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 .
Claims Status
Claims 1-24 are canceled.
Claims 25-48 are new.
Applicant’s election without traverse of the following species in the reply filed on 02/20/2026 is acknowledged: Type 2 SMA for the type of later-onset spinal muscular atrophy (SMA), 10 mg/kg for the dosage of apitegromab, and nusinersen for the SMN upregulation therapy.
Claims 38 and 40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/20/2026.
Therefore, claims 25-37, 39, and 41-48 are under examination.
Priority
The instant application is a 371 of PCT/US2021/056517 and claims priority to provisional application 63/105,850, 63/106,172, 63/200,955, 63/201,157, 63/202,317, 63/202,372, 63/202,900, 63/260,725, and 63/261,398. Priority is given with the earliest effective filing date of 10/26/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/25/2023, 11/20/2023, 01/17/2025, and 02/20/2026 are in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement is being considered by the examiner.
The NPL references lined through on the 11/20/2023 IDS (i.e. Cite No. 206) and on the 1/17/2025 IDS (i.e. Cite No. 222) were not considered because they were not attached. The NPL references lines through on the 02/20/2026 IDS (i.e. Cite Nos. 10 and 41) were not considered because they were not of sufficient quality and therefore could not be read.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Rejections - 35 USC § 112(b)
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 44-48 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.
Claim 44 recites the limitation “(e.g., 550-2400 ng/ml)” and claim 46 recites the limitation “(e.g., greater than 1.5 ng/ml, greater than 2 ng/ml, greater than 2.5 ng/ml, or greater than 3 ng/ml). First, MPEP 2173.05(d) states, “Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.” The “e.g.” should be removed entirely. Second, the range in claim 44 and amounts in claim 46 are referenced parenthetically. It is unclear due to the presence of the parentheses if the range/amounts are intended as limitations of the claims, or are merely exemplary. Therefore, the scope of this claim is indefinite.
Claims 45 and 47-48, which depend from claims 44 and 46, respectively, are therefore indefinite for the same reasons set forth above.
Claim Rejections - 35 USC § 112(a)
Enablement
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 44-48 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.
Factors to be considered in determining whether undue experimentation is required, are set forth in In re Wands 8 USPQ2d 1400. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the
presence or absence of working examples, (4) the nature of the invention, (5) the state
of the prior art, (6) the relative skill of those in the art, (7) the predictability or
unpredictability of the art and (8) the breadth of the claims.
(4) The nature of the invention and (8) The breadth of the claims:
Regarding claims 44-48, the nature of the invention is a method of treating SMA in a human subject in need thereof, comprising administering apitegromab in an amount sufficient to: (a) achieve a serum concentration of latent myostatin in the human subject of at least 250 ng/ml (e.g., 550-2400 ng/ml) at steady state after the administration of apitegromab; and/or (b) achieve a serum concentration of apitegromab in the human subject of at least 50 ug/ml at steady state after the administration of apitegromab. Therefore, the nature of the invention is a chemical case, where there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; see MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to use the claimed product, with a reasonable expectation of success, because it would not be predictable from the disclosure of any one particular species what other species may or may not work; see MPEP 2164.03.
The claims broadly encompass administration of any amount of apitegromab as long as it results in (a) achieves a serum concentration of latent myostatin in the human subject of at least 250 ng/ml (e.g., 550-2400 ng/ml) at steady state after the administration of apitegromab; and/or (b) achieves a serum concentration of apitegromab in the human subject of at least 50 ug/ml at steady state after the administration of apitegromab. Thus, there would be undue experimentation to determine at which doses of apitegromab would in result in (a) and/or (b).
(6) The amount of direction or guidance provided by the inventor; (7) The
existence of working examples:
The specification teaches administering 20 mg/kg apitegromab to achieve a serum concertation (Ctrough) of at least 110 ug/mL [see paragraphs 310, 318, 325 of the instant specification] and a serum concentration (Cmax) of at least 300 ug/mL [see paragraphs 311, 317, 324 of the instant specification].
However, while the specification provides this as an exemplary dose of apitegromab correlated to serum concentration of apitegromab by Ctrough and Cmax, Applicant has not provided any guidance as to what specific doses of apitegromab when administered (a) achieve a serum concentration of latent myostatin in the human subject of at least 250 ng/ml (e.g., 550-2400 ng/ml) at steady state after the administration of apitegromab; and/or (b) achieve a serum concentration of apitegromab in the human subject of at least 50 ug/ml at steady state after the administration of apitegromab. Thus, support is not provided for the breadth of the claims.
