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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114 was filed in this application after appeal to the Patent Trial and Appeal Board, but prior to a decision on the appeal. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on June 5, 2026 has been entered.
Status of Claims/Rejections
Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are currently pending and under examination on the merits in the instant case.
Any rejections not repeated in this Office action are withdrawn. The following rejections are the only rejections applied in this application.
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.
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.
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.
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 1-2, 4-5, 15-22, 31-35, and 41-48 are rejected under 35 U.S.C. 103 as being unpatentable over Bennett et al. (US 2016/0002627 A1, of record) in view of Rigo et al. (US 2019/0323006 A1, of record), Gidaro et al. (Developmental Medicine & Child Neurology, published online on September 17, 2018, 61:19-24, of record), and Govoni et al. (Molecular Neurobiology, 2018, 55:6307-6318, of record).
Bennett discloses a method of treating a human subject having SMA comprising a pharmaceutical composition comprising a pharmaceutically acceptable salt (e.g., sodium salt) of a chemically modified 18-mer antisense oligonucleotide ISIS 396443 of SEQ ID NO:1 (5’-TCACTTTCATAATGCTGG) that is fully modified with 2’-MOE and phosphorothioate linkage with 5-methylcytosines for all cytosines is administered at “an equivalent dose” of “10 to 20 milligrams” or “12 mg” or “25 mg” or “50 mg” “in a volume of 5 mL” provided in “a vial containing reconstituted oligonucleotide” as a “dosage unit” to a subject having SMA such as “SMA type I” or “SMA type II” or “SMA type III” by “a bolus injection” or by lumbar puncture into the intrathecal space/cerebrospinal fluid (CSF) of the subject through “a spinal anesthesia needle”, wherein a “second dose is administered 12-18 days after the first dose” or multiple doses of “at least four doses” are administered “with a dose frequency of about four months between doses”, wherein the pharmaceutical composition is formulated in a pharmaceutically acceptable diluent such as “phosphate-buffered saline (PBS)” and/or “artificial CSF”, wherein “the artificial CSF formulation vehicle comprises 1 mM phosphate buffer at pH 7.2”. See paragraphs 0005, 0034, 0080, 0115, 0122, 0125, 0134, 0144, 0153, 0159, 0179-0181, 0329-0330, 0396-0397, 0402, 0428-0429, and 0470; claims 1-240.
Bennett teaches that SMN2 “exists in a duplicated region on chromosome 5q13 and modulates disease severity” and that “SMN2 contains a translationally silent mutation (C→T) at position +6 of exon 7, which results in inefficient inclusion of exon 7 in SMN2 transcripts” thus “therapeutic compounds capable of modulating SMN2 splicing such that the percentage of SMN2 transcripts containing exon 7 is increased, would be useful for the treatment of SMA.” See paragraphs 0006 and 0414.
Bennett does not expressly disclose that the instantly claimed dosing schedules.
Rigo discloses that ISIS 396443 of Bennett is also known as “Nusinersen” or “Ionis-SMNRx” as shown below in Rigo’s paragraphs 0177-0178.
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Rigo teaches that Nusinersen can be used to treat “Spinal Muscular Atrophy Type IV in a patient” as well as “Type I SMA”, “Type II SMA”, and “Type III SMA”. See paragraph 0116; claims 119-122 and 124-127.
Stauber teaches that Nusinersen-based SMA treatment method in human patients comprises “intrathecal loading doses at day 1, 14, 28 and 63, followed by maintenance dose every 4 months.” See page S363.
Gidaro teaches that nusinersen was initially tested in types 2 and 3 SMA patients with a single dose of 1 mg, 3 mg, 6 mg, or 9 mg dose, which provided improvements in a dose-dependent manner, wherein the next clinical study was conducted with a 12 mg dose “on days 1, 29, 85, and 274” for type 2 SMA, followed by a study for type 1 SMA infants, wherein nusinersen is “administered by intrathecal injection for four initial loading doses: the first three loading doses were given at 14-day intervals, while the fourth loading dose was given 30 days after the third. Thereafter, a maintenance dose was given once every 4 months.” See pages 20-21.
Gidaro teaches that nusinersen was also administered “on treatment days 1, 15, 30, 60, and 180” for type 1 SMA patients. See page 21.
Gidaro teaches that “several gaps remain in our understanding of how to best to use – and when not to use – this medication in the several subgroups of patients with SMA” including “older patients” that “still need to be addressed.” See abstract and page 23.
Govoni teaches, “Presymptomatic treatment might provide an even greater clinical response; this hypothesis is being examined in an ongoing phase 2 study (Nurture, NCT02386553). Data presented at a meeting in April 2017 showed that pre-symptomatic treatment in SMA type 1 patients (treated within 6 weeks of age) is likely more beneficial than in symptomatic cohort”. See page 6313.
