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 . 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.
Priority
The instant application claims domestic benefit to US provisional application no. 63/415,451 filed on 10/12/2022.
Status of the Claims
Claims 1-31 are pending and being examined on the merits herein.
Claim Rejections - 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.
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.
Claim(s) 1-31 are rejected under 35 U.S.C. 103 as being unpatentable over Singhal et al. (Scientific reports 10.1 (2020): 8663, in PTO-892) in view of Lopez et al. (PLoS computational biology 7.3 (2011): e1002020, in PTO-892) and as evidenced by Sigma Aldrich (2-Hydroxypropyl-gamma-cyclodextrin product information in PTO-892).
Singhal teaches that 2-hydroxypropyl-γ-cyclodextrin (HPγCD) overcomes NPC1 deficiency by enhancing lysosome-ER association and autophagy (see Abstract).
Singhal teaches that Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations in NPC1 and NPC2 genes that result in an accumulation of cholesterol in lysosomes (see Abstract). Additionally, Singhal teaches that NPC-1 deficient cells exhibit defects in autophagy, which is a critical cellular process responsible for removing cytoplasmic macromolecules and damaged
organelles through the function of lysosomal enzymes. Thus, NPC1 deficiency seems to impair both lysosomal cholesterol trafficking and the autophagy-lysosomal pathway (see first paragraph on page 1). Singhal teaches that deficiency in autophagic function contributes to accumulation of aggregated proteins and are implicated in a range of neurodegenerative disorders such as Parkinson’s disease (PD) and Huntington’s disease (HD) Thus, strategies to enhance autophagy-lysosomal functions could improve cellular homeostasis and contribute to effective therapeutics for NPC disease as well as a number of neurodegenerative disorders (see first paragraph on page 2).
Singhal demonstrates in Figure 2 on page 4 that HPγCD alleviates cholesterol accumulation in NPC1 fibroblasts, and further demonstrates in Figures 6-7 on pages 8-9 that HPγCD promotes autophagy and TFEB activation in NPC1 fibroblasts. Singhal teaches that HPγCD enhancement of the autophagy pathway can alleviate the accumulation of toxic protein aggregates in cells, rescuing the cellular stress of NPC1 deficiency (see last paragraph page 7 through first paragraph page 8). Singhal teaches that HPγCD executes the NPC1-rescuing functions by extracting cholesterol from cell membranes as well as regulating cellular signaling mechanisms (see first paragraph on page 8). Singhal teaches a correlation between cholesterol accumulation and autophagy dysfunction, which leads to protein misfold and aggregation in NPC and other degenerative diseases, and further teaches that this dysfunction can be rescued by beta cyclodextrins (see last paragraph page 8). Singhal also teaches that the activation of TFEB by HPγCD plays a crucial role in mediating HPγCD induced rescue of autophagy-lysosomal functions and cellular homeostasis in NPC1-deficient cells (see second to last paragraph page 9). Singhal teaches that TFEB could be a promising target to restore lysosomal functions under pathological scenario, and further teaches that heterologous expression of TFEB have shown an improvement in clearance and amelioration of pathological conditions in rodent models of neurodegenerative disorders that include Alzheimer’s disease, tauopathy, Parkinson’s disease, and Huntington’s disease. Thus, HPγCD induction of autophagy-lysosomal functions could be exploited for therapeutic approaches for NPC disease as well as several other neurodegenerative disorders (see second to last paragraph page 9).
The difference between Singhal and the instant invention is that Singhal does not teach administering a gamma-cyclodextrin oligomer to an individual.
Lopez teaches the use of cyclodextrin (CD) dimers for cyclodextrin mediated cholesterol extraction (see Abstract).
Lopez teaches that the depletion of cholesterol from membranes, mediated by beta-cyclodextrin is well known and documented, but the molecular details of this process are largely unknown (see Abstract). Lopez used MD simulations to study how beta-CDs extract cholesterol from model membranes, and determined that efficient cholesterol removal requires the presence of beta-CD dimers (see last paragraph right column page 1) and as demonstrated in Figure 1 on page 3 and Figure 2 on page 5. Lopez demonstrates in Figure S2 that monomer forms of beta-CDs are not effective for cholesterol extraction in their simulations (see right column first paragraph page 10).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the HPγCD in Singhal by forming a HPγCD dimer as suggested in Lopez and to further use this modified HPγCD dimer for treating a proteinopathy such as Alzheimer or Parkinson’s in an individual by enhancing the autophagy pathway to alleviate toxic protein aggregates in cells as disclosed in Singhal to arrive at the instant invention. One of ordinary skill in the would have been motivated to make these modifications with a reasonable expectation of success because Singhal establishes that HPγCD may be a therapeutic agent for NPC and other neurodegenerative disorders such as Alzheimer’s or Parkinsons’s disease and further teaches that HPγCD executes the NPC1-rescuing functions by extracting cholesterol from cell membranes and further enhancing the autophagy pathway to alleviate accumulation of toxic protein aggregates in cells, and Lopez further teaches that dimeric forms of cyclodextrins are more efficient in cholesterol extraction than monomers. Therefore, an ordinary skilled artisan could have predictably considered modifying the HPγCD into a dimer form to obtain the advantage of more efficient cholesterol extraction, which may further enhance the NPC1-rescuing function and autophagy pathway to reduce protein aggregation in neurodegenerative disorders.
