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 Group I, electing species rs12741315 and GSA-rs6560830, and small molecule treatment in the reply filed on 10/14/2025 is acknowledged. Upon further consideration, species Rs3883014, Rs1525793, Rs10842262, and Rs6114708 are rejoined as options for the “at least one” additional SNP in claim 3 in view of identified prior art.
The election of species among different types of treatments is WITHDRAWN.
Claims 12-15 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (6) and inventions (12-15 and 19), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/14/2025.
Priority
The instant application claims priority to provisional application 62/897740 filed 9/9/19. However, the instant claims are not fully supported under 112a, as discussed herein. Therefore, the effective filing date of the instant claims is 9/9/2020.
Improper Markush Grouping
Claims 1, 3-5, 7, 9-11, 17-18, and 20 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of “at least one Single nucleotide polymorphism” recited in the claims where the alternative SNP are different variants is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The different SNP each have different structure and location in the human genome, and therefor do not share a single structural similarity.
The Markush grouping of “said agent is an antibody or functional fragment thereof, an siRNA, an antisense oligonucleotide, or a small molecule” recited in claim 5 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: there is no common structure among the different recited agents, nor is the grouping an art recognized class since “agent useful for treating POTS” that includes all of these members is not a known functional class prior to the invention.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
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 7, 17, 18 and 20 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.
Claim 7 is indefinite because it is not clear if the two recited SNP are exemplary or claim limitations. The claim could be clarified by reciting, “at least one single nucleotide polymorphism (SNP) selected from rs12741415 or rs691603 is present.”
Claim 7 is indefinite because part(a) recites detecting “when” at least one SNP is present, which is clearly inclusive of detecting no SNP is present, and if that is the case, there will be no diagnosis, yet the patient is still required to be administered an agent useful for the treatment of POTS. It is unclear if applicant intends to encompass treating patients who do not have or predisposition to POTS.
Any claim which is not specifically mentioned is indefinite because it depends from claim 7 and incorporates the indefiniteness issues of the independent claim.
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, 3-5, 7, 9-11, 17-18, and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature and an abstract idea without significantly more. The claim(s) recite(s) the naturally occurring relationship between polymorphic content at a human genome position and predisposition or presence of postural orthostatic tachycardia syndrome (POTS) which is a law of nature judicial exception. The claims further recite steps of “identifying” or “diagnosing” which are abstract idea judicial exceptions that are mental processes.
This judicial exception is not integrated into a practical application.
In addition to the judicial exception, claims 1, 3, and 9-11 recite a step of obtaining a nucleic acid and detecting the nucleic acid having at least one SNP selected from those listed. The claims do not apply or use the judicial exceptions in any way.
Claim 4 recites “administering to the subject having a predisposition for POTS at least one agent useful to treat POTS.” The claim does not integrate the judicial exception because it applies the treatment no matter what the outcome of the “identifying” step, and further, it recites the treatment at such a high level of generality that it is a mere invitation to “apply” the judicial exceptions. Claim 5 recites a more specific treatment step, however the administering step is not considered significantly more since there were no known agents for treating pots that were within most of those classes of agents, as discussed in the rejections under 112a herein. Because of this, the claims are considered to require limitations that attempt to cover any solution for treating POTS with no restriction on how the result is accomplished and no mechanism for accomplishing the result, and therefore does not provide significantly more because this type of recitation is equivalent to the words “apply it.” See MPEP 2106.05(f)(1). Treatments encompassed by the instant claim 5 were not known prior to the invention. The treating step cannot be considered a practical application of the judicial exceptions as the treating step is not actually an application of the law of nature, but rather a suggestion to find such a treatment, in a prior art context were no therapeutic agents within the scope of the instant claim was known. The addition of a highly general treating step that is not supported in the disclosure or prior art by any actual drugs or molecules for delivery is not sufficient to demonstrate that the invention as a whole is significantly more.
Claim 7 recites the genotyping and treatment steps in addition to the judicial exception.
The genotyping step is mere data gathering recited at a high level of generality and does not apply the judicial exception in any way. The treatment step does not apply the judicial exception because it occurs regardless of the outcome of the detecting whether and diagnosing- that is, it occurs even if the diagnosing does not occur. Furthermore, it is recited at an extremely high level of generality such that it encompasses all possible treatments for POTS and is statement to “apply” the judicial exceptions.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps in addition to the judicial exceptions are data gathering steps recited at an extremely high level of generality using well established techniques (see for example Syvanen et al. (Nature Reviews. Volume 2. December 2001 pages 931-942) and treatment steps that amount to instruction to “apply” the judicial exceptions.
