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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/21/2025 to has been entered.
Election/Restrictions
Applicant’s election without traverse of the species of glucosylceramide, (S)-quinuclidin-3 -yl (2-(4’ -(2-m ethoxyethoxy)-[ 1,1 ’ -biphenyl]-4-yl)propan-2-yl)carbamate and Parkinson’s disease in the reply filed on 6/8/2020 is acknowledged. Upon further consideration the species requirement of a glucosyl ceramide synthase inhibitor is no longer required.
Claims 4 and 8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 6/8/2020.
Claims 1, 3, 6, 10, 12, 16 and 19 and are under consideration in the instant Office action.
Maintained Rejections
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.
Claims 1, 3, 6, 10, 12, 16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Krainc et al., WO2012/177997 (IDS) and Groener et al., 2008 (9/17/2020 PTO-892) in view of Bourque et a. US2014/371460 (9/17/2020 PTO-89), Savica et al., 2016 (8/31/2021, PTO-892) and Mielke et al., 2011 (IDS)
The instant claims are towards a method of detecting sphingolipid levels before and after administering treatment to a subject with Parkinson’s disease to determine its effectiveness.
Krainc teaches methods that involve treatment or prophylaxis for neurodegenerative proteinopathies like Parkinson’s disease (see abstract, paragraph 4 and 72) as required in instant claims 1, 3, 6, 10 and 12. Krainc teaches methods and compositions relating to treatment of proteinopathic disease to identify agents useful in such treatment including lowering glucosylceramide levels (see paragraphs 122-124) as in instant claims 1, 3, 6. Krainc teaches that reducing glucosylceramide (GlcCer) levels by the inhibition of glucosylceramide synthase as treatment for -synucleinopathies like Parkinson’s disease and monitoring the disease progression (see paragraphs 4-7, 88-89, 91, 93, 13, 133, 143, 153 and claims 3-4) as in instant claims 1, 6, 10, 12, 16 and 19. Krainc teaches the biological samples includes blood and cerebrospinal fluid (see paragraph 76). Krainic teaches that a therapeutically effective amount is the amount that reduces glucosylceramide levels (see paragraph 89) as in instant claims 1, 3, 6 and 10.
Groener teaches measuring levels of the sphingolipids of glucosylceramide (GlcCer) and ceramide (Cer) in Gaucher disease patients (a proteinopathy disease) before and after treatment (see abstract; page 73, 2nd column, 3rd paragraph; page 771st column, 3rd paragraph) as required in instant claims 1, 3, 6, 10, 12 and 16. Groener teaches that the sample comprises plasma (see abstract, page 74, 2nd column) as in instant claims 1, 3, 6, 10. Groener teaches using a glucosyl ceramide synthase inhibitor, miglustat, as a treatment for Gaucher disease (see page 72, 2nd column) as in instant claims 1, 3, 6, 10, 16 and 19.
See Krainc and Groener as discussed above. Neither Krainc nor Groener specifically teaches determining a ratio of glucosylceramide to sphingomyelin as required in instant claim 10 or the isoforms of the sphingolipids. Groener does teach using ratios of sphingolipids in plasma which include 16:0 GlcCer/ 16.0 lactosylceramide as an indicator of the severity of disease (see page 77, 1st column, 3rd paragraph) but does not specifically teach other sphingolipid isoforms. Krainc teaches that ceramide is the central molecule for the precursor of all major sphingolipids including sphingomyelin and glucosylceramide (see paragraphs 230).
Bourque teaches using glucosylceramide synthase inhibitors as treatments for a variety of diseases which include Gaucher disease and Parkinson’s disease (see paragraphs 3 and 311) as in instant claims 1, 3, 6 and 10. Bourque teaches glucosylceramide synthase inhibitors as including eliglustast (see paragraph 683), miglustat (see paragraph 3) and other compounds based on the structure of paragraph 6 which reads on the limitations of claim 16 and 19 (iv and v); specifically Figures 2A and 2B and paragraphs 313-319. Bourque teaches quantifying glycosphingolipids including GlcCer. Bourque teaches that their inhibitors produce a decrease effect on glucocerebrosides, sphingomyelin and ceramide (see paragraph 489).
Savica teaches that clinical and pathological phenotype of dementia with Lewy bodies (DLB aka Parkinson’s disease) and Alzheimer’s disease overlap (see abstract). Savica teaches examining plasma from diagnosed patients with DLB and AD (see abstract and page 44) as in instant claims 1, 6, 10 and 12. Savica teaches that the glucosylceramide is linked to -synuclein and leads to neurodegeneration and needs to be studied for the connection to PD or AD (see page 44, top of 1st column) as in instant claims 1, 3 and 10. Savica does not teach the claimed treatment as in the instant claims.
