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 .
The preliminary amendments are received.
Claims 4-10, 14-19, 24-31, 33-36, 39-42, 44-47, 49, 53-66, 68-70 and 72-75 are canceled by Applicant.
Claims 1-3, 11-13, 20-23 ,32, 37-38, 43, 48 50-52, 67 and 71 are pending in this application and are being examined.
Claim Rejection - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 3 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.
In claim 2 the Markush group “one or more motor functions, cognitive, adaptive, and/or executive functions” is indefinite because the Markush grouping is not a closed group of alternatives.
Suggestion to obviate the rejection: for example, in claim 2, line 3, after motor functions, insert “are selected from the group consisting of--, and replace “and/or” with –or--.
In claim 3 the Markush group “the one or more motor functions comprise gross motor function” is indefinite because the Markush grouping is not a closed group of alternatives.
Suggestion to obviate the rejection: replace the phrase with – the motor functions are gross motor functions--.
Claim Rejection - 35 USC §103
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.
A)
Claims 1-3, 11-13, 32, 67 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Salamat-Miller et al. (WO 2011/163650, which is also cited in IDS filed on 12/17/2024) in view of Dali et al. (Ann Clin Transl Neurol. 2015 May;2(5):518-33).
Regarding claim 1, Salamat-Miller et al. teach a method of treating metachromatic leukodystrophy (MLD) Syndrome comprising a step of administering directly to the cerebrospinal fluid (CSF) of to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of at or greater than 100 mg and an administration interval for a treatment period of at least 12 months or more to stabilize or reduce brain lesion involvement relative to baseline (MLD mice treated with recombinant hASA, intrathecal injection of recombinant hASA, doses 520 mg/kg brain weight demonstrated reduction of sulfatide accumulation in the CSF, and dose 250 mg/Kg and treatment period for a year or more) (See for example, p. 2 [0006], p. 3 paragraphs [0010]-[0011], p. 8 paragraph [0031], p. 10 paragraph [0052], p. 55 paragraph [0218], p. 56 paragraph [0219]-Continued, and p. 127 paragraph [0384]).
Regarding claim 1, although Salamat-Miller et al. do not teach 24 months, however Salamat-Miller et al. teach the treatment interval is at least 6 months (a year or more) (See for example, p. 8 paragraph [0031]) and intrathecal administration are performed … one a week, every other week, monthly, etc. (See for example, p. 8 paragraphs [0030]- [0031]). Therefore, a person of ordinary skill in the art before the effective filing dated of the invention would have been capable of optimizing the treatment period based on the severity of the condition and subject being treated. Because Salamat-Miller et al. teach the treatment interval is at least 6 months and the intrathecal administration are performed … one a week, every other week, monthly.
Regarding claim 2, Salamat-Miller et al. teach the administering of the recombinant ASA enzyme further results in improvement, stabilization or reduction in decline of one or more motor functions, cognitive, adaptive, and/or executive functions (ameliorating one pr more symptoms, symptoms including motor and cognitive dysfunction partial or alleviation, reduction is severity of neurological impairment in an MLD patient) (See for example, p. 55 paragraphs [0218] and [0219]).
Regarding claim 3, Salamat-Miller et al. teach the one or more motor functions comprise gross motor function, wherein the gross motor function is assessed by a Gross Motor Function Measure (GMFM) test, wherein the GMFM test is GMFM-88 (GMFM-88 is measured) (See for example, p. 56 paragraph [0219]-Continued, and p. 127 paragraph [0384]).
Regarding claim 11, Salamat-Miller et al. teach administration of the recombinant ASA decreases levels of a biomarker that accumulates in MLD in a bodily fluid, wherein the bodily fluid is cerebrospinal fluid (reduction of sulfatide accumulation in the CSF, reduced storage of disease marker sulfatide in brain target tissues, etc.) (See for example, p. 10 paragraph [0052], p. 56 paragraph [0220], and p. 120 paragraph [0359]).
