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 .
This Office Action is in reply to Applicants’ correspondence of 02/23/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 08/22/2025 Applicants elected, without traverse, the invention of Group I (claims drawn to methods of identifying a PD phenotype or risk thereof), and the particular genes combination that is PARK16, ITPKB, MCCC1, SNCA, LRRK2, SV2C, and WBSCR17 and the particular SNPs that are rs6679073, rs16846351, rs2292056, rs6826785, rs141336855, rs246814, and rs9638616, as well the additional genes that are TMEM175-GAK-DGKQ, BST1, FGF20, VPS13C, and ASXL3 and the additional SNPs that are rs34311866, rs11724635, rs591323, rs2414739, and rs1941685.
Claim 17-21 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as set forth on page 2 of the Office Action of 11/21/2025
New claim 22 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (i.e.: requiring a non-elected combination of SNPs), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/22/2025.
Claim Objections
The objection to claims, as set forth on page 3 of the Office Action of 11/21/2025, is withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
Rejections of claims made under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on pages 3-5 of the Office Action of 11/21/2025, which are not reiterated/maintained below are withdrawn in light of the amendments to the claims.
Claim Rejections - 35 USC § 112 – Indefiniteness
Maintained/Modified as Necessitated by Claim Amendments
Claims 1, 3, 6 and 14-16 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.
Claims 1, 3, 6 and 14-16 are unclear over recitation of the phrase “detecting the presence of a single nucleotide polymorphism (SNP) at the loci of” gene, as recited in claim 1 and in claim 3. The phrase is unclear, because the term “single nucleotide polymorphism”, or “SNP”, as used in the claims and consonant with the teachings of the specification, is a relative term which renders the claim indefinite. As noted in the specification (para 0014 of the specification as filed):
As used herein, the term "SNV" or "SNP" refers to a variant with a single nucleotide substitution in a DNA sequence.
But the specification does not provide a standard reference genome for comparison, and as such it is unclear what nucleotide content at any locus is required to be detected to provide detection of a genetic variant. The term “SNP” as used in the art refers to a position in a genome that is variable among genome of a population; as such the limitation of “detecting the presence of a single nucleotide polymorphism (SNP)” in a sample from a subject (i.e.: from a single subject) is not an appropriate use of the term. While an allele of a SNP may be detected in a sample form a subject, it is not appropriate to recite “detecting the presences of a SNP” in a sample obtained from a particular subject.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112 as maintained above. Applicants have argued that the amendments to the claims to recite detecting a SNP, instead of detecting a genetic variant, obviate the rejection. The argument has been fully considered but is not persuasive to withdraw the rejection as set forth/maintained above. As noted above, the specification provides a definition of ‘SNP’ that is very similar to the previously recited “genetic variant”, which appear to require the comparison of detected genomic content to some reference. Furthermore, as noted in the rejection, where the term “SNP” as used in the art refers to a position in a genome that is variable among genome of a population; as such the limitation of “detecting the presence of a single nucleotide polymorphism (SNP)” in a sample from a subject (i.e.: from a single subject) is not an appropriate use of the term.
Withdrawn Claim Rejections – Improper Markush Group
The rejection of claims on the basis that they recite an improper Markush grouping of alternatives, as set forth on pages 5-6 of the Office Action of 11/21/2025, is withdrawn in light of the amendments to the claims.
Maintained Claim Rejections - 35 USC § 101
Modified as Necessitated by Claim Amendments
Claims 1, 3, 6 and 14-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas (e.g.: mental processes, mathematical calculations) and a natural phenomenon without significantly more.
The claim(s) recite(s) methods of identifying a PD related phenotype, and include “effect allele” of various SNP loci, where the specification defines an “effect allele” as the risk allele, which is confers the increased risk of developing PD. The claims are thus directed to the collection and comparing of information, which is and abstract idea that is a mental process (e.g.: MPEP 2106.04(a)(2)(III)(A)): the observation and evaluation of information to reach a judgment or conclusion. Where the evaluation of data to reach a conclusion is based in the asserted correlation between gene content and phenotype risk, such an association is accepted part of how a biological organism functions (i.e.: genotype:phenotype relationships), and as such this element of the claim is a natural phenomenon (e.g.: MPEP 2106.04(b)(I)). The claims additionally recite a step of measuring a number to calculate a score, which is a mathematical calculation (see MPEP 2106.04(a)(2)(I)(C)).