It would have been obvious to one of ordinary skill in the art before the effective filing date to practice Bennett’s SMA treatment method by providing multiple equivalent doses of ISIS 396443 or a sodium salt thereof comprising loading and maintenance doses that are optimized in view of Bennett’s disclosed doses, dose ranges, and dosing schedules/frequencies, thereby arriving at the instantly claimed method. One of ordinary skill in the art would have been motivated to optimize the dosing regimen with a reasonable expectation of success in an effort to improve the clinical outcome of ISIS 396443 (or Nusinersen) or a sodium salt thereof in a subject who is symptomatic or presymptomatic of SMA, because it is a normal desire of a person of ordinary skill in the clinical field to optimize pharmaceutical composition’s dose/dosing schedule so as to provide the most optimal treatment options with desired outcomes for a given patient as evidenced by the fact that Bennett disclosed multiple potential equivalent dose options (e.g., “12 mg” or “25 mg” or “50 mg”) and multiple dosing schedule/frequency options (e.g., “at least four doses”; “second dose is administered 12-18 days after the first dose”; “a dose frequency of about four months between doses”) for providing the most optimal treatment for a given SMA patient, and as further evidenced by the actual clinical use of Nusinersen with multiple doses including “intrathecal injection for four initial loading doses: the first three loading doses were given at 14-day intervals, while the fourth loading dose was given 30 days after the third” followed by “a maintenance dose” at the frequency of “once every 4 months” as reported by Gidaro. Since all of the instantly claimed doses of “about 50 mg”, “about 28 mg”, and “about 12 mg” as well as “at least four doses” were taught and suggested by Bennett, and since all of the instantly claimed dosing schedules such that “second dose is administered 12-18 days after the first dose” and maintenance doses are administered “once every 4 months” were also taught and suggested by Bennett and Gidaro, one of ordinary skill in the art would have had a reasonable expectation of success in obtaining the instantly claimed dosing regimen through mere routine clinical dosing optimization process in light of the teachings of Bennett and Gidaro, especially in view of the fact that various doses/dosing frequencies taught by Bennett showed clinical success in SMA patients as reported by Gidaro, thereby verifying the teachings of Bennett. Further, since there was an art-recognized “need to be addressed” on “how to use” or “how to best use” nusinersen for “subgroups of patients with SMA” including “older patients” as taught by Gidaro, one of ordinary skill in the art would have been motivated to higher doses within the teachings of Bennett for “older patients” with SMA after completing the 12 mg dosing regimen comprising four loading doses (first three loading doses were given at 14-day intervals, while the fourth loading dose was given 30 days after the third) and a maintenance dose of “every 4 months”, if the SMA patients are determined by a relevant artisan to be in need of further treatment after about 4 months of the last maintenance dose of the prior art’s 12 mg dosing regimen, because it would have been a normal desire of a relevant artisan of ordinary skill (e.g., clinician, medical professional) to provide higher doses within the art-recognized range of nusinersen doses (up to “50 mg”) as disclosed by Bennett to a patient who did not respond favorably to the 12 mg dosing regimen thus is deemed suitable for additional doses that are higher than the 12 mg that did not provide expected treatment effects, wherein it was recognized in the art that the 12 mg dosing regimen may not be applicable and suitable for all subgroups of SMA patients as it was recognized in the art that “several gaps remain in our understanding of how to best to use” nusinersen for untested subgroups of SMA patients who “need to be addressed”.
It is noted that “about 50 mg” of ISIS 396443 (or Nusinersen) or a sodium salt thereof “in a volume of 5 mL” provided in “a vial” as a dosage unit as taught by Bennett is equivalent to the concentration of about 10 mg/mL. Hence, the instantly claimed loading dose would have a concentration of about 10 mg/mL. It is also noted that “about 25 mg” in a volume of 5 mL” provided in “a vial” as a dosage unit as taught by Bennett is equivalent to the concentration of about 5 mg/mL. As such, the concentrations recited in claims 34-35 are prima facie obvious.
In addition, one of ordinary skill in the art would have been motivated to provide the multi-dosing regimen of Nusinersen to a presymptomatic SMA patient because providing a Nusinersen-based therapy to a presymptomatic SMA patient was an art-recognized goal as evidenced by Govoni, who expressly taught that “an even greater clinical response” by Nusinersen may be observed in presymptomatic SMA patients such that Nusinersen in presymptomatic SMA patients is “likely more beneficial than in symptomatic cohort”. It would also have been obvious for one of ordinary skill in the art to formulate Bennett’s ISIS 396443 or a sodium salt thereof in 5 mL of artificial CSF at pH 7.2 for intrathecal lumbar puncture or intrathecal bolus injection because such formulation with the instantly claimed limitations was expressly disclosed by Bennett, who also taught that “the percentage of SMN2 transcripts containing exon 7 is increased” in SMA patients treated with ISIS 396443, wherein SMN2 “exists in a duplicated region on chromosome 5q13 and modulates disease severity” and that “SMN2 contains a translationally silent mutation (C→T) at position +6 of exon 7, which results in inefficient inclusion of exon 7 in SMN2 transcripts”.