Regarding claim 12, Salamat-Miller et al. teach the biomarker is selected from the group consisting of sulfatide, lysosulfatide, and combinations thereof (reduction of sulfatide accumulation in the CSF, reduced storage of disease marker sulfatide in brain target tissues, etc.) (See for example, p. 10 paragraph [0052], p. 56 paragraph [0220], and p. 120 paragraph [0359]).
Regarding claim 13, although Salamat-Miller et al. do not explicitly teach the baseline biomarker sulfatide level in the cerebrospinal fluid is greater than 0.1 µg/mL. However, before the effective filing date of the invention Dali et al. (2015) teach baseline biomarker sulfatide level in the cerebrospinal fluid is for example, 2200 nmol/L, which is equivalent to ~1.96 µg/mL (MW of sulfatide X nmol/L divided by 1,000,000 to obtain sulfatide level in µg/mL) (See for example, p. 520 Table 2 2nd column form the right “CSF sulfatide in nmol/L” and the legend “molecular weight of sulfatide has a molecular weight of 889”).
Therefore, a person of ordinary skill in the art before the effective filing date of the invention would have been motivated to apply the teaching of Salamat-Miller et al. and Dali et al. (2015) with a reasonable expectation of success to provide the claimed method of treating metachromatic leukodystrophy (MLD) Syndrome. Because Salamat-Miller et al. teach a method of treating metachromatic leukodystrophy (MLD) Syndrome comprising a step of administering directly to the cerebrospinal fluid (CSF) of to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of at or greater than 100 mg and an administration interval for a treatment period of at least 12 months or more to stabilize or reduce brain lesion involvement relative to baseline, and because Dali et al. (2015) teach baseline biomarker sulfatide level in the cerebrospinal fluid is greater than 0.1 µg/mL.
B)
Claims 20-23, 37, 38, 43, 48 and 50-52 are rejected under 35 U.S.C. 103 as being unpatentable over Salamat-Miller et al. (WO 2011/163650, which is also cited in IDS filed on 12/17/2024) in view of Dali et al. (Neurology, 2010, Vol. 75, p. 1896-1903, which is also cited in IDS filed on 12/17/2024).
Regarding claim 20, Salamat-Miller et al. teach a method of treating metachromatic leukodystrophy (MLD) Syndrome comprising a step of administering directly to the cerebrospinal fluid (CSF) of a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of at or greater than 100 mg and an administration interval for a treatment period of at least 12 months sufficient to increase levels of a biomarker that is decreased in MLD in a brain tissue relative to a baseline level of the biomarker (MLD mice treated with recombinant hASA, intrathecal injection of recombinant hASA, doses 520 mg/kg brain weight demonstrated reduction of sulfatide accumulation in the CSF, and dose 250 mg/Kg and treatment period for a year or more) (See for example, p. 2 [0006], p. 3 paragraphs [0010]-[0011], p. 8 paragraph [0031], p. 10 paragraph [0052], p. 55 paragraph [0218], p. 56 paragraph [0219]-Continued, and p. 127 paragraph [0384]). Salamat-Miller et al. teach reduction of sulfatide accumulation in the CSF, reduced storage of disease marker sulfatide in brain target tissues, etc. (See for example, p. 10 paragraph [0052], p. 56 paragraph [0220], and p. 120 paragraph [0359]).
Regarding claim 20, although Salamat-Miller et al. do not teach 24 months, however Salamat-Miller et al. teach the treatment interval is at least 6 months (a year or more) (See for example, p. 8 paragraph [0031]) and intrathecal administration are performed … one a week, every other week, monthly, etc. (See for example, p. 8 paragraphs [0030]- [0031]). Therefore, a person of ordinary skill in the art before the effective filing dated of the invention would have been capable of optimizing the treatment period based on the severity of the condition and subject being treated. Because Salamat-Miller et al. teach the treatment interval is at least 6 months and the intrathecal administration are performed … one a week, every other week, monthly.
Regarding claim 32, Salamat-Miller et al. teach the therapeutically effective dose is less than 200 mg (from about 0.005 mg/Kg to about 100 mg/Kg and from about 0.005 mg/Kg to about 10 mg/Kg) (See for example, p. 61 paragraph [0236]).
