg. 30 claim 23a). Pfefen et al. further discloses dosages of 0.15 mg/kg of body weight in studies as part of clinical dosing regimens (pg. 18 paragraph [0279]). These values render obvious the Applicant’s claimed 0.20 mg/kg of body weight dosage which would be motivated by routine optimization based on the prior art dosing regimen.
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With regard to the limitations of (D) Pfefen et al. also teaches measurement of Risdiplam in a blood-derived matrix as required by claims 94 and 95. Figure 7 discloses an exposure-response relationship for Risdiplam (referred to in Figure 7 as RG7916) in which higher SMN2 splice correction is observed at higher time-matched plasma concentrations of Risdiplam near 100 ng/mL (Fig.7) with the most pronounced correction observed at ~160 ng/mL. Pfefen et al. therefore teaches monitoring Risdiplam concentrations in a blood-derived matrix and corresponding therapeutic benefits at concentrations near or above 100 ng/mL with a motivation to initiate treatment near that level due to the increased SMN2 splice correction. Moreover, cord blood is a blood sample associated with neonates that would be obtained at the time of delivery thus it would be obvious to a person of ordinary skill in the art to use cord blood in order to obtain a measurement of Risdiplam levels in a neonatal subject.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time
the invention was filed to take the teachings of Ratni et al., which utilized Risdiplam to treat Types 1-4 of SMA, and combine them with the teachings of Baptiste et al. (2021) which emphasizes in utero treatment of a fetus through a carrier. Baptiste et al. (2021) provided the motivation for in utero SMA treatment because they teach that SMA can be diagnosed prenatally, and that early treatment in infants leads to improved outcomes (pg. 923, left column, lines 32-34). In addition, McCampbell suggested early in utero treatment followed by continued neonatal treatment for SMA using a method comprising Risdiplam. McCampbell provides a similar motivation as Baptiste et al. (2021) where SMA is detected in a fetus at around 30 to 36 weeks of pregnancy thus it may be desirable to treat the neonate as soon as possible after delivery (pg. 39, paragraph [0443]) with treatment continuing based on the debilitating nature of SMA. Lastly, Pfefen et al. taught relevant dosing regiments and plasma concentration measurements of Risdiplam. Pfefen et al. disclosed similar weight based Risdiplam dosages as taught by Baptiste et al. (2021) with the motivation for the dosages derived from patient and clinical studies.
In view of these teachings and suggestions, one of ordinary skill in the art would have been motivated to combine, with a reasonable expectation of success, the teachings of Ratni et al. in view of Baptiste et al. (2021), McCampbell, and Pfefen et al. as detailed above to achieve Applicant’s claims 75-101.
Conclusion
No claims are allowed in this action.
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/RAJESH JAIPRASHAD/Examiner, Art Unit 1691