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 .
Election/Restrictions
Applicant’s election without traverse of the invention of Group I (drawn to methods comprising gene content analysis) and the particular combination of genes that is TRPV1 and DRD2, in the reply filed on 09/25/2025 is acknowledged.
Claims 2 and 8 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/25/2025.
Objections to the Drawings
Figure 2 of the drawings should be designated by a legend such as --Prior Art-- because only that which is old is illustrated. The drawing appears to be the same as a figure from Fu et al (2014) cited on the IDS of 11/09/2022 as reference number 8. See MPEP § 608.02(g). Corrected drawings in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to because Figure 2 of the drawing has illegible text, and the drawing appears to include the label “Figure 1”, which is not consonant with the presentation of the drawing as “FIG. 2”. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 1, 3, 4, 7 and 9 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.
Clams 1 and 7 are unclear over recitation of the limitation “detecting a variant sequence, marker or allele”, as recited in claim 1 from which claim 7 depends. The term “variant” is a relative term, but it is unclear what is required to detect any “variant” because there is no standard or reference for comparison set forth in the claims. The term “variant”, as recited in the claims, is a relative term which renders the claim indefinite.
Claim 3, 4 and 9 are unclear over recitation of the limitation “determining treatment based on the presence of the sequence, marker or allele” in combination with the limitation “analyzing the sample for a sequence, marker or allele”, as recited in claim 3 from which claims 4 and 9 depend. The limitations are unclear because the “determining treatment” is “based on”, and thus appears to require “the presence of the sequence, marker or allele”. But the relevant practical step of “analyzing the sample for” does not appear to require the genetic content is in fact present and detected; “analyzing for” appears to encompass detecting the presence of absence of any marker allele. Thus it is unclear if the “determining treatment” is neccerarily performed in the scope of the claimed method.
Claims 7 and 9 is unclear over recitation of the limitation “useful proximity thereto”, as recited in each of claims 7 and 9. Neither the claims, nor the speciation or related art, provide any guidance or limiting definition of what may be considered a “useful proximity”. The term “useful”, as recited in the claims, is essentially a relative term which renders the claim indefinite. The term “useful” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 7 and 9 are unclear over recitation of the limitations “a haplotype of ATGG of TRPV1; TCCC of DRD2; and/or TCAA of TRPV1” and “a diplotype of ATGG/GTGG of TRPV1; TCCC/CCCC of DRD2; and/or TCAA/GCAA of TRPV1”. The claims are unclear because a haplotype is a combination of alleles that are on the same particular chromosome (i.e.: one of the two chromosomes of a pair) of a genome (and a diplotype is the combination of haplotypes on each chromosome). But neither the claims, nor the speciation or related art, provide any guidance as to what alleles are intended to be required for the recited haplotypes. The application as filed only provides for a single particular SNP in DRD2, and while there are two disclosed SNPs in TRPV1 they are not disclosed as a haplotype nor are they a basis for haplotypes comprising four alleles.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3, ,4, 7 and 9 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 diagnosing (i.e.: claim 1) and as well as “determining” a treatment “based on” genetic content. The claims are thus directed to the assessment of collected data, which is and abstract idea that is a mental process (e.g.: MPEP 2106.04(a)(2)(III)(A)); it is 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 likelihood of the presence of CHS, such an association is accepted part of how a biological organism functions (i.e.: genotype:phenotype relationships), and as such this element of the claims is a natural phenomenon (e.g.: MPEP 2106.04(b)(I)).
This judicial exception is not integrated into a practical application because there are no practical steps related to the determination of likelihood of CHS in a subject (relevant to claim 1) or the determining of a treatment (relevant to claim 3). There are no additional steps of the claims that are directed to applying or using the judicial exception(s) noted above (e.g.: MPEP 2106.04(d)(I)). The claims end with “diagnosing”, or “determining treatment” a, both of which are abstract ideas (as noted above). Here it is noted that “determining treatment based on the presence” is noted a requirement that any treatment is in fact administered to the subject. Merely presenting the results of a process otherwise unpatentable under section 101 is insufficient to establish eligibility under the statute. See FairWarning IP, LLC v. Iatric Sys., Inc., (Fed. Cir. Oct. 11, 2016) (claim unpatentable despite recitation of the step: "providing notification if [an] event has occurred"). The courts have affirmed that merely collecting data, extracting information from the data and/or storing data are not patent-eligible (see, For example, Content Extraction and Transmission LLC v. Wells Fargo Bank., N.A. 776 F.3d 1343, 112 USPQ2d 1354 (Fed. Cir. 2014) and Electric Power Group LLC v Alstom S.A. CAFC 2015-1778).
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 determining a genotype in a sample. However, such steps were well understood, routine and convention in the prior art (e.g.: MPEP 2106.05(d)). For example, the steps of marker analysis are recited at a high level of generality, and the instant specification indicates that such method are routine in the art (e.g.: specification at pages 18-25). Additionally in this regard it is noted that probes for detecting genotypes in both the TRPV1 and DRD2 genes, including the particular SNP positions disclosed in the instant application, were included in commercially available genotyping arrays such as the HumanOmni2.5-8v1_A array from Illumina; e.g.: see the Submitted SNP(ss) Details for: ss835836702 (related to rs879207); ss834221786 (related to rs11655540); and ss833997392 (related to rs4648318).
Claim Rejections - 35 USC § 112 – Written Description
Claims 1, 3, 4, 7 and 9 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant rejection of claims for lack of an adequate written description of the claimed subject matter in the application as originally filed is relevant to several aspects of the claimed methods.