Regarding claim 37, Salamat-Miller et al. teach the subject is human (subject or patient being treated is human) (See for example, p. 58 paragraph [0226]).
Regarding claims 38 and 43, Salamat-Miller et al. teach the subject is sixteen years old or younger (patient or subjects being treated including infant child, adolescent or adult human) (See for example, p. p. 58 paragraph [0026]).
Regarding claim 48, Salamat-Miller et al. teach the subject has exhibited at least one symptom of metachromatic leukodystrophy (subjects having MLD) (See for example, p. 58 paragraph [0226]).
Regarding claim 50, Salamat-Miller et al. teach the subject has been diagnosed with metachromatic leukodystrophy (subjects having MLD) (See for example, p. 58 paragraph [0226]).
Regarding claim 51, Salamat-Miller et al. teach the subject has been identified as being at risk of developing metachromatic leukodystrophy (subjects having the potential to develop MLD) (See for example, p. 58 paragraph [0226]).
Regarding claim 52, Salamat-Miller et al. teach the arylsulfatase A administered intraparenchymally, intracerebrally, intracerebroventricularly, or intrathecally (intrathecal administration/delivery) (See for example, p. 46 paragraph [0182] - [0184]).
Regarding claims 67 and 71, Salamat-Miller et al. teach the recombinant ASA enzyme comprises an amino acid sequence that is at least 85% identical at the amino acid level to SEQ ID NO: 1, and the recombinant ASA enzyme comprises an amino acid sequence of SEQ ID NO: 1 (See for example, p. 4 paragraph [0014]).
It should be noted that SEQ ID NO:1 as taught by Salamat-Miller et al. is the recombinant ASA enzyme comprises an amino acid sequence of SEQ ID NO: 1 (See sequence search results copied below, Result No.1, second row 100% match for SEQ ID NO: 1 of PCT-US11-41926-1 or WO 2011/163650).
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Salamat-Miller et al. do not teach the brain tissue is the deep white matter of the brain (claim 21), the biomarker is a metabolite claim 22) and the metabolite is N-acetylaspartate, wherein the levels of N-acetylaspartate are assessed by proton magnetic resonance spectroscopy (claim 23).
However, regarding claims 21-23, Dali et al. teach N-acetylaspartate (NAA) is a sensitive biomarker for MLD, and teach the strong correlation between standardized measures of motor and cognitive function and NAA levels in brain white matter in children with MLD suggesting NAA as a sensitive marker for therapeutic clinical trials in this disorder, GMFM-88 scores decreased linearly with loss of NAA signal in the centrum semiovale, and further teach assessing the NAA signal levels of N-acetylaspartate (by proton magnetic resonance spectroscopy or MRS) (See for example, p. 1897 both columns, p. 1899, p. 1900 Table -Continued on p. 1901, showing the results of motor and cognitive function tests and metabolites including NAA levels in MLD subjects, p. 1902 left-hand column, Figure 4 showing GMFM-88 scores decreased linearly with loss of NAA signal in the centrum semiovale, and last paragraph-Continued on right-hand column, and abstract/conclusions).
Therefore, a person of ordinary skill in the art before the effective filing date of the invention would have been motivated to substitute N-acetylaspartate (NAA) taught by prior art to be a sensitive biomarker for monitoring therapeutic clinical trials of MLD disorder (teachings of Dali et al.) for the biomarker in the method of Salamat-Miller et al. and further apply the known technique of proton magnetic resonance spectroscopy (MRS) to assess the amount of said biomarker N-acetylaspartate (NAA) (as taught by Dali et al.) with a reasonable expectation of success in assessing the decrease of the levels of N-acetylaspartate (NAA) in the brain tissue relative to a baseline level of the biomarker and providing the claimed method of treating MLD syndrome. The claimed method would have been obvious because substitution of one known biomarker for another known biomarker taught by the prior art to be useful for the same purpose would have been within the capabilities of a person of ordinary skill in the art before the effective filing date of the invention. The claimed method would have been obvious further because applying a known technique of assessing the biomarker N-acetylaspartate (NAA) taught by the prior art to be useful in assessing therapeutic clinical trials patients with MLD would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention. Because Dali et al. teach N-acetylaspartate (NAA) is a sensitive biomarker for MLD, the strong correlation between standardized measures of motor and cognitive function and NAA levels in brain white matter in children with MLD suggesting NAA as a sensitive marker for therapeutic clinical trials in this disorder, GMFM-88 scores decreased linearly with loss of NAA signal in the centrum semiovale of patients.