In conclusion, the claimed invention does not provide enablement for treating SMA in a human subject in need thereof, comprising administering apitegromab in an amount sufficient to: (a) achieve a serum concentration of latent myostatin in the human subject of at least 250 ng/ml (e.g., 550-2400 ng/ml) at steady state after the administration of apitegromab; and/or (b) achieve a serum concentration of apitegromab in the human subject of at least 50 ug/ml at steady state after the administration of apitegromab as encompassed by the instant claims. Thus, for reasons outlined above, the specification is not considered to be enabling for one skilled in the art to use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims and the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claims 45-48, which depend from claim 44, are therefore rejected for the same reasons set forth above.
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 25-28, 30-31, 39, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over CureSMA, 2019 (instant PTO-892).
Regarding claims 25, 30, and 39, CureSMA teaches SRK-015, a highly specific inhibitor of myostatin activation demonstrated robust and sustained target engagement in humans in a Phase 1 study [page 1, first paragraph], and teaches that in the Phase 1 study, SRK-015 was intravenously administered to adult (human) healthy volunteers to inform dosing for the Phase 2 trial [page 1, second paragraph] at doses of 10, 20, and 30 mg/kg [page 2, first paragraph] and concluded that SRK-015 was well tolerated with no dose-limiting toxicities up to 30 mg/kg [page 2, second paragraph]. CureSMA further teaches a Phase 2 (TOPAZ) Trial Overview, which will assess the safety and efficacy of SRK-015 in patients with Type 2 and Type 3 spinal muscular atrophy (SMA) where patients will receive SRK-015 dosed once every four weeks (Q4W) [page 2, fourth paragraph] for at least 6 months of treatment exposure up to a full 12-month (52 weeks) treatment period [page 2, fifth paragraph].
Note: Applicant defines apitegromab as also being known as SRK-015 [see paragraph 10 of the instant specification] and that apitegromab is a myostatin inhibitor [see paragraph 33 of the instant specification]. Therefore, the SRK-015 of CureSMA is the same as the apitegromab as claimed.
However, CureSMA does not teach the limitations in a manner as required by 35 U.S.C. 102.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have intravenously administered apitegromab (i.e. SRK-015) in an amount of 10 mg/kg (as claimed in instant claim 39) at an interval of once every four weeks or once a month for at least 24 weeks or six months in order to treat SMA in a human subject in need thereof. One would have been motivated to have picked among the various doses and arrived at 10 mg/kg because CureSMA teaches administering SRK-015 at a dose of 10 mg/kg and that this was a well-tolerated dose.
MPEP 2144.05 (I) states “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facia case of obviousness exists.” It further would have been obvious to one of ordinary skill in the art because the dose of the apitegromab is recognized as a variable in the art and therefore would engage in routine optimization.
Claims 26-28 and 31 are included in this rejection because they merely recite effects or results of administering the apitegromab. Because it would have been obvious to have administered the apitegromab at a dose of greater than 2 mg/kg but no more than 20 mg/kg (i.e. 10 mg/kg) as described above, a person of ordinary skill in the art would have reasonably expected these effects to occur, absent evidence to the contrary.
Claim 42 is included in this rejection because CureSMA teaches that patients will receive SRK-015 dosed in conjunction with an approved SMN upregulating therapy [page 2, fourth paragraph].
Claims 25-31, 39, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over CureSMA, 2019 (instant PTO-892), as applied to claims 25-28, 30-31, 39, and 42 above, in view of Mercuri et al., 2017 (instant PTO-892).
The teachings of CureSMA are above. Additionally, CureSMA teaches that a primary efficacy endpoint will measure motor function through clinically meaningful outcome measure validating in SMA such as the HFMSE [page 2, fourth paragraph].
However, CureSMA does not specifically teach that the motor function is measured by a Hammersmith Functional Motor Scale Expanded score (HFMSE) at 6 months after the start of treatment relative to HFMSE at baseline.