A first aspect is the generic breadth of the claims as they may encompass any sequence, marker or allele in the TRPV1 and/or DRD2 gene(s). Claim 1 recites the elements as ‘variant’; claim 3 is generic with regard to the detected elements. The claims thus encompass the detection of any nucleotide content in the recited genes, and include the detection of any ‘variant’ that is and single or multi-nucleotide insertion, deletion or substitution, as well as larger chromosomal rearrangements. The claims thus encompass an enormous genus of a variety of structures. But the claims also recite particular functionality of the detected sequence, marker or allele as indicative of a likelihood of CHS (claim 1) or associated with CHS (claim 3). However, neither the teachings of the specification nor the related art provides the skilled artisan with the ability to select, from the large encompassed genus, those particular elements which have the required functionality.
The structures of the generically encompassed variant sequences, markers and alleles of the claims is relevant in light of the particular disclosure of only several particular SNPs in the relevant genes (Table 1 of the specification). The nature of alleles is that they are variant structures, and in the present state of the art, the structure of one allele does not provide guidance to the existence or structure of other alleles. In other words, the existence and structure of other alleles are not predictable from the particular species disclosed in the specification. In this regard it is relevant to point out that the specification discloses only human genomic variations, where the claims generically encompass any subject organism. Juppner (1995) teaches that despite significant structural conservation, rat, opossum, and human PTH/PTHrP receptor homologs display distinct functional characteristics (Abstract; pp.39S-40S).
The breadth of the claims in view of the particular teachings of the application as originally filed is notable where specification (p.31-32) only provides the general assertion that, in a case control analysis of CHS and non-CHS subjects:
Findings included mutations in genes coding COMT (p=0.0009), TRPV1 (p=0.021), CYP2C9 (p=0.0414), DRD2 (p=0.027) and ABCA1 (p=0.008), providing several lines of evidence relating to CHS pathophysiology and clinical manifestations (Table 2).
And while Table 2 discloses several particular SNPs (in DRD2 and TRPV1, as consonant with the election), the specification does not teach which allele of any SNP is associated with the presence of absence of CHS; it is not clear which allele presented in Table 2 is considered a “variant”.
The required associations of the claims (e.g.: markers indicative of risk or presence of CHS) are particularly relevant when considering that a disclosed marker in TRPV1 (i.e.: rs11655540; Table 2) is indicated as having a p-value of association that is above that typically required to establish significance. Thisted (1998) provides guidance as to what is required to indicate that an association is statistically significant (i.e.: Thisted teaches that it has become scientific convention to say that a P-value of 0.05 is considered significant (p.5 - What does it mean to be 'statistically significant'), and that values above the conventional reference point of 0.05 would not be considered strong enough for the basis of a conclusion).
Thus where the claims encompass a large variety of possible alleles while only disclosing a few particular SNPs, and also require a functional association of the alleles with CHS, it is relevant to point out that given the establish volatility is establishing such associations, the particular disclosures of the specification are not a description of the encompassed subject matter. 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 beta-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)). An association between genotype and phenotype is not apparent from any detected allele a priori, but must be established by statistical analysis in each case.
Given that the claims also encompass any “marker in useful proximity” with the recited markers of the claims (part c of each of claims 7 and 9), it is relevant to point out that Wall (2003) teaches that linkage disequilibrium (LD) refers to the fact that particular alleles at nearby sites can co-occur on the same haplotype more often than is expected by chance (page 587, 1st column, 1st paragraph). But Wall teaches that patterns of LD are known to be noisy and unpredictable as pairs of sites tens of kilo bases apart might be in complete LD, whereas nearby sites from the same region can be in weak LD (page 587, 2nd column, last paragraph). Wall teaches that population history, population size, and population structure lead to differences in LD (page 588, 1st column, top). Wall teaches, “Measuring LD across a region is not straightforward" (box 1, last paragraph, page 588). Wall teaches it is difficult to compare results from different LD studies directly because of the variation in study design and methods of analyzing the data (page 591, 2nd column, 1st full paragraph).
Another instance of a gap between the teachings of the application as originally filed and the subject matter encompassed by the claims is the recitation in claim 4 which requires “ a competitive ligand of the receptor capable of ameliorating the symptoms”. In this regard, the specification provides only:
… TRPV1 ligand capable of acting as an agonist/desensitizer. The ligand can bea natural compound such as compounds in ginger (Zingiber officinale) (page 5 of the specification);
Capsaicin, which is readily absorbed through the skin to an extent greater than gastrointestinal tract, is a natural agonist and desensitizer of TRPV1, as is cannabidiol (CBD). While endocannabinoids anandamide and 2- arachidonylglycerol are also ligands, THC is not (p.27 of the specification).
But neither the specification, nor the related art, provide any particular structures or chemical elements of the asserted compounds such that the skilled artisan can readily identify any other different ligands. Furthermore, neither the specification nor the related art teach a method of treatment (e.g.: how much of a substance; treatment duration; methods of administration) that is in fact suitable for amelioration of any symptoms. It is noted that while the application asserts that ligand identification may be an inventive method (e.g.: p.33 – Example 4), a general assertion of how to potentially identify treatments that might be used in the claimed methods is not sufficient to establish that Applicants were in possession of the invention as broadly claimed.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The IDS of 11/09/2022 includes WO 2009/117122, which is a reference that is cited in the written opinion (PCT/ISA/237) associated with PCT/US2021/019724 (the instant application is a 371 of PCT/US2021/019724). Here it is noted that while WO 2009/117122 is broadly directed to genotype:phenotype associations, and the reference recites the DRD2 gene (i.e.: one of the elected genes) and the pathology CVS (i.e.: cyclical vomiting syndrome) which is related to the instantly claimed CHS pathology, the prior art does not provide any particular gene alterations or specific associations with CVS. As such the prior art is not an enabled disclosure of the instantly claimed methods, not does it provide any particular guidance to arrive at the associations of the instant claims.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683