Therefore, following all of this, the claims are rejected because they do not amount to significantly more than the recited judicial exceptions.
Claim Rejections - 35 USC § 112
Claims 1, 3-5, 7, 9-11, 17-18, and 20 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.
Note: The prior art rejections in this Office action are written against embodiments of these claims that do not require identifying, diagnosing or treating POTS due to the current claim construction. The specification and prior art are enabling for the detection of the recited SNP in biological samples, as discussed in the prior art rejections.
The specification teaches that a SNP is a change in which a single base differs from “the usual base” at that position (p. 7, line 30). The specification states that the ancestral allele of elected SNP rs12741415 is G and the variant allele is A or T (p. 5, line 10). Following this, the “usual allele” is G and the SNP is A or T. That is understood to mean that A or T are the minor alleles.
Claim 1 sets forth that when the A or T is present, there is an increased likelihood of POTS.
The data in the specification appear to contradict the statement in the claims. The specification teaches that the “GG” genotype was more frequent in cases than controls (p. 5, line 13), and that in the association study the A allele has the dominant effect had an odds ratio of less than 1, suggesting that the A allele indicates a decreased likelihood of POTS (p. 5, line 15). Figure 7 provides additional data, but the columns are not adequately labeled to allow interpretation of the data. The meaning of the “T” and “U” columns is not described. Allele frequencies are given in Table 7 for the case control sample, where the figure discloses that the frequency of the minor allele was lower in the affected than unaffected patients. However, the specification also teaches that some GG in the study could be GT and “0” could be TT (p. 5, line 13). The data in the specification and the “predicting” in the claims contradict one another, and this supports a that it would have been highly unpredictable with how to “make and use” the invention as currently claimed.
If a prediction is made according to the claim language it would be inaccurate based on the evidence of record. The prior art is silent as to a relationship between the elected SNP and POTS. The relationship between a particular SNP and POTS disease is not predictable, a priori, it must be discovered using patient and control populations. Applicant demonstrates here using thousands of patients to develop the instantly disclosed data, and it would be highly unpredictable whether or not one would be able to identify an additional relationship. Thus, having considered all of this, it is concluded that it would require undue experimentation to practice the instant invention as currently claimed since the predicting step in the claims contradicts the data shown in the specification.
Furthermore, with regard to claim 5, which administering an agent that is “useful to treat POTS” it is relevant (1) very limited treatments for POTS were known (see specification, p. 27) and (2) none of the known treatments for POTS were “an antibody, an siRNA, or an antisense oligonucleotide.” Only a very few small molecules for treating POTS were known, as disclosed in the specification.
The claimed invention requires administering an agent that treats POTS. The recitation is of sufficient breadth that it encompasses agents that treat POTS by any mechanism using any of the classes of treatments. The specification specifically contemplates employing drugs that target genes with SNP within them.
Considering the elected gene, specification teaches that PPP1R12B provides suitable targets for the rational design of therapeutic agents, and that small molecules corresponding to these regions may be used to advantage in the design of therapeutic agents which effectively modulate the activity of the encoded proteins (p. 19, line 15 and following). The specification suggests using molecular library and the screening of libraries of compound to discover the small molecules (p. 20-23).
Instantly elected RS12741415 is a single nucleotide polymorphism that maps to the intronic region of the protein phosphatase 1 regulatory subunit 12B gene (PPP1R12B) (specification, p. 4, line 20-21). The specification does not provide any guidance as to how the SNP causes “adverse functional consequences” such that a drug targeting it could be discovered and used to treat POTS. The specification does not disclose any other variants that cause “adverse functional consequences” to PPP1R12B gene. The specification discloses that whole exome sequencing found 4 rare variants in PPP1R12B that could functionally impact the gene, but there is no guidance given in the specification as to the identity of these four variants or how they impact the gene.