It would have been obvious to one of ordinary skill in the art to administer the multi-dosing regimen of Nusinersen rendered obvious in the instant rejection to any one of art-recognized SMA patient subtypes: SMA type I, type II, type III, and type IV. One or ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Nusinersen was taught to be useful in treating a subject having any one of SMA type I, type II, type III, and type IV as evidenced by Bennett (types I-III) and Rigo (types I-IV). Thus, one of ordinary skill in the art would have selected all four types of SMA patients as the patient population to be treated with the Nusinersen multi-dosing regimen rendered obvious in the instant rejection.
Accordingly, claims 1-2, 4-5, 15-22, 31-35, and 41-48 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments
Applicant's arguments filed on June 5, 2026 have been fully considered but they are not persuasive. Applicant argues that the instant claims are not obvious over the cited art because none of Bennett, Rigo, Gidaro, and Govoni individually or in combination teaches the dosing regimen as exactly claimed in the instant case. In response, it is noted that applicant did not provide any substantial rebuttal arguments as to why the cited references in combination fail to render obvious the instantly claimed dosing regimen. As such, applicant’s arguments fail to comply with 37 CFR 1.111(b) because they merely amount to a general allegation that the claims are not obvious without specifically pointing out how the combined teachings of the cited references fail to render the claims obvious. That is, there is no rebuttal argument specifically addressing the obviousness rationale set forth in the last Office actions, wherein the same obviousness rationale as originally set forth in the Office action mailed on July 30, 2025 is included hereinabove.
Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are rejected under 35 U.S.C. 103 as being unpatentable over Bennett et al. (US 2016/0002627 A1, of record) in view of Australian Government, Department of Health, Therapeutic Goods Administration (“Australian Public Assessment Report for nusinersen (as heptadecasodium)”, August 2018, of record; “Australian Assessment Report” hereinafter) and European Medicines Agency Science Medicines Health (Assessment report, Spinraza, International non-proprietary name: nusinersen”, April 21, 2017, of record; “European Assessment Report” hereinafter).
Bennett discloses a method of treating a human subject having SMA comprising a pharmaceutical composition comprising a pharmaceutically acceptable salt (e.g., sodium salt) of a chemically modified 18-mer antisense oligonucleotide ISIS 396443 of SEQ ID NO:1 (5’-TCACTTTCATAATGCTGG) that is fully modified with 2’-MOE and phosphorothioate linkage with 5-methylcytosines for all cytosines is administered at “an equivalent dose” of “10 to 20 milligrams” or “12 mg” or “25 mg” or “50 mg” “in a volume of 5 mL” provided in “a vial containing reconstituted oligonucleotide” as a “dosage unit” to a subject having SMA such as “SMA type I” or “SMA type II” or “SMA type III” by “a bolus injection” or by lumbar puncture into the intrathecal space/cerebrospinal fluid (CSF) of the subject through “a spinal anesthesia needle”, wherein a “second dose is administered 12-18 days after the first dose” or multiple doses of “at least four doses” are administered “with a dose frequency of about four months between doses”, wherein the pharmaceutical composition is formulated in a pharmaceutically acceptable diluent such as “phosphate-buffered saline (PBS)” and/or “artificial CSF”, wherein “the artificial CSF formulation vehicle comprises 1 mM phosphate buffer at pH 7.2”. See paragraphs 0005, 0034, 0080, 0115, 0122, 0125, 0134, 0144, 0153, 0159, 0179-0181, 0329-0330, 0396-0397, 0402, 0428-0429, and 0470; claims 1-240.
Bennett teaches that SMN2 “exists in a duplicated region on chromosome 5q13 and modulates disease severity” and that “SMN2 contains a translationally silent mutation (C→T) at position +6 of exon 7, which results in inefficient inclusion of exon 7 in SMN2 transcripts” thus “therapeutic compounds capable of modulating SMN2 splicing such that the percentage of SMN2 transcripts containing exon 7 is increased, would be useful for the treatment of SMA.” See paragraphs 0006 and 0414.
Bennett does not expressly disclose the dosing schedules as recited in the claims.
The Australian Assessment Report discloses that ISIS 396443 is also known as nusinersen. See Table 11.