Regarding claim 29, Mercuri teaches that clinical assessment in SMA include different means of assessments of strength and range of joint motion, relevant motor functional scales and timed tests to monitor those aspects of function that reflect activities of daily living, referencing Table 1, and that these assessments should be performed routinely by trained examiners every 6 months [page 106, right column, second-third paragraph]. Table 1 of Mercuri teaches HFMSE is a functional scale of assessment [see page 107; Table 1].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have measured motor function by a Hammersmith Functional Motor Scale Expanded score (HFMSE), as taught by CureSMA, at 6 months after the start of treatment relative to HFMSE at baseline, as taught by Mercuri. One would have been motivated to have measured motor function by a HFMSE at 6 months after the start of treatment relative to HFMSE at baseline because CureSMA teaches that a primary efficacy endpoint will measure motor function through clinically meaningful outcome measure validating in SMA such as the HFMSE and Mercuri teaches that clinical assessment of SMA, such as the HFMSE, should be performed routinely by trained examiners every 6 months. Additionally, one of skill in the art would want to perform this assessment after 6 months after the start of treatment relative to baseline in order to evaluate how well the treatment is working and how well the patient is responding to the treatment.
Claims 25-28, 30-37, 39, and 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over CureSMA, 2019 (instant PTO-892), as applied to claims 25-28, 30-31, 39, and 42 above, in view of NCT03921528, 2019 (instant PTO-892).
The teachings of CureSMA are above.
However, CureSMA does not specifically teach that the human subject is 2-5 years of age, as set forth in instant claims 32-35, that the SMA is later-onset SMA, as set forth in instant claim 36, that the later-onset SMA is Type 2 SMA, as set forth in instant claim 37, or that the SMN upregulation therapy comprises nusinersen, as set forth in instant claim 43.
Regarding claims 32-37 and 43, NCT03921528 teaches administering SRK-015 intravenously every 4 weeks to patients with Type 2 SMA/Non-Ambulatory Type 3 SMA [page 11, Arms and Interventions section]. NCT03921528 also teaches that eligibility criteria includes a minimum age of 2 years and a maximum age of 21 years [page 12, Eligibility section]. NCT03921528 further teaches that SMA must be later-onset and that patients can be on a SMN upregulator therapy, that the SMN upregulator therapy can be nusinersen, and the patient must be anticipated to remain on the therapy throughout the duration of the study [page 13, Eligibility section].
Note: Applicant defines apitegromab as also being known as SRK-015 [see paragraph 10 of the instant specification] and that apitegromab is a myostatin inhibitor [see paragraph 33 of the instant specification]. Therefore, the SRK-015 of NCT03921528 is the same as the SRK-015 of CureSMA and the apitegromab as claimed.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the apitegromab (i.e. SRK-015) of CureSMA to the patient population of later-onset Type 2 SMA/Non-Ambulatory Type 3 SMA patients aged 2-21 on an SMN regulator therapy of nusinersen of NCT03921528. One would have been motivated to have administered the apitegromab (i.e. SRK-015) of CureSMA to the specific patient population of NCT03921528 because NCT03921528 teaches administering SRK-015 intravenously every 4 weeks to patients with Type 2 SMA/Non-Ambulatory Type 3 SMA, that the patients must be a minimum age of 2 years and a maximum age of 21 years, that SMA must be later-onset and can be on an SMN upregulator therapy, which can be nusinersen. MPEP 2144.05 (I) states “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facia case of obviousness exists.” Thus, this is a known patient population in the art to administer apitegromab (i.e. SRK-015) to in order to treat the SMA in the subjects in need thereof, and therefore, there would be a reasonable expectation of success.
Claims 25-28, 30-31, 39, and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over CureSMA, 2019 (instant PTO-892), as applied to claims 25-28, 30-31, 39, and 42 above, in view of Prior et al., 2009 (instant PTO-892).
The teachings of CureSMA are above.
However, CureSMA does not specifically teach that the human subject has an SMN1 mutation and at least two copies of the SMN2 gene.