This judicial exception is not integrated into a practical application because the claims end with a step of “treating the subject identified in (d) with a PD therapy”, as recited in the final clause/step of claim 1. But this recitation is not sufficient to amount to an integration into a practical application that amounts to significantly more that the judicial exception(s) recited in the claims. The recitation is provided at the highest level of generality, amounting to an instruction to the skilled artisan to merely perform the judicial exception and “apply it”. MPEP 2106.04(d)(2) provides “the treatment or prophylaxis limitation must be “particular,” i.e., specifically identified so that it does not encompass all applications of the judicial exception(s).” Furthermore, it is noted that the specification makes it clear that any “treatment” may be the observation of a subject for monitoring, which does not require and practical aspect of treating the subject (e.g.: see specification at para 0035).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims only broadly recite steps of obtaining a DNA sample, and detecting the presence of a genetic variant at the loci recited in the claims. However, such steps were well understood, routine and convention in the prior art (e.g.: MPEP 2106.05(d)). For example, the array to collect the SNP allele data of the instant claims is a a commercially available product (see Infininium Global Screening Array (2018) as cited on the IDS of 110/1/2022), and the array is used in the collection of genotypes in the prior art (e.g.: Park et al (2019). Similary, Foo et al (2017) teaches (e.g.: p.227 – Results; Supplementary Table 1) a genome wide analysis of over 2,400,000 SNPs in a variety of human subjects. And Li et al (2019) teaches genome wide analysis of SNP allele content using the Affymetrix GeneChip 6.0, which features 1.8 million genetic markers, including more than 906,600 single nucleotide polymorphisms (SNPs) and more than 946,000 probes for the detection of copy number variation.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 101 as maintained above. Applicants have argued (p.11 of the Remarks of 02/23/2026) that the amendments to the claims obviate the rejection. The argument has been fully considered but is not persuasive to withdraw the rejection as set forth/maintained above. As noted above, the claims are directed to abstract ideas and natural phenomena, and the “treating” step is not sufficient to amount to an integration into a practical application that amounts to significantly more that the judicial exception(s) recited in the claims.
Maintained Claim Rejections - 35 USC § 112 – Enablement
Modified as Necessitated by Claim Amendments
Claims 1, 3, 6 and 14-16 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.
Nature of the invention and breadth of the claims
The methods of the rejected claims are directed to identifying whether a subject is at risk of developing Parkinson's disease (PD), whether a subject is suffering from PD, whether a subject is in need of early therapeutic intervention for PD, and determining a prognosis of a subject with PD or a subject at risk of developing PD. The identifications of the methods are based on the detection of the presence of a SNP at rs246814, rs9638616, rs6679073, rs16846351,rs2292056, rs6826785, and rs141336855 in the gene loci PARK16, ITPKB, MCCC1, SNCA, LRRK2, SV2C, and WBSCR17 (as consonant with the Election).
The claims encompass the detection of alleles at the SNP loci .
The nature of the claims thus requires knowledge of an association between particular nucleotide content and the presence of, a predisposition to, or a prognosis of PD in a subject.
Direction provided by the specification and working example
The specification provides (p.28 – Example 1) the results of an analysis of SNP allele association studies with 6,724 PD cases 24,851 controls. Relevant to the methods as consonant with the Election, the specification teaches that various particular alleles of PARK16, ITPKB, MCCC1, SNCA, LRRK2, SV2C, and WBSCR17 are overrepresented in PD cases (e.g.: Table 2 on p29), and have particular effect sizes related to the presence of PD (e.g.: Tables 7 and 8 on pages 42-43).
Where the methods, consonant with the election, require the detection of the presence of genetic variants in SV2C and WBSCR17 associated with the PD phenotype, it is noted that the specification does not provide for any variants in SV2C and WBSCR17 associated with the PD other than the T allele of rs9638616 (WBSCR17) and the T allele of rs246814 (SV2C).
The specification does not provide any prognostic analysis of any subjects, or any associations of particular allele of variable genetic content with any outcomes (e.g.: disease progression, disease severity) related to PD.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to detecting a nucleotide variation in any particular gene sequence is advanced, the unpredictability with regard to associating the presence of any particular nucleotide variation with the presence of, a predisposition to, or the prognosis of any particular disease phenotype is high. This unpredictability is demonstrated by the related art and the instant specification.