The Australian Assessment Report discloses that multidosing nusinersen regimen can be administered to patients having “Infantile onset SMA”, “Later onset SMA”, “Infantile or later onset SMA”, and “Pre-symptomatic SMA”. See pages 30-31; Table 5.
The Australian Assessment Report discloses that “Type I SMA” is “Infantile onset”; “Types II and III” are “later onset”; and “SMA Type IV is adult onset, generally appearing after 18 years of age” “with normal life expectancy.” See pages 9-10.
The Australian Assessment Report discloses that the “most common variants (Type I to III) all present with an asymptomatic (pre-symptomatic) period followed by symptoms.” See page 9.
The Australian Assessment Report discloses that “3 drug product presentations were developed for clinical trials a 5 mL vial containing 2.5 mL of a 20 mg/mL solution [of nusinersen] with a diluent of aCSF in 2 vials, a 5 mL of a ready to use 1.8 mg/mL nusinersen solution in aCSF and a 5 mL of a ready to use 2.4 mg/mL nusinersen solution in aCSF.” See pages 52-53. It is noted that 2.5 mL of a 20 mg/mL nusinersen is equivalent to the dose strength of 50 mg. It is noted that 5 mL of 1.8 mg/mL is equivalent to the dose strength of 9 mg. It is noted that 5 mL of 2.4 mg/mL is equivalent to the dose strength of 12 mg.
The Australian Public Assessment Report discloses the following at page 32, wherein underline has been added for emphasis.
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The Australian Public Assessment Report discloses the following at page 33 disclosing the following, wherein underline has been added for emphasis.
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See also pages 36-37 disclosing the following: “Another uncertainty is whether the proposed dose of nusinersen (12 mg intrathecally administered once every 4 months after an initial loading regimen) is optimal or whether higher or more frequent dosing may further improve outcomes.” (emphasis added).
See also page 38 disclosing the following: “There is still significant uncertainty as to whether 12 mg is the optimal dose or further benefits could be gained by increasing the dose.” (emphasis added).
See also page 40 disclosing that there “are some outstanding issues regarding whether 12 mg is the optimal dosing…However, these can be addressed with the suggested changes to the product information and ongoing post marking surveillance.” (emphasis added).
See also page 66 disclosing that “there has been no head to head comparison of different dosage regimens to determine which provides more favorable outcomes.” (emphasis added).
The Australian Assessment Report discloses that the “CSF turnover rate is similar in monkeys and human subjects (4 times a day). Therefore, monkeys are considered an appropriate species from a pharmacokinetic perspective to assess local toxicity following IT dosing.” (emphasis added). See page 19.
The European Assessment Report discloses that nusinersen is “also cited as ISIS 396443” and that the “deliverable volume is 5 mL.” See pages 11-12.
The European Assessment Report discloses that the cumulative dose of the nusinersen at the NOAEL in toxicology assessment for 53 weeks in monkeys provides human equivalent dose (HED) of 520 mg for 53 week-dosing regimen. See Table 2.
The European Assessment Report discloses, “The earlier onset and greater magnitude of the improvements in subjects who received the 12-mg loading dose (Cohort 2) compared with those who received the 6-mg loading dose (Cohort 1) are indicative of greater nusinersen exposure from the higher loading dose for subjects in Cohort 2.” (emphasis added). See page 73.
The European Assessment Report discloses, “Dose dependent changes in HFMSE score were observed, with greater increases in subjects who had received 9 mg in CS1 compared to the subjects who received 3 and 6 mg in CS1.” (emphasis added). See page 75.
The European Assessment Report discloses, “Time- and dose-dependent improvements in mean total HFMSE score were observed, with the largest improvements seen in the 9- and 12-mg dose cohorts. Improvement was maintained through Day 253 (~6 months after the last dose of study drug).” (emphasis added). See page 75.
The European Assessment Report discloses, “In subjects with later-onset SMA, the terminal elimination half-life in CSF is approximately 135 to 177 days supporting infrequent (e.g., 4 to 6 months) maintenance dosing.” (emphasis added). See page 39.
The European Assessment Report discloses that SMA patients were administered “a scaled equivalent 12-mg dose of nusinersen” via an intrathecal (IT) lumbar puncture (LP) injection “as a slow bolus (1 to 3 minutes) using a spinal anaesthesia needle and 5 mL syringe” during “a loading regimen (dosing on Study Days 1, 15, 29, and 64), followed by maintenance dosing once every 4 months (dosing on Study Days 183 and 302).” See page 46.
The European Assessment Report discloses, “Prior to each injection of study drug, 4 to 5 mL of CSF was collected for PK analyses.” See page 46.