Regarding claim 41, Prior teaches that the SMN1 gene is the SMA-determining gene, with the gene being absent (i.e. mutated) in about 95% of affected patients [page 408, left column, second paragraph]. Prior further teaches that the SMN2 copy number modifies the severity of the disease, with most patients that have type II SMA having three SMN2 copies and most patients with type III SMA having three or four SMN2 copies [page 408, right column, first paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically treated a human subject that has an SMN1 mutation and at least two copies of the SMN2 gene, as taught by Prior, with the method of treating SMA, as taught by CureSMA. One would have been motivated to have treated a human subject that has an SMN1 mutation and at least two copies of the SMN2 gene with the method of treating SMA of CureSMA because Prior teaches that the SMN1 gene is the SMA-determining gene, with the gene being absent (i.e. mutated) in about 95% of affected patients and that most patients that have type II SMA have three SMN2 copies and most patients with type III SMA have three or four SMN2 copies. There would be a reasonable expectation of success in treating this patient population having SMA with the method of CureSMA because CureSMA teaches a method of treating Type 2 and Type 3 SMA.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 10,751,413 (‘413)
Claims 25-28, 30-31, 39, and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7-10 of U.S. Patent No. 10,751,413 (‘413) in view of CureSMA, 2019 (instant PTO-892).
Regarding claims 25, 30, and 39, claim 1 of ‘413 teaches an isolated antibody that specifically binds pro/latent myostatin, comprising a heavy chain comprising an amino acid sequence of SEQ ID NO:50 and a light chain comprising an amino acid sequence of SEQ ID NO:51, claim 7 of ‘413 teaches a method of treating a subject having, or at risk of developing, a myopathy, muscle atrophy, and/or metabolic disorder, the method comprising administering to the subject the antibody of claim 1 in an amount effective to treat the myopathy, muscle atrophy, and/or metabolic disorder, claim 8 of ‘413 teaches the method of claim 7, wherein the antibody is administered in an amount effective to increase muscle mass, enhance force generation, and/or prevent muscle loss in the subject, and claim 9 of ‘413 teaches the method of claim 7, wherein the amount is between about 0.3 and 30 mg/kg per dose, and claim 10 teaches the method of claim 7, wherein the method comprises intravenous administration or subcutaneous administration.
Note: Applicant defines apitegromab as comprising a heavy chain amino acid sequence of SEQ ID NO: 15 and a light chain amino acid sequence of SEQ ID NO: 16 [see paragraph 66 of the instant specification]. SEQ ID NOs: 50 and 51 of ‘413 have 100% sequence identity to SEQ ID NOs: 15 and 16 of the instant application. Thus, the antibody of ‘413 is the same as the apitegromab as claimed.
However, ‘613 does not specifically teach a method of treating spinal muscular atrophy (SMA) in a human subject in need thereof, comprising intravenously administering apitegromab in an amount greater than 2 mg/kg and no more than 20 mg/kg at an interval of once every four weeks or once a month for at least 24 weeks or six months.
CureSMA teaches SRK-015, a highly specific inhibitor of myostatin activation demonstrated robust and sustained target engagement in humans in a Phase 1 study [page 1, first paragraph], and teaches that in the Phase 1 study, SRK-015 was intravenously administered to adult (human) healthy volunteers to inform dosing for the Phase 2 trial [page 1, second paragraph] at doses of 10, 20, and 30 mg/kg [page 2, first paragraph] and concluded that SRK-015 was well tolerated with no dose-limiting toxicities up to 30 mg/kg [page 2, second paragraph]. CureSMA further teaches a Phase 2 (TOPAZ)Trial Overview, which will assess the safety and efficacy of SRK-015 in patients with Type 2 and Type 3 spinal muscular atrophy (SMA) where patients will receive SRK-015 dosed once every four weeks (Q4W) [page 2, fourth paragraph] for at least 6 months of treatment exposure up to a full 12-month (52 weeks) treatment period [page 2, fifth paragraph].