Mielke teaches that plasma sphingomyelins (SM) are associated with cognitive progression in Alzheimer’ s disease and teaches using ratios of sphingomyelin and ceramides to predict Alzheimer’s disease (see abstract and page 260, 1st column, 2nd paragraph and page 264, 2nd column, 1st paragraph). Mielke teaches using total ceramides, total SM and all the summation of all detectable species (see page 261, 2nd column, 2nd paragraph) as in instant claim 6. Mielke does not teach treating PD as required in the instant claims.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Krainc, Groener, Bourque, Savica and Mielke. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Krainc and Groener both teach using glucosylceramide levels as a way of accessing response to a treatment. Krainc and Groener teach using glucosylceramide synthase inhibitors as a way to treat proteinopathies and reduces glucosylceramide levels which include Parkinson’s disease and Bourque teaches the specific glucosylceramide synthase inhibitors required in instant claims 16 and 19 and as in stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)." Further, it would have been prima facie obvious to one of ordinary skill in the art choosing different GluCer isoforms, such as glucosylceramide C18:0 or glucosylceramide C22:0, for example; such would amount to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; which is proper to support a finding of obviousness under 35 U.S.C. 103(a). See the Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf). See also MPEP §2143(E). Looking at all of the possible GlcCer isoform levels would be a reasonable step to determine the best inhibitor. Finally, one ordinary skill in the art would be motivated to use a ratio of different sphingolipids to determine the effects of treatment as already suggest by Groener, Savica and Mielke and one of ordinary skill in the art would be able to determine the best ratio use depending on the proteinopathy being treated through routine optimization of the method (see MPEP § 2144.05) using the claimed ratio of GlcCer and sphingomyelin since both have been shown to be effected by glucosyl ceramide synthase inhibitors and have already been shown to be useful in ratios to assess a patient population for disease diagnosis. Finally, one of ordinary skill in the art would be motivated to use this assay to monitor the prognosis of the disease in patient population and determine if the treatment is effective and determine what is the best treatment to administer since the prior art already teaches that these sphingolipids are altered in the disease model and patient populations with cognitive decline, as taught by Krainc, Groener, Bourque, Savica and Mielke, and would be a useful tool to determine if the treatment is effective in the patient population. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Response to Arguments
Applicant's arguments filed 5/21/2025 have been fully considered but they are not persuasive. Applicant argues that the 103 obvious rejection does not provide reasonable expectation of success and that one of ordinary skill in the art would not have expected that the levels of any sphingolipid isoform recited in the instant claims can be used to accurately determine the efficacy of a GCS inhibitor in a subject with Parkinson’s disease.
Applicant argues that none of the references teaches the claimed method of determining a level of a sphingolipid listed in claim 1 in a sample from plasma obtained from a subject with Parkinson’s disease or the determining the total level of one of the specific sphingolipids. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). This is not found persuasive because all of the components are taught in all of the combined references and provide a clear motivation to looks at the sphingolipid levels in this specific patient population, Parkinson’s disease. The Krainc reference teaches methods and compositions relating to treatment of proteinopathic disease to identify agents useful in such treatment including lowering glucosylceramide levels (see paragraphs 122-124) and that reducing glucosylceramide (GlcCer) levels by the inhibition of glucosylceramide synthase as treatment for -synucleinopathies like Parkinson’s disease and monitoring the disease progression (see paragraphs 4-7, 88-89, 91, 93, 13, 133, 143, 153 and claims 3-4). Therefore, there is a clear teaching and guidance in the prior art that this would be a favored method to monitor the changes when applying the treatment to particular patient population, like Parkinson’s patients. The references of record clearly show what was known at the time of filing by one of ordinary skill in the art. Mielke et al., 2013 (IDS) teaches plasma ceramide and glucosylceramide are altered in Parkinson’s disease. Therefore, the correlation between changes in sphingolipids and Parkinson’s disease is well established in the prior art and the combination of references already of record clearly set forth a reasonable expectation of determining the best assay of sphingolipid levels to monitor and the efficacy of using glucosyl ceramide synthase inhibitors for Parkinson’s disease. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007). All of the references of record in the 103 obvious rejection clearly set forth guideposts in the art that provide clear guidance for which sphingolipids to determine the best effect with a reasonable expectation of success. Applicant’s argument that the sphingolipids are a broad category with a varied amount of species is not found persuasive since the references of record, like the Krainc reference, narrow the scope significantly to specific types, including ceramide lipids. Krainc teaches reducing glucosylceramide (GlcCer) levels by the inhibition of glucosylceramide synthase as treatment for -synucleinopathies like Parkinson’s disease and monitoring the disease progression (see paragraphs 4-7, 88-89, 91, 93, 13, 133, 143, 153 and claims 3-4). Further, the 103 obvious rejection is not just limited to the Krainc teachings but all of teachings of the other references of record which teach the possible different sphingolipids to monitor treatment in a proteinopathy subject like a Parkinson’s disease subject with a reasonable expectation of success. Therefore, applicant’ argument that there is a large and unpredictable number of target sphingolipids to choose from is not correct as already set forth above. Further, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also >Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005).