The European Assessment Report discloses that the 12 mg nusinersen administration regimen as “limitations” as discussed at page 111 such that whether the 12 mg unit dose is “the most appropriate dose to be used for different patients, both according to their disease severity and according to their changed disease progression” and the nusinersen-based SMA treatment method studies have not “significantly ascertained that the proposed therapeutic dose is the optimal one in terms of potential benefit to be gained, and that a higher dose cannot bring additional benefits.” (emphasis added).
It would have been obvious to one of ordinary skill in the art before the effective filing date to try Bennett’s expressly enumerated “50 mg” intrathecal bolus injection dose of ISIS 396449 in the volume of 5 mL as the loading dose that comprises at least “a first dose” and “a second dose” that are about 12-18 days or 14 days apart from each other when practicing the human SMA patient treatment method disclosed in Bennett. One of ordinary skill in the art would have tried the 50 mg dose in a volume of 5 mL for IT bolus injection for SMA treatment because not only such specific dose expressly disclosed by Bennett, but a “higher dose” than the 12 mg dose in a volume of 5 mL by “increasing the dose” was deemed worthwhile to try in order to ascertain “optimal dose” or “optimal dosing” for providing “further benefits”, “additional benefits”, and “more favorable outcomes” than those provided by the 12 mg dose of nusinersen (ISIS 396449) as expressly suggested by persons of ordinary skill in the relevant art and the same field of endeavor to the instantly claimed subject matter as evidenced by both the Australian Assessment Report and the European Assessment Report pertaining to the 12 mg dose of nusinersen. That is, one of ordinary skill in the art would have been motivated to optimize the 12 mg loading doses by “increasing the dose” to the maximally enumerated unit dose, 50 mg, in the narrowest embodiment disclosed in Bennett’s paragraph 0470 because there was an express criticism, “uncertainty”, and “limitations” regarding the 12 mg loading dose being the “optimal” dose as expressly recognized by both the Australian Assessment Report and the European Assessment Report. Further, “a 5 mL vial containing 2.5 mL of a 20 mg/mL solution” that is equivalent to containing 50 mg of nusinersen was already manufactured and available in the art as reported in the Australian Assessment Report. As such, one of ordinary skill in the art would have had more than a reasonable expectation of success in making and using a single vial of the 50 mg of nusinersen formulated for IT bolus injection for each of the loading doses of nusinersen because such was expressly disclosed by Bennett and because such formulation was available in the art, and further because making and using nusinersen IT bolus injection formulations at various doses were within the technical grasp of one of ordinary skill in the art before the effective filing date as evidenced by the disclosures of Bennett, the Australian Assessment Report, and the European Assessment Report. It would also have been obvious to one of ordinary skill in the art before the effective filing date to try “increasing the dose” of the maintenance doses of 12 mg of nusinersen in order to optimize the 12 mg maintenance doses that are criticized and/or doubted by both the Australian Assessment Report and the European Assessment Report pertaining to the 12 mg doses during the maintenance dosing period. One of ordinary skill in the art would have had a reasonable expectation of success in “increasing the dose” of the 12 mg of nusinersen by simply doubling the dose, thus 24 mg, or by simply utilizing Bennett’s expressly enumerated dose of “25 mg” in paragraph 0470 for the suggested optimization of the 12 mg nusinersen during the maintenance dosing that is known to occur every four months in order to ascertain the suggested “optimal dose” or “optimal dosing” for providing “further benefits”, “additional benefits”, and “more favorable outcomes” than those provided by the 12 mg dose of nusinersen during the maintenance dosing. One of ordinary skill in the relevant art would have readily determined that the total dosage of nusinersen administered during the nusinersen-based SMA treatment regimen comprising at least four loading dosing of 50 mg of nusinersen and at least two maintenance dosing of 24-25 mg of nusinersen does not exceed the human equivalent dose (HED) of 520 mg for a 53-week regimen disclosed in the European Assessment Report even for a patient who was previously treated with 5 dosing of 12 mg of nusinersen thus would have reasonably deemed that the increased doses rendered obvious above would be safe thus would have tried the increased doses with a reasonable expectation of success. It is noted that 50 mg of nusinersen in the “deliverable volume” of 5 mL in a single vial as taught by the European Assessment Report and as further taught and suggested by Bennett is equivalent to the concentration of 10 mg/mL. Hence, the nusinersen loading dose would have a concentration of about 10 mg/mL. It is also noted that the 25 mg dose of nusinersen in the volume of 5 mL for the maintenance dose is equivalent to the concentration of 5 mg/mL. As such, the concentrations recited in claims 34-35 are prima facie obvious.