Note: Applicant defines apitegromab as also being known as SRK-015 [see paragraph 10 of the instant specification] and that apitegromab is a myostatin inhibitor [see paragraph 33 of the instant specification]. Therefore, the SRK-015 of CureSMA is the same as the apitegromab as claimed.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have intravenously administered apitegromab (i.e. the isolated antibody of claim 1 in ‘413), as taught by ‘413, in an amount of 10 mg/kg (as claimed in instant claim 39) at an interval of once every four weeks or once a month for at least 24 weeks or six months in order to treat SMA in a human subject in need thereof, as taught by CureSMA. One would have been motivated to have used the apitegromab of ‘413 in the method of treating SMA as taught by CureSMA with a reasonable expectation of success because CureSMA teaches administering SRK-015 (apitegromab) in patients with Type 2 and Type 3 spinal muscular atrophy (SMA) once every four weeks (Q4W) for at least 6 months of treatment exposure up to a full 12-month (52 weeks) treatment period. It is prima facie obvious to substitute equivalents known for the same purpose (see MPEP 2144.06 (II)). Further, it would have been obvious to one of ordinary skill in the art to have picked among the various doses and arrived at 10 mg/kg because ‘413 teaches that the apitegromab can be administered at a dose of about 0.3 and 30 mg/kg and CureSMA teaches administering SRK-015 at a dose of 10 mg/kg and that this was a well-tolerated dose. MPEP 2144.05 (I) states “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facia case of obviousness exists.” It additionally would have been obvious to one of ordinary skill in the art because the dose of the apitegromab is recognized as a variable in the art and therefore would engage in routine optimization.
Claims 26-28 and 31 are included in this rejection because they merely recite effects or results of administering the apitegromab. Because it would have been obvious to have administered the apitegromab at of dose of greater than 2 mg/kg but no more than 20 mg/kg as described above, a person of ordinary skill in the art would have reasonably expected these effects to occur, absent evidence to the contrary.
Claim 42 is included in this rejection because CureSMA teaches that patients will receive SRK-015 dosed in conjunction with an approved SMN upregulating therapy [page 2, fourth paragraph].
Claims 25-31, 39, and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7-10 of U.S. Patent No. 10,751,413 (‘413) in view of CureSMA, 2019 (instant PTO-892), as applied to claims 25-28, 30-31, 39, and 42 above, in view of Mercuri et al., 2017 (instant PTO-892).
The teachings of ‘413 and CureSMA are above. Additionally, CureSMA teaches that a primary efficacy endpoint will measure motor function through clinically meaningful outcome measure validating in SMA such as the HFMSE [page 2, fourth paragraph].
However, ‘413 and CureSMA do not specifically teach that the motor function is measured by a Hammersmith Functional Motor Scale Expanded score (HFMSE) at 6 months after the start of treatment relative to HFMSE at baseline.
Regarding claim 29, Mercuri teaches that clinical assessment in SMA include different means of assessments of strength and range of joint motion, relevant motor functional scales and timed tests to monitor those aspects of function that reflect activities of daily living, referencing Table 1, and that these assessments should be performed routinely by trained examiners every 6 months [page 106, right column, second-third paragraph]. Table 1 of Mercuri teaches HFMSE is a functional scale of assessment [see page 107; Table 1].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have measured motor function by a Hammersmith Functional Motor Scale Expanded score (HFMSE), as taught by CureSMA, at 6 months after the start of treatment relative to HFMSE at baseline, as taught by Mercuri. One would have been motivated to have measured motor function by a HFMSE at 6 months after the start of treatment relative to HFMSE at baseline because CureSMA teaches that a primary efficacy endpoint will measure motor function through clinically meaningful outcome measure validating in SMA such as the HFMSE and Mercuri teaches that clinical assessment of SMA, such as the HFMSE, should be performed routinely by trained examiners every 6 months. Additionally, one of skill in the art would want to perform this assessment after 6 months after the start of treatment relative to baseline in order to evaluate how well the treatment is working and how well the patient is responding to the treatment.
Claims 25-28, 30-37, 39, and 42-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7-10 of U.S. Patent No. 10,751,413 (‘413) in view of CureSMA, 2019 (instant PTO-892), as applied to claims 25-28, 30-31, 39, and 42 above, in view of NCT03921528, 2019 (instant PTO-892).
The teachings of ‘413 and CureSMA are above.
However, ‘413 and CureSMA do not specifically teach that the human subject is 2-5 years of age, as set forth in instant claims 32-35, that the SMA is later-onset SMA, as set forth in instant claim 36, that the later-onset SMA is Type 2 SMA, as set forth in instant claim 37, or that the SMN upregulation therapy comprises nusinersen, as set forth in instant claim 43.
Regarding claims 32-37 and 43, NCT03921528 teaches administering SRK-015 intravenously every 4 weeks to patients with Type 2 SMA/Non-Ambulatory Type 3 SMA [page 11, Arms and Interventions section]. NCT03921528 also teaches that eligibility criteria includes a minimum age of 2 years and a maximum age of 21 years [page 12, Eligibility section]. NCT03921528 further teaches that SMA must be later-onset and that patients can be on a SMN upregulator therapy, that the SMN upregulator therapy can be nusinersen, and the patient must be anticipated to remain on the therapy throughout the duration of the study [page 13, Eligibility section].
