DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/13/2026 has been entered.
Priority
The present application is filed pursuant to 35 U.S.C. 371 as a U.S. National Phase application of International Patent Application No. PCT/EP2021/087483 which was filed December 23, 2021, claiming the benefit of U.S. Provisional Application No. 63/130,438, filed December 24, 2020, EP Application 21155579.2, filed February 5, 2021 and U.S. Provisional Application No. 63/185,111, filed May 6, 2021.
Status of Claims
Acknowledgement is made of the receipt and entry of claims filed on April 13, 2026. Claims 1-64, and 75 are canceled. Claims 65-74 and 76-88 are pending and under examination.
Action Summary
Claims 65-95 rejected under 35 U.S.C. 103 as being unpatentable over NCT02612129 (clinical trial.org, 08/25/2020) in view of Ingemann et al (Abstract/Molecular Genetics and Metabolism, Academic Press, Amsterdam, vol. 129, No. 2, January 31, 2020) are withdrawn.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 65-71, and 77-87 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCT02612129 (clinical trial.org, 08/25/2020, but first submitted or available on 06/14/2016).
NCT02612129 teaches a method of treating With Niemann-Pick Disease Type C to a patient, the method comprising administering three times a day 100 mg capsule arimoclomol in combination with a therapeutically effective amount of miglustat to a patient subject, wherein the subject is identified as having one mutation in one allele of NPC1 and NPC2. (See Title, Aim Section, and Arm and Intervention Section.) The 100 mg 3x daily results 300 mg/day as recited in claims 77-79, 83-84, and 93-94. The 100 mg reads on claims 80 and 81. The daily administration reads on at least seven days a week of claim 82. A missense mutation in the NPC1 gene is an ER-type mutation. Arimoclomol is the isomer of citrate salt recited in claim 67.
Accordingly, while the prior art does not teach miglustat contains N-alkyl derivative of 1,5-dideoxy-1,5-imino- D-glucitol in which said alkyl contains from 2-8 carbon atoms and arimoclomol is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)- propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, miglustat contains N-alkyl derivative of 1,5-dideoxy-1,5-imino- D-glucitol in which said alkyl contains from 2-8 carbon atoms and arimoclomol is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)- propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate absent evidence to the contrary. A chemical compound and its properties are inseparable. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
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 non-obviousness.
Claims 72-74, 76, and 88 are rejected under 35 U.S.C. 103 as being unpatentable over NCT02612129 (clinical trial.org, 08/25/2020, but first submitted or available on 06/14/2016).as applied to claims 65-71, and 77-87 in view of Shammas et al. (Scientific Reports, (2019) 9:5292) and Kirkegaard et al. (Research Article, 7 September 2016 Vol 8 Issue 355).
The teachings of NCT02612129 have been highlighted in the above 102-rejection.
NCT02612129 does not expressly teach the NPC1 gene is at least one endoplasmic reticulum ER-type missense mutation including R1186H/R1186H homozygous.
Shammas teaches Niemann-Pick Type C (NP-C) is an inherited neurovisceral lysosomal storage disease characterized by a defect in the trafficking of endocytosed cholesterol. In 95% of patients the gene encoding NPC1 is affected. The correlation of the genetic background in NP-C with the clinical phenotype such as, severity and onset of liver dysfunction, ataxia, dystonia and vertical gaze palsy, has not been elucidated at the molecular level. The first group comprised mutants in which the NPC1 protein revealed virtually similar structural features to the wild type species. It was trafficked to the lysosomes and colocalized with the lysosomal protein marker Lamp2. The second class of NPC1 mutants was only partially trafficked to the lysosomes, but predominantly localized to the endoplasmic reticulum (ER). In the third group with the most severe phenotype, NPC1 mutants were entirely retained in the ER, colocalizing with the ER-protein marker calnexin. (See Abstract.) Moreover, Shammas teaches it is important to allude to the interaction between the different classes of NPC1 mutants and the resulting hierarchy of the biochemical as well as the clinical phenotype in compound heterozygous patients. For instance, the homozygosity of the ER-located NPC1-I1061T mutant elicits a severe biochemical phenotype, which could be attributed to degradation of misfolded NPC1 mutant in the ER via the ERAD pathway. On the other hand, the combination of the NPC1-I1061T with either NPC1-P1007A or NPC1-V950M, both of which are normally intracellularly transported, resulted in a mild biochemical phenotype. This proposes the existence of a hierarchy among NPC1 mutants in which a wild type-like mutant, such as NPC1-P1007A, determines the overall biochemical pattern in the disease. Therefore, a potential interaction between two mutants in a homozygote or compound heterozygote back ground has to be taken into consideration when the genotype is correlated with the clinical phenotype. (See sixth paragraph of page 9.) Moreover, Shammas expressly teaches the NCP1 R1186H mutation in the homozygous state (i.e., R1186H/R1186H), which is classified as an endoplasmic reticulum (ER)-block mutation exhibiting a severe biochemical phenotype and occurring in homozygous cell lines. (See Table 2.)