Double Patenting Rejection:
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.
A)
Claims 1, 2, 11, 12 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 12 and 14 of U.S. Patent No. 11,020,461 B2. Although the claims at issue are not identical, they are not patentably distinct from each other, as compared below:
Claims 1, 6, 7, 12 and 14 of U.S. Patent No. 11,020,461 B2:
Claims 1, 2, 11, 12 and 32 of instant Application:
1. A method of treating metachromatic leukodystrophy (MLD) comprising determining brain lesion involvement using magnetic resonance imaging (MRI) to obtain an MLD MRI severity score, administering intrathecally to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of greater than 100 mg and an administration interval for a treatment period of at least 6 months sufficient to stabilize or reduce brain lesion involvement relative to baseline; and assessing brain lesion involvement by the MLD MRI severity score.
1. A method of treating metachromatic leukodystrophy (MLD) Syndrome comprising a step of administering directly to the cerebrospinal fluid (CSF) of to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of at or greater than 100 mg and an administration interval for a treatment period of at least 24 months to stabilize or reduce brain lesion involvement relative to baseline.
14. The method of claim 1, wherein administering the recombinant ASA enzyme further results in improvement, stabilization or reduction decline of one or more cognitive, adaptive, and/or executive functions.
2. The method of claim 1, wherein the administering of the recombinant ASA enzyme further results in improvement, stabilization or reduction in decline of one or more motor functions, cognitive, adaptive, and/or executive functions.
7. The method of claim 1, further comprising determining levels of a biomarker that is decreased in MLD in a brain tissue relative to a baseline level of the biomarker.
11. The method of claim 1, wherein administration of the recombinant ASA decreases levels of a biomarker that accumulates in MLD in a bodily fluid, wherein the bodily fluid is cerebrospinal fluid.
12. The method of claim 11, wherein the biomarker is selected from the group consisting of sulfatide, lysosulfatide, and combinations thereof.
12. The method of claim 11, wherein the biomarker is selected from the group consisting of sulfatide, lysosulfatide, and combinations thereof.
6. The method of claim 1, wherein the therapeutically effective dose is less than 200 mg.
32. The method of claim 1, wherein the therapeutically effective dose is less than 200 mg.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to apply the teaching of claims 1, 6, 7, 12 and 14 of U.S. Patent No. 11,020,461 B2, and provide the claimed method of treating metachromatic leukodystrophy (MLD) Syndrome as disclosed by claims 1, 2, 11, 12 and 32 of instant application. The treating period would have been optimized by a person of ordinary skill in the art before the effective filing dated of the invention.
B)
Claims 1-3, 11-13, 32, 67 and 71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8 and 14 of U.S. Patent No. 11,020,461 B2 in view of Dali et al. (2010) and Salamat-Miller et al. and Dali (2015) (cited in 103 rejection above). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The teaching of over claims 1, 4-8 and 14 of U.S. Patent No. 11,020,461 B2, with respect to the claims 1, 2, 11, 12 and 32 of instant application were discussed above.