The specification demonstrates an association between RS12741415 and the presence of POTS, but it does not provide any evidence or support that the relationship is causative of the disorder or any evidence that treatment with a molecule that modulates PPP1R12B would be effective for treating POTS. This is extremely relevant in view of the fact that “assigning specific regulatory elements to the genes they control is not straightforward since they can be millions of base pairs apart (Orozco et al. Front Cell Dev Biol. 2022 Oct 20;10:995388).” Orozoco teaches that enhancer sequences, which can activate or increase expression of a gene can be located in the intron of a gene and can operate over very large genomic distances to control the expression of a gene millions of base pairs away (Section 1.1.1). Shaid et al. emphasizes “the importance of caution when considering the lead SNP as likely causal, and the importance of fine mapping to identify causal variants.” It cannot be assumed that just because RS12741415 was identified as a SNP associated with POTS that it is causal. There is no data presented in the specification to support a causal relationship, and there is no guidance as to what “deleterious effect” this SNP or any SNP identified causes. Without this knowledge, it is highly unpredictable how to even select a drug that would overcome the deleterious effect.
The specification teaches that PPP1R12B is more highly expressed in males than females, and hypothesizes that since male subjects are more likely to develop POTS the increased expression PPP1R12B “likely prevents POTS.” Following this, the specification suggests that treatments of POTS enhancing the activity of PPP1R12B (p. 32). However, there is no showing that PPP1R12B is downregulated in POTS patients, or that the RS12741415 has any correlation with the expression levels of PPP1R12B.
There is no description in the specification of drugs of any kind that would reverse any adverse effects any variant causes on PPP1R12B. The scope of potential encompassed drugs, even for just the elected “small molecules” is infinite, and there is no guidance as to any structure or partial structure that is common to all of these drugs. It would require an enormous amount of experimentation to (1) identify SNP that cause “deleterious effects” on PPP1R12B and then (2) to identify drugs that reverse those effects. Given that the specification provides no guidance as to the SNP that cause deleterious effects, the nature of the “deleterious effects”, or the structure of any drug or drugs to reverse those deleterious effects, many, many unpredictable experiments would have to be carried out to fill in the gaps of knowledge for each aspect of the invention. Such work itself in drug discovery would be
Thus, having carefully considered all of these factors, it is concluded that it would require undue experimentation to practice the claimed invention.
Claim 5 is 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.
Claim 5 is directed a method administering an agent that is “useful to treat POTS.” It is relevant that (1) very limited treatments for POTS were known (see specification, p. 27) and (2) none of the known treatments for POTS were “an antibody, an siRNA, or an antisense oligonucleotide.” Only a very few small molecules for treating POTS were known, as disclosed in the specification.
The specification does not disclose any treatments for POTS other than those that are disclosed as being known in the art. There are no drawings or structural formulas disclosed of agents that have the recited function. There is no partial structure disclosed of the agents. There is no teaching in the specification regarding any specific structure that accomplishes the reversal of adverse functional consequences of variants impacting the PPP1R12B gene, as suggested on p. 19 of the specification as a treatment target for POTS. Further, there is no art-recognized correlation between any and this function, based on which those of ordinary skill in the art could predict which agents of all possible antibodies, siRNA, antisense oligonucleotide or small molecules have this function. Consequently, there is no guidance as to the identity of the agents for administering.
The level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which agents (if any) have the activity the reversal of adverse functional consequences of variants impacting the PPP1R12B gene. Based on the lack of knowledge and predictability in the art, those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of methods which include administering agents based on the general disclosure in the specification.
The specification fails to satisfy the written description requirement of 35 U.S.C.
112, first paragraph, with respect to claim 5.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 3, 9, and 10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huentelman et al. (US 9127316).
The reference teaches a method comprising obtaining a nucleic acid sample from said subject and detecting alleles present at rs12741415. The reference teaches that the minor allele is associated with the phenotype, thus evidencing that the minor alelle was detected (Example 1, Col. 13-14 and Col. 29, lines 10 and 19-20). The reference teaches practicing the method using the Affymetrix 6.0 SNP array, and this array inherently has probes thereupon for detecting the elected rs12741415 and also rs1525793, rs12842262, rs3883014, and rs6114708. This was confirmed by query at ldlink.nih.gov, with the results displayed as follows:
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Therefore, when the reference teaches carrying out genotyping using the Affymetrix 6.0 array, it inherently comprises detecting the nucleotides present at each of these polymorphic positions. With regard to claim 9, the step of detecting with the microarray uses detection of specific hybridization, and with regard to claim 10, the target nucleic acid is DNA.