Note: Applicant defines apitegromab as also being known as SRK-015 [see paragraph 10 of the instant specification] and that apitegromab is a myostatin inhibitor [see paragraph 33 of the instant specification]. Therefore, the SRK-015 of NCT03921528 is the same as the antibody of ‘413, the SRK-015 of CureSMA, and the apitegromab as claimed.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the apitegromab (i.e. SRK-015) of ‘413 and CureSMA to the patient population of later-onset Type 2 SMA/Non-Ambulatory Type 3 SMA patients aged 2-21 on an SMN regulator therapy of nusinersen of NCT03921528. One would have been motivated to have administered the apitegromab (i.e. SRK-015) of ‘413 and CureSMA to the specific patient population of NCT03921528 because NCT03921528 teaches administering SRK-015 intravenously every 4 weeks to patients with Type 2 SMA/Non-Ambulatory Type 3 SMA, that the patients must be a minimum age of 2 years and a maximum age of 21 years, that SMA must be later-onset and can be on an SMN upregulator therapy, which can be nusinersen. MPEP 2144.05 (I) states “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facia case of obviousness exists.” Thus, this is a known patient population in the art to administer apitegromab (i.e. SRK-015) to in order to treat the SMA in the subjects in need thereof, and therefore, there would be a reasonable expectation of success.
Claims 25-28, 30-31, 39, and 41-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7-10 of U.S. Patent No. 10,751,413 (‘413) in view of CureSMA, 2019 (instant PTO-892), as applied to claims 25-28, 30-31, 39, and 42 above, in view of Prior et al., 2009 (instant PTO-892).
The teachings of ‘413 and CureSMA are above.
However, ‘413 and CureSMA do not specifically teach that the human subject has an SMN1 mutation and at least two copies of the SMN2 gene.
Regarding claim 41, Prior teaches that the SMN1 gene is the SMA-determining gene, with the gene being absent (i.e. mutated) in about 95% of affected patients [page 408, left column, second paragraph]. Prior further teaches that the SMN2 copy number modifies the severity of the disease, with most patients that have type II SMA having three SMN2 copies and most patients with type III SMA having three or four SMN2 copies [page 408, right column, first paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically treated a human subject that has an SMN1 mutation and at least two copies of the SMN2 gene, as taught by Prior, with the method of treating SMA, as taught by ‘413 and CureSMA. One would have been motivated to have treated a human subject that has an SMN1 mutation and at least two copies of the SMN2 gene with the method of treating SMA of ‘413 and CureSMA because Prior teaches that the SMN1 gene is the SMA-determining gene, with the gene being absent (i.e. mutated) in about 95% of affected patients and that most patients that have type II SMA have three SMN2 copies and most patients with type III SMA have three or four SMN2 copies. There would be a reasonable expectation of success in treating this patient population having SMA with the method of ‘413 and CureSMA because CureSMA teaches a method of treating Type 2 and Type 3 SMA.
Copending Application No. 18/862,079
Claims 25-28, 30-35, 39, and 42-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22, 28-30, and 47-48 of copending Application No. 18/862,079 (reference application) in view of CureSMA, 2019 (instant PTO-892).
Regarding claims 25, 30, 39, and 42, claim 22 of the reference application teaches a method of treating spinal muscular atrophy (SMA) in a subject who receives a survival motor neuron (SMN) therapy, comprising administering an effective amount of apitegromab to a subject, wherein the subject suffers from fatigue, impaired bulbar function, and/or impaired emptying, and claim 48 teaches the method of claim 22, wherein apitegromab is administered at 10 mg/kg.
However, the reference application does not specifically teach that the apitegromab is administered intravenously at an interval of once every 4 weeks or once a month for at least 24 weeks or six months to a human subject.