Regarding the limitation of claim 3, before the effective filing date of the invention Dali et al. teach strong correlation between standardized measures of motor and cognitive function and NAA levels in brain white matter in children with MLD, measuring gross motor function i.e., GMFM-88, GMFM-88 scores decreased linearly with loss of NAA signal in the brain (See for example, p. 1897 right -hand column 5th paragraph, p. 1899 and p. 1902 left-hand column, Figure 4, showing GMFM-88 scores decreased linearly with loss of NAA signal in the centrum semiovale). Also as shown above, claims of U.S. Patent No. 11,020,461 B2 teach therapeutically effective dose of greater than 100 mg and an administration interval for a treatment period of at least 6 months sufficient to stabilize or reduce brain lesion involvement relative to baseline; and assessing brain lesion involvement by the MLD MRI severity score, determining levels of a biomarker N-acetylaspartate (NAA).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to apply the method of treating metachromatic leukodystrophy (MLD) comprising administering intrathecally to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of greater than 100 mg and an administration interval for a treatment period of at least 6 months sufficient to stabilize or reduce brain lesion involvement relative to baseline; and assessing brain lesion involvement by the MLD MRI severity score, wherein administering the recombinant ASA enzyme results in stabilization of the MLD MRI severity score in the subject relative to baseline as taught claims 1, 4-8 and 14 of U.S. Patent No. 11,020,461, to provide the method of treating metachromatic leukodystrophy (MLD) Syndrome, method of treating metachromatic leukodystrophy (MLD) Syndrome comprising a step of administering intrathecally to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce decline of one or more motor functions relative to baseline, as disclosed by claims of instant application.
Regarding the limitation of claims 12 and 13, although claims of U.S. Patent No. 11,020,461 B2 do not explicitly teach the baseline biomarker sulfatide level in the cerebrospinal fluid is greater than 0.1 µg/mL. However, before the effective filing date of the invention Dali et al. (2015) teach baseline biomarker sulfatide level in the cerebrospinal fluid is for example, 2200 nmol/L, which is equivalent to ~1.96 µg/mL (MW of sulfatide X nmol/L divided by 1,000,000 to obtain sulfatide level in µg/mL) (See for example, p. 520 Table 2 2nd column form the right “CSF sulfatide in nmol/L” and the legend “molecular weight of sulfatide has a molecular weight of 889”). Therefore, it would have been obvious to a person of ordinary skill in the art to apply the teachings of prior art and to modify the method taught by claims of U.S. Patent No. 11,020,461 B2 and to determine the level of biomarker sulfatide.
Regarding claims 67 and 71, before the effective filing date of the invention Salamat-Miller et al. teach recombinant ASA enzyme comprises an amino acid sequence that is at least 85% identical at the amino acid level to SEQ ID NO: 1, and the recombinant ASA enzyme comprises an amino acid sequence of SEQ ID NO: 1.
Therefore, a person of ordinary skill in the art before the effective fling date of the invention would have been capable of substituting the recombinant ASA enzyme taught by the prior art to be effective in treating metachromatic leukodystrophy (MLD) Syndrome for the recombinant ASA enzyme in the method taught by claims 1, 4-8 and 14 of U.S. Patent No. 11,020,461 B2 with a reasonable expectation of success in providing the claimed method of treating metachromatic leukodystrophy (MLD) Syndrome.
C)
Claims 20, 22, 23, 37, 38, 43, 48 and 50-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 7, 8, 9, 15 and 16 of U.S. Patent No. 11,020,461 B2. Although the claims at issue are not identical, they are not patentably distinct from each other, as compared below:
Claims 1-16 of U.S. Patent No. 11,020,461 B2:
Claims 20, 22, 23, 37, 38, 43, 48 and 50-52 of instant Application:
1. A method of treating metachromatic leukodystrophy (MLD) comprising determining brain lesion involvement using magnetic resonance imaging (MRI) to obtain an MLD MRI severity score, administering intrathecally to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of greater than 100 mg and an administration interval for a treatment period of at least 6 months sufficient to stabilize or reduce brain lesion involvement relative to baseline; and assessing brain lesion involvement by the MLD MRI severity score.
7. The method of claim 1, further comprising determining levels of a biomarker that is decreased in MLD in a brain tissue relative to a baseline level of the biomarker.
20. A method of treating metachromatic leukodystrophy (MLD) Syndrome comprising a step of administering directly to the cerebrospinal fluid (CSF) of a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of at or greater than 100 mg and an administration interval for a treatment period of at least 24 months sufficient to increase levels of a biomarker that is decreased in MLD in a brain tissue relative to a baseline level of the biomarker.
52. The method of claim 48, wherein the arylsulfatase A is administered intraparenchymally, intracerebrally, intracerebroventricularly, or intrathecally.