Kirkegaard teaches lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl) glycero-phosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla−/−), Sandhoff disease (Hexb−/−), and Niemann-Pick disease type C (Npc1−/−) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb−/− and Npc1−/− mice. Oral administration of arimoclomol, a small-molecule co-inducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein–based therapies merit clinical evaluation for treating LSDs. (Abstract.) Kirkegaard teaches recent reports of the critical role of HSP70 in the maturation of the NPC1 protein, salvage of the in vitro phenotypes of NPC … by upregulation of HSPs; heat shock response has been implicated … in disease associated with compromised protein function because genetic alterations; arimoclomol reduces lysosomal storage and cholesterol accumulation in NPC patient fibroblast. Most importantly Kirkegaard expressly recognizes that the commonly occurring NPC missense mutations affect folding and maturation of NPC1, even though the Npc1 knockout mouse cannot model those mutations. (See page 8.)
It would have been prima facie obvious to one ordinary skill in the art at the time the invention was filed to administer arimoclomol to a subject having R1186H/R1186H NPC1 genotype because NCT02612129 teaches treating NPC patient with arimoclomol as a therapeutic treatment for NPC patients having NPC1 mutations. Shammas expressly identifies R1186H/R1186H as clinically relevant NPC1 genotype exhibiting an ER-retention phenotype resulting from defective folding and trafficking of NPC1 protein. Kirkegaard teaches that HSP70 is critically involved in NPC folding and maturation and that arimoclomol, through induction of HSP70, reduceds lysosomal storage pathology and improved NPC cellular phenotypes associated with defective NPC1 protein function. A person of ordinary skill in the art would have been motivated to administer the known NPC therapeutic arimoclomol to patients possessing the known R1186H/R1186H genotype with a reasonable expectation that enhancement of HSP70-mediated protein folding would improve the folding, maturation, trafficking, and function of the mutant NPC1 protein.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on April 13, 2026.
Applicant arguments have been fully considered but are not persuasive.
Applicant argues that NCT02612129 and Ingemann et al. cannot properly serve as prior art because both disclosures allegedly fall within the exceptions of 35 U.S.C. 102(b)(1)(A) and/or 102(b)(1)(B). This argument is not persuasive. The anticipation rejection of claims 65-71 and 77-87 under 35 U.S.C. 102(a)(1) is based solely upon NCT02612129. Accordingly, Applicant’s extensive arguments regarding the publication date, inventorship, common ownership, and alleged derivation of Ingemann et al. are not directed to, and therefore do not overcome, the anticipation rejection based upon NCT02612129.
Moreover, Applicant has not provided persuasive evidence that disclosure of Ingemann et al. qualifies for the exception under 35 U.S.C. 102(b)(1). Although Applicant asserts that several authors of the Ingemann abstract are also named inventor of the present application and that the remaining authors were employed be the same company, these assertions, without supportive evidence, do not establish that every portion of the disclosure relied upon was made by, or obtained directly or indirectly from, a joint inventor required by 35 U.S.C. 102(b)(1)(A). Mere common employment, common ownership, or overlapping authorship does not, by itself, establish derivation. Applicant has not submitted a declaration under 37 C.F.R 1.130 or other competent evidence demonstration that the subject matter relied upon by the Examiner was obtained directly or indirectly from the joint inventors. Accordingly, these unsupported attorney arguments are insufficient to establish entitlement to the statutory exceptions.