CureSMA teaches SRK-015, a highly specific inhibitor of myostatin activation demonstrated robust and sustained target engagement in humans in a Phase 1 study [page 1, first paragraph], and teaches that in the Phase 1 study, SRK-015 was intravenously administered to adult (human) healthy volunteers to inform dosing for the Phase 2 trial [page 1, second paragraph] at doses of 10, 20, and 30 mg/kg [page 2, first paragraph] and concluded that SRK-015 was well tolerated with no dose-limiting toxicities up to 30 mg/kg [page 2, second paragraph]. CureSMA further teaches a Phase 2 (TOPAZ) Trial Overview, which will assess the safety and efficacy of SRK-015 in patients with Type 2 and Type 3 spinal muscular atrophy (SMA) where patients will receive SRK-015 dosed once every four weeks (Q4W) [page 2, fourth paragraph] for at least 6 months of treatment exposure up to a full 12-month (52 weeks) treatment period [page 2, fifth paragraph]. CureSMA also teaches that patients will receive SRK-015 dosed in conjunction with an approved SMN upregulating therapy [page 2, fourth paragraph].
Note: Applicant defines apitegromab as also being known as SRK-015 [see paragraph 10 of the instant specification] and that apitegromab is a myostatin inhibitor [see paragraph 33 of the instant specification]. Therefore, the SRK-015 of CureSMA is the same as the apitegromab as claimed and the apitegromab of the reference application.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have the apitegromab at a dose of 10 mg/kg, as taught by the reference application, intravenously and at an interval of once every four weeks or once a month for at least 24 weeks or six months in order to treat SMA in a human subject in need thereof, as taught by CureSMA. One would have been motivated to have administered the 10 mg/kg apitegromab of the reference application intravenously and at an interval of once every four weeks or once a month for at least 24 weeks or six months in order to treat SMA in a human subject in need thereof because CureSMA teaches intravenously administering SRK-015 (i.e. apitegromab) in human patients with Type 2 and Type 3 spinal muscular atrophy (SMA) once every four weeks (Q4W) for at least 6 months of treatment exposure up to a full 12-month (52 weeks) treatment period. Thus, this is a known treatment schedule in the art for SMA, and therefore would have a reasonable expectation of success.
Claims 26-28 and 31 are included in this rejection because they merely recite effects or results of administering the apitegromab. Because it would have been obvious to have administered the apitegromab at a dose of greater than 2 mg/kg but no more than 20 mg/kg (i.e. 10 mg/kg) as described above, a person of ordinary skill in the art would have reasonably expected these effects to occur, absent evidence to the contrary.
Claims 32-35 are included in this rejection because claim 28 of the reference application teaches the method of claim 22, wherein: d) the subject is 2 years of age or older, claim 29 of the reference application teaches the method of claim 28, wherein the subject is 2-12 years of age, and claim 30 teaches the method of claim 28, wherein the subject is 2-21 years of age. MPEP 2144.05 (I) states “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facia case of obviousness exists.”
Claim 43 is included in this rejection because claim 47 of the reference application teaches the method of claim 22, wherein the SMN therapy comprises nusinersen or risdiplam.
This is a provisional nonstatutory double patenting rejection.
Claims 25-35, 39, and 42-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22, 28-30, and 47-48 of copending Application No. 18/862,079 (reference application) in view of CureSMA, 2019 (instant PTO-892), as applied to claims 25-28, 30-35, 39, and 42-43 above, and further in view of Mercuri et al., 2017 (instant PTO-892).
The teachings of the reference application and CureSMA are above. Additionally, CureSMA teaches that a primary efficacy endpoint will measure motor function through clinically meaningful outcome measure validating in SMA such as the HFMSE [page 2, fourth paragraph].
However, CureSMA and the reference application do not specifically teach that the motor function is measured by a Hammersmith Functional Motor Scale Expanded score (HFMSE) at 6 months after the start of treatment relative to HFMSE at baseline.
Regarding claim 29, Mercuri teaches that clinical assessment in SMA include different means of assessments of strength and range of joint motion, relevant motor functional scales and timed tests to monitor those aspects of function that reflect activities of daily living, referencing Table 1, and that these assessments should be performed routinely by trained examiners every 6 months [page 106, right column, second-third paragraph]. Table 1 of Mercuri teaches HFMSE is a functional scale of assessment [see page 107; Table 1].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have measured motor function by a Hammersmith Functional Motor Scale Expanded score (HFMSE), as taught by CureSMA, at 6 months after the start of treatment relative to HFMSE at baseline, as taught by Mercuri. One would have been motivated to have measured motor function by a HFMSE at 6 months after the start of treatment relative to HFMSE at baseline because CureSMA teaches that a primary efficacy endpoint will measure motor function through clinically meaningful outcome measure validating in SMA such as the HFMSE and Mercuri teaches that clinical assessment of SMA, such as the HFMSE, should be performed routinely by trained examiners every 6 months. Additionally, one of skill in the art would want to perform this assessment after 6 months after the stat of treatment relative to baseline in order to evaluate how well the treatment is working and how well the patient is responding to the treatment.