The preamble of claim 1 recites an intended use. The final step of the claim sets forth that it is the detection that “identifies” the patient. Since the reference teaches the detecting, based on the claim language, the detecting is all that is necessary to identify the patient. The method of the reference could be used as intended; it would genotype the relevant sample.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huentelman et al. (US 9127316).
The teachings of the reference as they relate to claim 1, from which claim 11 depends are given previously in this Office action and are fully incorporated here. The reference teaches the detection method in claim 1, but it is silent as to the sample used in Example 1.
Regarding claim 11, the reference teaches, in a different section, that the sample may be any sample derived from the subject in skin or blood, urine, cerebrospinal fluid, or any one of a variety of body tissues. Col. 9, ln 55 and following.
It would have been obvious to have used any one of the samples taught in Col. 9 of the reference in the example of Table 1, particularly a non-invasive blood sample, since genomic DNA would be expected to be present in all of the samples and the assay is for detecting genomic alleles. One would have been motivated to do so by the express teaching of the reference that these sample types are appropriate for genotyping.
Response to Remarks
Any rejection which is not updated or otherwise specifically addressed was overcome by amendment.
Regarding the Markush grouping, applicant states that the members belong to the same “art-recognized class of genetic alterations” because they are all SNP useful in identifying a subject with a predisposition to POTS. However, this group is not “art recognized” because there is no indication in the prior art that these members were POTS related, and not all SNP are POTS related. The rejection is maintained.
Applicant traverses the 101 rejection stating that the claims do not recite or describe any recognized exception. However, the rejection addresses why the amended claims persist in reciting judicial exceptions. The response further argues that the claims embody a practical application. However, no step in addition to the exceptions integrates the exception or amounts to significantly more for the reasons given in the rejection. The rejection is maintained.
Applicant traverses the rejection under 112a regarding which allele of the elected rs1274145 SNP is associated with POTS. The specification clearly teaches on page 5 of the specification that the “A” (i.e. the minor allele) is more frequent in controls than in cases. This is further supported by the OR 0.328, where an OR of <1 indicates that an outcome is less likely to occur in the group being studied (the "cases" group) compared to the control group. Applicant’s remarks do not address these data.
Applicant argues that it would have been known which allele of the SNP was the minor allele; this is not disputed the specification sets forth clearly that the variant allele is A or T for the elected SNP, see p. 5, line 10.
Applicant argues that the frequency of each asthma-associated SNP is low, pointing to the value 0.4173 in Figure 8. (Note: “asthma” here is presumed to be a mistake since the instant claims deal with POTS not asthma). However, there is nothing in Table 8 to suggest that the cited value is the "frequency" of an allele. That value appears under the heading "OR" which is not defined in the description of the drawings (p. 5, line 20 of original specification) and usually represents "odds ratio" in genomics literature. It is not a known abbreviation for "frequency" of an allele. Further, an OR of less than 1 is understood to mean that an outcome is less likely to occur in the group being studied (the "cases" group) compared to the control group. The relevant portion of the figure is below:
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Applicant further points to the specification paragraph which states:
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Applicant argues "found in lesser frequency" supports the position that the risk allele is the "minor allele," although the specification does not say that. This sentence could also be understood to mean that the risk allele is less frequent in normal subject cohorts than in diseased cohorts. As noted above, there the minor allele is more frequent in normal subject cohorts.
Applicant further refers to an NCBI SNP record as support for which allele is the minor allele. However, the record was not submitted. Applicant argues that based on this record it would have been clear what alle is the minor allele for rs6917603. This SNP is non-elected and was not considered discussed in the enablement rejection. Nonetheless, as stated previously, it is not disputed which allele for the elected SNP is the minor allele.
The response fails to address the data that are mentioned in the rejection. The data give in the figure 7 description clearly suggest that the "A" allele is less represented in cases than controls; it is more frequent in cases than in controls. This does not support the claims which suggest the presence of the minor allele indicates predisposition to POTS.
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The rejection is updated to address the amended claims, and maintained.
The rejection of claim 5 is updated to address the amended claim.
The 102 rejection has been updated to address how the reference addresses the newly added claim limitations.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Boris teaches that a genome wide association study was performed to determine the genetic underpinnings of postural tachycardia syndrome. The reference teaches identifying a non-coding variant in the PPP1R12B gene, and that this gene is a candidate marker for POTS. The reference does not, however, give the identity or structure of the variant. (Boris and Hakonarson. Clinical Autonomic Research, (2019), Vol. 29, No. 5, p. 500).
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 Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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