With respect to the newly presented claim 88, Applicant argues that the claimed NPC1 genotypes would have been expected to respond to arimoclomol because endoplasmic reticulum ER-retained mutations produce misfolded proteins that may exhibit dominant-negative effects and that simply increasing protein levels would necessarily provide therapeutic benefit. Applicant therefore concludes that the claimed invention would not have been obvious.
This argument is likewise unpersuasive. NCT02612129 teaches treating Neimann-Pick disease type C patients having NPC1 mutation with orally administered arimoclomol. Thus, the primary reference was already recognized as a therapeutic treatment for NPC patients possessing NPC1 mutations. Shammas et al. teaches that claimed R1186H/R1186H genotype is a clinically recognized NPC missense mutation exhibiting an ER-block trafficking phenotype, sever biochemical phenotype, and occurrence in homozygous cell lines. Shammas further teaches that ER-block mutations are characterized by defective folding, trafficking, and maturation of NPC1 protein and emphasizes the importance of correlating specific NPC1 genotypes with biochemical and clinical phenotypes. Kirkegaard et al. teaches that heat shock protein 70 (HSP70) plays a critical role in the folding and maturation of NPC1 protein, that arimoclomol induced HSP70 expression, and that HSP70 upregulation rescues NPC cellular phenotypes associated with defective NPC1 protein folding. Kirkegarrd further teaches that arimoclomol reduces lysosomal storage pathology and cholesterol accumulation in NPC patient fibroblasts and expressly recognizes that commonly occurring NPC1 missense mutations impair folding and maturation of NPC1 protein.
Accordingly, the combined teachings of the references would have suggested administering arimoclomol to patients possessing the R1186H/R1186H genotype with a reasonable expectation that arimoclomol-induced HSP70 upregulation would improve folding, maturation, trafficking, and function of the mutant NPC1 protein. Rather than teaching away from such treatment, the cited references collectively provide a scientific rationale supporting the therapeutic use of arimoclomol in NPC1 mutations involving defective protein folding.
Applicant further argues that person of ordinary skill in the art would have expected ER-retained mutation to be particularly difficult to treat because mutant protein may interfere with wild-type protein function. However, even assuming such challenges were recognized in the art, obviousness does not require absolute predictability of success. Rather, the proper inquiry is whether one of ordinary skill would have possessed a reasonable expectation that the known treatment would provide therapeutic benefit. Here, Kirkegaard expressly teaches that HSP70-mediated protein folding represents a therapeutic mechanism for rescuing defective NPC1 protein function, thereby providing precisely such a reasonable expectation.
Applicant additionally relies upon experimental date purportedly demonstrating unexpectedly favorable response in patients possessing ER-retention mutations. However, Applicant has not established that the alleged unexpected results are commensurate in scope with claim 88, Claim 88 encompasses four distinct NPC1 genotypes, including R1186H/R1186H, N968S/R1186H, N1156S/F1199sp2, and P1007A/R1186H. The evidence presented does not demonstrate that each claimed genotype individually exhibits the alleged unexpected therapeutic response relative to the closest prior art. Instead, Applicant’s evidence generally discusses broader ER-retention mutation populations. Consequently, Applicant has not established that the asserted unexpected properties extend across the full scope of the claimed subject matter. Furthermore, Applicant has not demonstrated that the alleged results would have been unexpected in view of the combined teachings of NCT02612129, Shammas et al., and Kirkegaard et al., which collectively teach treatment of NPC patients using arimoclomol, identify the claimed genotype as an ER-retained NCP mutation, and explain that arimoclomol- induced HSP70 upregulation improves folding and maturation of defective NPC1 protein. Accordingly, the evidence submitted is insufficient to outweigh the strong prima facie case of obviousness established by the cited references.
For the foregoing reasons, Applicant’s arguments have been considered but are not persuasive.
Conclusion
Claims 65-74 and 76-88 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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