This is a provisional nonstatutory double patenting rejection.
Claims 25-28, 30-37, 39, and 42-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22, 28-30, and 47-48 of copending Application No. 18/862,079 (reference application) in view of CureSMA, 2019 (instant PTO-892), as applied to claims 25-28, 30-35, 39, and 42-43 above, and further in view of NCT03921528, 2019 (instant PTO-892).
The teachings of the reference application and CureSMA are above.
However, the reference application and CureSMA do not specifically teach that the SMA is later-onset SMA, as set forth in instant claim 36, or that the later-onset SMA is Type 2 SMA, as set forth in instant claim 37.
Regarding claims 36 and 37, NCT03921528 teaches administering SRK-015 intravenously every 4 weeks to patients with Type 2 SMA/Non-Ambulatory Type 3 SMA [page 11, Arms and Interventions section]. NCT03921528 also teaches that SMA must be later-onset [page 13, Eligibility section].
Note: Applicant defines apitegromab as also being known as SRK-015 [see paragraph 10 of the instant specification] and that apitegromab is a myostatin inhibitor [see paragraph 33 of the instant specification]. Therefore, the SRK-015 of NCT03921528 is the same as the SRK-015 of CureSMA and the apitegromab of the reference application and as claimed.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the apitegromab (i.e. SRK-015) of the reference application and CureSMA to the patient population of later-onset Type 2 SMA/Non-Ambulatory Type 3 SMA patients of NCT03921528. One would have been motivated to have administered the apitegromab (i.e. SRK-015) of the reference application and CureSMA to the specific patient population of NCT03921528 because NCT03921528 teaches administering SRK-015 intravenously every 4 weeks to patients with Type 2 SMA/Non-Ambulatory Type 3 SMA. Thus, this is a known patient population in the art to administer apitegromab (i.e. SRK-015) to in order to treat the SMA in the subjects in need thereof, and therefore, there would be a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 25-28, 30-35, 39, and 41-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22, 28-30, and 47-48 of copending Application No. 18/862,079 (reference application) in view of CureSMA, 2019 (instant PTO-892), as applied to claims 25-28, 30-35, 39, and 42-43 above, and further in view of Prior et al., 2009 (instant PTO-892).
The teachings of the reference application and CureSMA are above. Further, claim 28 of the reference application teaches that the subject has a) type 2 SMA or type 3 SMA, and/or b) 2-5 copies of the SMN2 gene.
However, the reference application and CureSMA does not specifically teach that the human subject has an SMN1 mutation and at least two copies of the SMN2 gene.
Regarding claim 41, Prior teaches that the SMN1 gene is the SMA-determining gene, with the gene being absent (i.e. mutated) in about 95% of affected patients [page 408, left column, second paragraph]. Prior further teaches that the SMN2 copy number modifies the severity of the disease, with most patients that have type II SMA having three SMN2 copies and most patients with type III SMA having three or four SMN2 copies [page 408, right column, first paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically treated a human subject that has an SMN1 mutation and at least two copies of the SMN2 gene, as taught by Prior, with the method of treating SMA, as taught by the reference application and CureSMA. One would have been motivated to have treated a human subject that has an SMN1 mutation and at least two copies of the SMN2 gene with the method of treating SMA of the reference application and CureSMA because claim 28 of the reference application teaches that the subject has 2-5 copies of the SMN2 gene and Prior teaches that the SMN1 gene is the SMA-determining gene, with the gene being absent (i.e. mutated) in about 95% of affected patients and that most patients that have type II SMA have three SMN2 copies and most patients with type III SMA have three or four SMN2 copies. There would be a reasonable expectation of success in treating this patient population having SMA with the method of the reference application and CureSMA because both teach a method of treating Type 2 and Type 3 SMA.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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