Applicant has failed to show how the prior art of record would not motivate one of ordinary skill in the art to use the known sphingolipids and determine the best assay for monitoring the disclosed treatment for Parkinson’s disease or any other disease that involves sphingolipid abnormal levels. It would have been prima facie obvious to one of ordinary skill in the art to choose from the known sphingolipids as set forth by the references of record; such would amount to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; which is proper to support a finding of obviousness under 35 U.S.C. 103(a). See the Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396). See also MPEP §2143(E).
Applicant argues that choosing from different sphingolipids is not a finite number of solutions since it reads on hundreds of species. This is not found persuasive because it has already been established above that the prior art has already narrowed down the scope of potential sphingolipid species and set forth species that encompass reducing glucosylceramide (GlcCer) levels. Just because there are large number of options does not detract from one ordinary skill being capable of determining the best sphingolipid species to monitor during treatment with a glucosyl ceramide synthase inhibitor in Parkinson’s disease based on the available knowledge at the time of filing.
See KSR, 127 S. Ct. at 1740. "When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product is not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show it was obvious under 35 U .S.C. 103." KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1742, 82USPQ2d 1385, 1396 (2007).
Applicant argues that all the references of record fail to teach the instantly claimed invention due to the fact that the references address different diseases, besides Parkinson’s disease, that have different etiology. This is not found persuasive because it is clear from all of the prior art that all of the different diseases all share the same characteristic of affecting sphingolipids and being a prognosticator of what is occurring in the diseased subject. Therefore, one of ordinary skill in the art would be able determine the best assays to indicate effectiveness of treatment with a glucosyl ceramide synthase inhibitor by looking to the same field of endeavor, such as the references of record. It is pointed out that while the claimed assay is intended to monitor Parkinson’s patients that it can also easily be applied and adapted by one of ordinary skill in the art to any disease with abnormal sphingolipid levels to determine the best sphingolipids needed as a diagnostic and treatments for each particular disease through routine optimization of the method.
Applicant argues that none of the references teach the specific assays and ratio assays in the instant claims in the Parkinson’s disease and that there is a reliance of impermissible hindsight. Applicant fails to specifically point out what is missing from the prior art and is only gleamed from the instant specification or claims. It is noted that most of the arguments seem to be focused on the fact that the claimed invention is not anticipated by only one reference in the prior art but rather that the rejection is an obvious rejection based on the known facts at the time of filing. The obvious rejection clearly set forth above all of the required motivation of why one of ordinary skill in the art would be motivated to perform the same determination of efficacy since the prior art already knows that sphingolipid levels are affected in the required patient population, Parkinson’s disease, and the required treatment was also being applied to the patient population. Therefore, there is a clear motivation in the art to monitor those levels of sphingolipids since the glucosyl ceramide synthase inhibitors were already being used to treat and monitor the specified patient population.
Applicant argue that there is unpredictability in the art and point to evidentiary exhibit B, the Esfandary et al., 2022, which is a post filing reference. Applicant argues that based on the Table 1 of Esfandary et al., 2022, one of ordinary skill even after their filing date would not have a reasonable expectation of success since there is not obvious connection with sphingolipids and Parkinson’s disease diagnosis. It is pointed out that the Esfandary et al., 2022 is toward diagnosis endemic PD and not monitoring treatment in PD. Therefore, this is not found persuasive because the instant claims are not towards a method of diagnosing Parkinson’s disease but rather a method of monitoring levels of sphingolipids in a Parkinson’s patient receiving glucosyl ceramide synthase inhibitors. The prior art, as already set forth above (see Krainc) already teaches this idea and sets forth a reasonable expectation of success.
Therefore, applicant’s arguments are not found persuasive and the rejection is maintained.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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