8. The method of claim 7, wherein the biomarker is N-acetylaspartate (NAA).
9. The method of claim 8, wherein levels of N-acetylaspartate (NAA) are assessed by proton magnetic resonance spectroscopy.
22. The method of claim 20, wherein the biomarker is a metabolite.
23. The method of claim 22, wherein the metabolite is N-acetylaspartate, wherein the levels of N-acetylaspartate are assessed by proton magnetic resonance spectroscopy.
3. The method of claim 1, wherein the subject is human.
37. The method of claim 20, wherein the subject is human.
15. The method of claim 1, wherein the subject is 16 years old or younger.
38. The method of claim 20, wherein the subject is sixteen years old or younger.
16. The method of claim 1, wherein the subject is three years old or younger.
43. The method of claim 38, wherein the subject is three years old or younger.
1. … a subject in need of … treating metachromatic leukodystrophy (MLD) comprising determining brain lesion involvement using magnetic resonance imaging (MRI) to obtain an MLD MRI severity score …
48. The method of claims 20, wherein the subject has exhibited at least one symptom of metachromatic leukodystrophy.
1. … a subject in need of … treating metachromatic leukodystrophy (MLD) comprising determining brain lesion involvement using magnetic resonance imaging (MRI) to obtain an MLD MRI severity score …
50. The method of claim 48, wherein the subject has been diagnosed with metachromatic leukodystrophy.
51. The method of claim 48, wherein the subject has been identified as being at risk of developing metachromatic leukodystrophy.
Therefore, the method as disclosed by claims 1, 3, 7, 8, 9, 15 and 16 of U.S. Patent No. 11,020,461 B2 make obvious the claimed method of treating metachromatic leukodystrophy (MLD) Syndrome
as disclosed by claims 20, 22, 23, 37, 38, 43, 48 and 50-51 of instant application.
D)
Claims 20-23, 37, 38, 43, 48 and 50-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 7, 8, 9, 15 and 16 of U.S. Patent No. 11,020,461 B2 in view of Dali et al. (2010) and Salamat-Miller et al. and Dali (2015) (cited in 103 rejection above). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The teaching of over claims 1, 3, 7, 8, 9, 15 and 16 of U.S. Patent No. 11,020,461 B2, with respect to the claims 20, 22, 23, 37, 38, 43, 48 and 50-51 of instant application were discussed above.
Regarding claim 21, the brain tissue is the deep white matter of the brain, before the effective filing date of the invention Dali et al. (2010) teach strong correlation between standardized measures of motor and cognitive function and NAA levels in brain white matter in children with MLD, measuring gross motor function i.e., GMFM-88, GMFM-88 scores decreased linearly with loss of NAA signal in the brain (See for example, p. 1897 right -hand column 5th paragraph, p. 1899 and p. 1902 left-hand column, Figure 4, showing GMFM-88 scores decreased linearly with loss of NAA signal in the centrum semiovale). Also as shown above, claims of U.S. Patent No. 11,020,461 B2 teach therapeutically effective dose of greater than 100 mg and an administration interval for a treatment period of at least 6 months sufficient to stabilize or reduce brain lesion involvement relative to baseline; and assessing brain lesion involvement by the MLD MRI severity score, determining levels of a biomarker, a metabolite N-acetylaspartate (NAA).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to apply the method of treating metachromatic leukodystrophy (MLD) comprising administering intrathecally to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of greater than 100 mg and an administration interval for a treatment period of at least 6 months as taught claims 1, 3, 7, 8, 9, 15 and 16 of U.S. Patent No. 11,020,461, to provide the method of treating metachromatic leukodystrophy (MLD) Syndrome, method of treating metachromatic leukodystrophy (MLD) Syndrome comprising a step of administering intrathecally to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce decline of one or more motor functions relative to baseline, as disclosed by claims 20-23, 37, 38, 43, 48 and 50-52 of instant application.
Conclusion(s):
No claim(s) is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KADE ARIANI whose telephone number is (571)272-6083. The examiner can normally be reached IFP, Monday - Friday, 8:00 AM -4:00 PM EST.
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/KADE ARIANI/Primary Examiner, Art Unit 1651
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