In regards to instant claims 2-5, even though the combined teachings of Singhal and Lopez described above do not disclose the recited reduced 10% protein aggregation relative to the level of protein prior to treatment as well as the recited results in instant claims 3-5, the combined teachings provide guidance of administering the same 2-hydroxypropyl-γ-cyclodextrin oligomer with the same molecular weights and molar substitutions as described below to reduce toxic protein aggregation in the same patient population having a proteinopathy such as Alzheimer (Tau and amyloid beta proteins) as shown in Example 2 on pages 23-24, Example 4 on pages 25-26, and Example 6 on pages 27-28 of the instant specification. Furthermore, the combined teachings of Singhal and Lopez also provide guidance of administering the same therapeutically effective amount of the 2-hydroxypropyl- γ-cyclodextrin oligomer because Singhal teaches administering 2-hydroxypropyl- γ-cyclodextrin at 1 mM concentration, which would equal ~3 mg/mL given a ~3 kDa (3000 Da) molecular weight as described below, and the instant specification discloses a therapeutically effective amount for the 2-hydroxypropyl- γ-cyclodextrin oligomer being 0.01 mg/mL to 20 mg/mL (see page 3 last three lines). Therefore, since the combined references teach all of the same active steps and limitations as the instant invention, the recited results in instant claims 2-5 would necessarily flow from the combined teachings of Singhal and Lopez. MPEP 2145 II recites “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
In regards to instant claims 6, 10, 19, 23, 27, and 31, the modified HPγCD dimer as suggested by the combined teachings of Singhal and Lopez described above would have a kDa of ~3 and a 0.6 molar substitution because Singhal teaches that their HPγCD was obtained from Sigma Aldrich (see last paragraph on page 10), and as evidenced by Sigma Aldrich, their HPγCD has a molar substation of 0.6 and a MW of ~1580 g/mol, which equates to ~1.5 kDa and would have a 3 kDa with the formation of the suggested dimer.
Therefore, claims 6, 10, 19, 23, 27, and 31 are also prima facie obvious.
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.
Claims 1-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-41 of copending Application No. 17/915,943 (‘943) in view of Singhal et al. (Scientific reports 10.1 (2020): 8663, in PTO-892) and Lopez et al. (PLoS computational biology 7.3 (2011): e1002020, in PTO-892).
Claim 27 of ‘943 recites a method of preventing or alleviating a disease related to cholesterol metabolism dysregulation, the method comprising administering a composition comprising a gamma-cyclodextrin polymer having a molecular weight of 2.5 to 50 kDa. Claim 29 of ‘943 recites wherein the derivative of gamma-cyclodextrin polymer is substituted with hydroxypropyl. Claim 30 of ‘943 recites wherein the disease related to cholesterol metabolism dysregulation is selected from the group consisting of Alzheimer’s, Parkinson’s, and among others. Claim 38 of ‘934 recites wherein the gamma-cyclodextrin monomer substituted with hydroxypropyl has a molar substitution value of 0.375 to 1.5.
The independent teachings of Singhal and Lopez are as described above.
Even though the claims of ‘943 do not recite a method of reducing protein aggregation, this recited method would naturally flow from the method recited in the claims of ‘943 as suggested by Singhal and Lopez because Singhal establishes that HPγCD may be a therapeutic agent for the same neurodegenerative disorders such as Alzheimer’s or Parkinsons’s disease and further teaches that HPγCD executes the NPC1-rescuing functions by extracting cholesterol from cell membranes and further enhancing the autophagy pathway to alleviate accumulation of toxic protein aggregates in cells, and Lopez further teaches that dimeric forms of cyclodextrins are more efficient in cholesterol extraction than monomers.
In regards to instant claims 2-5, even though the combination of the claims of ‘934 and the teachings of Singhal and Lopez described above do not recite the reduced 10% protein aggregation relative to the level of protein prior to treatment as well as the recited results in instant claims 3-5, the combined references provide guidance of administering the same 2-hydroxypropyl-γ-cyclodextrin oligomer to reduce toxic protein aggregation in the same patient population having a proteinopathy such as Alzheimer (Tau and amyloid beta proteins) as shown in Example 2 on pages 23-24, Example 4 on pages 25-26, and Example 6 on pages 27-28 of the instant specification. Furthermore, the combination of the claims of ‘934 and the teachings of Singhal and Lopez described above also provide guidance of administering the same therapeutically effective amount of the 2-hydroxypropyl- γ-cyclodextrin oligomer because Singhal teaches administering 2-hydroxypropyl- γ-cyclodextrin at 1 mM concentration, which would equal ~3 mg/mL given a ~3 kDa (3000 Da) molecular weight as described below, and the instant specification discloses a therapeutically effective amount for the 2-hydroxypropyl- γ-cyclodextrin oligomer being 0.01 mg/mL to 20 mg/mL (see page 3 last three lines). Therefore, since the combined references teach all of the same active steps and limitations as the instant invention, the recited results in instant claims 2-5 would necessarily flow from the combination of the claims of ‘934 and the teachings of Singhal and Lopez described above. MPEP 2145 II recites “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
In regards to instant claims 10, 23, and 31, it would have been prima facie obvious before the effective filing date of the claimed to have arrived at the recited molar substitution value range for the method as recited by the combination of the claims of ‘934 and the teachings of Singhal and Lopez described above because the claims of ‘943 recites an overlapping molar substitution value of 0.375 to 1.5. See MPEP 2144.05 I.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693