Because the claims generically encompass the detection of any alleles in the recited SNPs in the gene loci PARK16, ITPKB, MCCC1, SNCA, LRRK2, SV2C, and WBSCR17, where the variant is associated with presence, risk or prognosis of PD, it is relevant to point out the unpredictability in correlating any particular nucleotide variation with any different phenotype. Even in cases where an association between a particular gene and a phenotypic state is known to exist, such as with the LPL gene and heart disease risk or the β-globin gene and sickle cell anemia, researchers have found that when using polymorphism analysis it was difficult to associate SNPs with disease states or to even identify key genes as being associated with disease (Pennisi (1998)). The unpredictability in genotype:phentpype association studies are further evidenced by Lucentini (2004), which teaches that it is strikingly common for follow-up studies to find gene-disease associations wrong (left column, 3rd paragraph), and Hegele (2002), which teaches that often initial reports of an association are followed by reports of non-replication and refutation (p.1058, right col., lns.24-30). Even more germane to the breadth of the claimed methods in view of the particular teachings of the specification, Evangelou et al (2010) teaches a failure to replicate previously reported associations between genpotypes and PD in a different sample population data set.
Even considering the particularly disclosed alleles of the instant specification, the particular required associations of the claims are clearly associated with PD as set forth in the claims. Considering for example that the claims encompass (as consonant with the election) detection of a genetic variant in the MCCC1 gene that identifies a subject as at risk for or suffering from PD (claim 1 step b), and that detected genetic variant is a a G allele of rs2292056 (claims 12 and 13, which depend from claim 1). The claimed subject matter is thus the detection of a G allele at rs2292056 in MCCC1 as associated with the presence of PD. But turning to the teachings of the instant disclosure, the specification teaches that (para 0066):
An effect allele refers to the allele whose effects in relation to the disease are being studied. In some examples, the effect allele may be the risk allele, which is the allele of a SNP that confers the risk of developing the disease. Such an allele has genome-wide significance and has an odds ratio> 1.0, which indicates an increased risk relative to the other allele. In other words, risk allele is associated with a positive effect size as opposed to negative effect size. In the present disclosure, the term "effect allele" refers to the risk allele, which is confers the increased risk of developing PD.
and provides for an allelic association as (para 0071)
the genetic variant at the loci of MCCC1 is rs2292056, and the effect allele of rs2292056 is guanine (G).
But the specification further provides, in Tables 2, 7 and 8, that the effect size of the G allele of rs2292056 is -0.19 (Table 2) and -0.192 (Table 7 and 8). Thus the “effect size” of the G allele is negative, which would appear to require that allele is in fact protective with regard to risk of PD. Thus, it is unpredictable if the associations required by the specific embodiments of the claims are supported by the data of the specification.
Quantity of experimentation required
A prohibitively large an amount of experimentation would be required to make and use the claimed invention. Such experimentation would include large case:control analyses of any genetic variants in PARK16, ITPKB, MCCC1, SNCA, LRRK2, SV2C, and WBSCR17 (as consonant with the election), and the risk or prognosis of PD. Such experimentation would require validation in a replicated sample population, and even if such a large amount of experimentation were to be performed, there is no assurance that any reliable and robust association would be identified. Given the discrepancies of the disclosure (i.e.: the risk allele designation, versus the negative effect value, of the G allele of rs2292056), the experimentation of the instant disclosure may have to be repeated to validate any assertions of the instant application.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, the lack of guidance by the applicant and the particular examples, it is the conclusion that an undue amount of experimentation would be required to make and use the claimed invention.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112 as maintained above. Applicants have argued (p.12-13 of the Remarks of 02/23/2026) that the amendments to the claims, in view of the teaching so the specification, obviate the rejection. The argument has been fully considered but is not persuasive to withdraw the rejection as set forth/maintained above.
As noted above, the claims encompass any identification of prognosis (e.g.: a prediction of the probable course and outcome of a clinical condition or disease, as noted in para 0011 of the specification), but the specification only teaches an association of alleles with the presence, and age of onset, of PD. The specification does not provide any prognostic analysis of any subjects, or any associations of particular allele of variable genetic content with any outcomes (e.g.: disease progression, disease severity) related to PD.
Additionally, as noted in the rejection, while the claims recite the “effect allele” of particular SNP loci, there is no requirement in the claims that it is these particular alleles that are used in the calculation of a polygenic risk score to identify PD phenotypes in the subject. Furthermore, the rejection as maintained above addresses the requirement of the G allele of rs2292056 in MCCC1 as a risk allele (as recited in the claims) in view of the teachings of the specification which appear to provide a negative correlation between the G allele at rs2292056 and risk of PD (as set forth in Tables 2, 7 and 8, as noted in the rejection).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683