It would also have been obvious to one of ordinary skill in the art to administer the loading and maintenance dosing regimen rendered obvious hereinabove about 4 months after the last maintenance dose administered “once every 4 months” to an SMA patient previously treated with the 12 mg nusinersen dosing regimen comprising “a loading regimen (dosing on Study Days 1, 15, 29, and 64), followed by maintenance dosing once every 4 months (dosing on Study Days 183 and 302).” One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to provide more effective treatment to SMA patients who are “poor responders” to the 12 mg dosing regimen thus are determined by the ordinarily skilled artisan that “further benefits could be gained by increasing the dose” in the “poor responders”, wherein it was suggested in the art that “an increased dose may be of benefit to poor responders”, wherein it was also suggested in the art that the “most appropriate dose” may differ “for different patients, both according to their disease severity and according to their changed disease progression” thus, the higher doses rendered obvious above would have been reasonably deemed more appropriate, if not most appropriate, for the SMA patients who responded poorly to the 12 mg dosing regimen. Further, since it was known in the art that nusinersen’s “half-life in CSF is approximately 135 to 177 days supporting infrequent (e.g., 4 to 6 months) maintenance dosing”, one of ordinary skill in the relevant art would have reasonably deemed that providing the higher dose regimen to the “poor responders” about 4 months after the last maintenance dose while nusinersen is still retained in the CSF of SMA patient would be appropriate for managing the treatment of the “poor responders” who had completed the 12 mg dosing regimen.
It would have been obvious to one of ordinary skill in the art to administer the multi-dosing regimen of nusinersen rendered obvious in the instant rejection to any one of art-recognized SMA patient subtypes: SMA type I, type II, type III, and type IV, wherein types I-III all have a pre-symptomatic period before displaying symptoms. One or ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because nusinersen was taught to be useful in treating a subject having any one of SMA type I, type II, type III, and type IV as evidenced by Bennett (types I-III) and the Australian Assessment Report (types I-IV including pre-symptomatic patients). Thus, one of ordinary skill in the art would have selected any of the art-recognized SMA patient types as the patient population to be treated with the nusinersen multi-dosing regimen rendered obvious in the instant rejection.
In view of the foregoing, claims 1-2, 4-5, 15-22, 31-35, and 41-48 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments
Applicant's arguments filed on June 5, 2026 have been fully considered but they are not persuasive. Applicant argues that the instant claims are not obvious over the cited art because none of Bennett, the Australian Assessment Report, and the European Assessment Report individually or in combination teaches the dosing regimen as exactly claimed in the instant case. In response, it is noted that applicant did not provide any substantial rebuttal arguments as to why the cited references in combination fail to render obvious the instantly claimed dosing regimen. As such, applicant’s arguments fail to comply with 37 CFR 1.111(b) because they merely amount to a general allegation that the claims are not obvious without specifically pointing out how the combined teachings of the cited references fail to render the claims obvious. That is, there is no rebuttal argument specifically addressing the obviousness rationale set forth in the last Office actions, wherein the same obviousness rationale as originally set forth in the Office action mailed on July 30, 2025 is included hereinabove.
Double Patenting - Nonstatutory
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.
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Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-45 of U.S. Patent No. 9,717,750 B2 in view of Bennett et al. (US 2016/0002627 A1, of record), Australian Assessment Report (August 2018, of record), and European Assessment Report (April 21, 2017, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘750 patent claims drawn to a method of treating SMA by an intrathecal injection of SEQ ID NO:1, which is also known as “nusinersen” as evidenced by the Australian Assessment Report (see Table 11 disclosing “ISIS 396443 (nusinersen)”) and the European Assessment Report (see page 12 disclosing “nusinersen (also cited as ISIS 396443)”). It would have been obvious to provide intrathecal bolus injections as the loading and maintenance doses when practicing the SMA treatment method of the ‘750 patent claims because such SMA treatment dosing regimen was known and taught in the art as evidenced by Bennett, the Australian Assessment Report, and the European Assessment Report. It would also have been obvious to practice dosing/dosing schedule optimizations for the intrathecal bolus injection of SEQ ID NO:1 of the ‘750 patent claims, thereby obtaining the instantly claimed doses and doing schedules as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated. That is, the method steps/materials including the administration methodologies using a spinal anesthesia needle for bolus injection and the doses/concentrations/dosing schedule recited in the instant claims are nothing but obvious as they were known or suggested or rendered obvious in view of Bennett, the Australian Assessment Report, and the European Assessment Report for the reasons stated in the §103 rejection above.
Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9,926,559 B2 in view of Bennett et al. (US 2016/0002627 A1, of record), Australian Assessment Report (August 2018, of record), and European Assessment Report (April 21, 2017, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘559 patent claims drawn to a method of treating SMA by a CSF/intrathecal administration of SEQ ID NO:1, which is also known as “nusinersen” as evidenced by the Australian Assessment Report (see Table 11 disclosing “ISIS 396443 (nusinersen)”) and the European Assessment Report (see page 12 disclosing “nusinersen (also cited as ISIS 396443)”). It would have been obvious to provide intrathecal bolus injections as the loading and maintenance doses when practicing the SMA treatment method of the ‘750 patent claims because such SMA treatment dosing regimen was known and taught in the art as evidenced by Bennett, the Australian Assessment Report, and the European Assessment Report. It would also have been obvious to practice dosing/dosing schedule optimizations for the intrathecal bolus injection of SEQ ID NO:1 of the ‘559 patent claims, thereby obtaining the instantly claimed doses and doing schedules as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated. That is, the method steps/materials including the administration methodologies using a spinal anesthesia needle for bolus injection and the doses/concentrations/dosing schedule recited in the instant claims are nothing but obvious as they were known or suggested or rendered obvious in view of Bennett, the Australian Assessment Report, and the European Assessment Report for the reasons stated in the §103 rejection above.
Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,436,802 B2 in view of Bennett et al. (US 2016/0002627 A1, of record), Australian Assessment Report (August 2018, of record), and European Assessment Report (April 21, 2017, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘802 patent claims drawn to a method of treating SMA by administering multiple intrathecal injections of SEQ ID NO:1, which is also known as “nusinersen” as evidenced by the Australian Assessment Report (see Table 11 disclosing “ISIS 396443 (nusinersen)”) and the European Assessment Report (see page 12 disclosing “nusinersen (also cited as ISIS 396443)”). It would have been obvious to provide intrathecal bolus injections as the loading and maintenance doses when practicing the SMA treatment method of the ‘750 patent claims because such SMA treatment dosing regimen was known and taught in the art as evidenced by Bennett, the Australian Assessment Report, and the European Assessment Report. It would also have been obvious to practice dosing/dosing schedule optimizations for the intrathecal bolus injection of SEQ ID NO:1 of the ‘802 patent claims, thereby obtaining the instantly claimed doses and doing schedules as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated. That is, the method steps/materials including the administration methodologies using a spinal anesthesia needle for bolus injection and the doses/concentrations/dosing schedule recited in the instant claims are nothing but obvious as they were known or suggested or rendered obvious in view of Bennett, the Australian Assessment Report, and the European Assessment Report for the reasons stated in the §103 rejection above.
Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,474,113 B2 in view of Bennett et al. (US 2016/0002627 A1, of record), Australian Assessment Report (August 2018, of record), and European Assessment Report (April 21, 2017, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘113 patent claims drawn to a method of treating SMA comprising administering “nusinersen or a nusinersen salt” or “nusinersen sodium”. Regarding the dosing regimen claimed in the instant case, it would have been obvious to provide intrathecal bolus injections as the loading and maintenance doses when practicing the SMA treatment method of the ‘113 patent claims because such SMA treatment dosing regimen was known and taught in the art as evidenced by Bennett, the Australian Assessment Report, and the European Assessment Report. It would also have been obvious to practice dosing/dosing schedule optimizations for the intrathecal bolus injection of nusinersen of the ‘113 patent claims, thereby obtaining the instantly claimed doses and doing schedules as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated. That is, the method steps/materials including the administration methodologies using a spinal anesthesia needle for bolus injection and the doses/concentrations/dosing schedule recited in the instant claims are nothing but obvious as they were known or suggested or rendered obvious in view of Bennett, the Australian Assessment Report, and the European Assessment Report for the reasons stated in the §103 rejection above.
Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12,013,403 B2 in view of Bennett et al. (US 2016/0002627 A1, of record), Australian Assessment Report (August 2018, of record), and European Assessment Report (April 21, 2017, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘403 patent claims drawn to a method of treating SMA by administering multiple intrathecal injections of SEQ ID NO:1, which is also known as “nusinersen” as evidenced by the Australian Assessment Report (see Table 11 disclosing “ISIS 396443 (nusinersen)”) and the European Assessment Report (see page 12 disclosing “nusinersen (also cited as ISIS 396443)”). It would have been obvious to provide intrathecal bolus injections as the loading and maintenance doses when practicing the SMA treatment method of the ‘750 patent claims because such SMA treatment dosing regimen was known and taught in the art as evidenced by Bennett, the Australian Assessment Report, and the European Assessment Report. It would also have been obvious to practice dosing/dosing schedule optimizations for the intrathecal bolus injection of SEQ ID NO:1 of the ‘403 patent claims, thereby obtaining the instantly claimed doses and doing schedules as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated. That is, the method steps/materials including the administration methodologies using a spinal anesthesia needle for bolus injection and the doses/concentrations/dosing schedule recited in the instant claims are nothing but obvious as they were known or suggested or rendered obvious in view of Bennett, the Australian Assessment Report, and the European Assessment Report for the reasons stated in the §103 rejection above.
Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 15-16, and 19-44 of Application No. 18/283,925 in view of Bennett et al. (US 2016/0002627 A1, of record), Australian Assessment Report (August 2018, of record), and European Assessment Report (April 21, 2017, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘925 claims drawn to a method that intrathecally injecting a chemically modified antisense oligonucleotide of SEQ ID NO:1 for the purpose of treating SMA in a subject, wherein SEQ ID NO:1 is also known as “nusinersen” as evidenced by the Australian Assessment Report (see Table 11 disclosing “ISIS 396443 (nusinersen)”) and the European Assessment Report (see page 12 disclosing “nusinersen (also cited as ISIS 396443)”). It would have been obvious to practice dosing/dosing schedule optimizations for the intrathecal bolus injection of SEQ ID NO:1 of the ‘925 claims, thereby obtaining the instantly claimed doses and doing schedules as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated. That is, the method steps/materials including the administration methodologies using a spinal anesthesia needle for bolus injection and the doses/concentrations/dosing schedule recited in the instant claims are nothing but obvious as they were known or suggested or rendered obvious in view of Bennett, the Australian Assessment Report, and the European Assessment Report for the reasons stated in the §103 rejection above.
Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 1-4, 6-7, 19-20, 24-33, 37, and 39-41 of Application No. 19/036,880 in view of Bennett et al. (US 2016/0002627 A1, of record), Australian Assessment Report (August 2018, of record), and European Assessment Report (April 21, 2017, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over and/or encompassed by the ‘880 claims drawn to a method of treating SMA in a human subject comprising administering “an antisense oligonucleotide (ASO), “wherein the ASO is nusinersen” at “20 mg per dose” or “12 mg per dose” that is “administered into the intrathecal space” or “intracisternal magna space of the subject.” It would also have been obvious to practice dosing/dosing schedule optimizations for the administration of “nusinersen” of the ‘880 claims, thereby obtaining the instantly claimed doses and doing schedules as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated. That is, the method steps/materials including the administration methodologies using a spinal anesthesia needle for bolus injection and the doses/concentrations/dosing schedule recited in the instant claims are nothing but obvious as they were known or suggested or rendered obvious in view of Bennett, the Australian Assessment Report, and the European Assessment Report for the reasons stated in the §103 rejection above.
Claims 1-2, 4-5, 15-22, 31-35, and 41-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 1-46 of Application No. 19/462,387 in view of Bennett et al. (US 2016/0002627 A1, of record), Australian Assessment Report (August 2018, of record), and European Assessment Report (April 21, 2017, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over and/or encompassed by the ‘387 claims drawn to a method of treating SMA in a human subject comprising administering “an SMA therapy”, which is defined to read on “SPINRAZA®, a compound containing nusinersen” as disclosed at page 14 of the ‘387 specification. It would also have been obvious to practice dosing/dosing schedule optimizations for the administration of the “SMA therapy” that is “SPINRAZA®” of the ‘387 claims, thereby obtaining the instantly claimed doses and doing schedules as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated. That is, the method steps/materials including the administration methodologies using a spinal anesthesia needle for bolus injection and the doses/concentrations/dosing schedule recited in the instant claims are nothing but obvious as they were known or suggested or rendered obvious in view of Bennett, the Australian Assessment Report, and the European Assessment Report for the reasons stated in the §103 rejection above.
Response to Arguments
Applicant's arguments filed on June 5, 2026 have been fully considered but they are not persuasive. Applicant argues that the reference claims in the reference patents/applications do not teach the instantly claimed method. In response, it is noted that the all NSDP rejections set forth in the instant Office action are obviousness-type, wherein the claimed dosing regimen that is not expressly claimed in the reference claims is rendered obvious in view of the teachings of Bennett, the Australian Assessment Report, and the European Assessment Report. Hence, the mere fact that the reference claims do not claim the instantly claimed dosing regimen is not sufficient to show that the instant claims are not obvious over the reference claims.
Applicant argues none of Bennett, the Australian Assessment Report, and the European Assessment Report individually or in combination teaches the dosing regimen “features” recited in the instant claims. In response, it is noted that applicant did not provide any substantial rebuttal arguments as to why the cited references in combination fail to render obvious the instantly claimed dosing regimen, which can be readily incorporated into the reference claims, thereby rendering the instant claims patentably indistinct from the reference claims. Accordingly, applicant’s arguments are not found persuasive.
Conclusion
No claim is allowed.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
Prosecution Insights