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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/08/2026 has been entered.
Claim Status
Amended claims 1, 2, 17-19, 21-22, 38-40, 42-43, 100-102 are pending and examined here, along with the following species: 1) hypertension, 2) Arg171Trp-Long, 3) genomic nucleic acid molecule of SEQ ID NO: 2 with thymine (T) at position 9519.
Priority
The application’s benefit to U.S. provisional applications 63/217,909 and 63/221031, filed on 07/02/2021 and 07/13/2021, respectively, is recognized. All claims enjoy the benefit of ‘909 filing date.
Claim Rejections - 35 USC § 112
Rejection of claims 1, 2, 17-19, 21-22, 38-40, and 42-43 for lacking enablement requirement is maintained, and new claims 100-101 are also rejected for lacking enablement requirement.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 17-19, 21-22, 38-40, and 42-43, 100-101 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.
When considering the scope of enablement, the Wands factors need to be reviewed, which poses whether the experimentation needed to practice the invention is undue or unreasonable. Determining undue experimentation requires analysis of, but not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In the instant case:
The breadth of the claims: The claims are drawn to a method of treating a subject having any type of elected hypertension or at risk of developing any type of hypertension by decreasing expression of SLC9A3R2 polypeptide in the subject, the method comprising administering to a subject a Solute Carrier Family 9 Isoform A3 Regulatory Factor 2 (SLC9A3R2) inhibitor, wherein the inhibitor comprises any inhibitory nucleic acid molecule (NAM), which comprises antisense nucleic acid molecule (ASN), siRNA, or shRNA that hybridizes to an SLC9A3R2, wherein the subject is SLC9A3R2 reference or is heterozygous for an SLC9A3R2 missense variant nucleic acid molecule encoding the elected Arg171Trp-Long. Cl. 2 limits hypertension to secondary, resistant or malignant hypertension; cl. 17 recites method of cl. 1 further comprising detecting the presence or absence of SLC9A3R2 missense variant nucleic acid molecule in a biological sample from the subject; cl. 18 further comprising administering any therapeutic agent for treating hypertension wherein the SLC9A3R2 missense variant nucleic acid molecule is reference; cl. 19 is to administer the therapeutic agent that treats hypertension to a subject heterozygous for the SLC9A3R2 missense variant; cl. 21 limits SLC9A3R2 missense variant to recited encoded variants; cl. 22 recites an elected genomic variant according to SEQ ID NO: 2; cl. 100 recites the claimed inhibitor is modified. Cl. 38-40, 42-43 recite a method of treating a subject with any therapeutic agent that treats the elected hypertension, wherein the subject with hypertension or is at risk of developing hypertension by decreasing expression of a SLC9A3R2 polypeptide in a cell in the subject, the method comprising determining whether the subject has a SLC9A3R2 missense variant nucleic acid molecule encoding the recited variants, by obtaining sample from the subject, conducting sequencing of the sample, genotyping for one of the recited SLC9A3R2 missense variants; and administering or continuing to administer the therapeutic agent that treats elected hypertension to the subject who is SLC9A3R2 reference or is heterozygous for the recited SLC9A3R2 missense variants and/or administer SLC9A3R2 inhibitory nucleic acid molecule, which is any ASN, siRNA or shRNA, that hybridizes to an SLC9A3R2 nucleic acid molecule; cl. 43 recites SLC9A3R2 missense variant nucleic acid molecule is genomic nucleic acid according to SEQ ID NO: 2. Cl. 101 recites the claimed inhibitor is modified.
The nature of the invention: The invention is treating a subject with hypertension or at risk of hypertension by administering a recited SLC9A3R2 inhibitory nucleic acid molecule, wherein the subject is SLC9A3R2 reference or is heterozygous for the SLC9A3R2 missense variant nucleic acid molecules encoding one of the recited variants and with or without any therapeutic agent that treats elected hypertension, the method further comprising obtaining a sample from a subject, sequencing the sample, and genotyping for SLC9A3R2 missense variant encoding for the recited SLC9A3R2 missense variants for the subject that has or is at risk of developing hypertension.
The state of the prior art: Solute Carrier Family 9 Isoform A3 Regulatory Factor 2 (SLC9A3R2, also called Na+/H+ exchanger regulatory factor-2 (NHERF2) and the abbreviations will be used interchangeably) is a scaffolding protein that binds to Na+/H+ exchanger 3 (NHE3) (par. 4). NHEs, involved in sodium absorption, have been suggested to be involved in pathogenesis of hypertension (Kobayashi, 2004, pg. 1723). NHERF2 is localized in the kidney, amongst other tissues, and is co-localized with a complex of other proteins (par. 4). NHERF2 also plays a role in intestinal sodium absorption by regulating the activity of the NHE3 and may also regulate cystic fibrosis transmembrane regulator (CFTR) ion channel (par. 4).
Various studies have been conducted to understand the role of SLC9A3R2.
Genome Wide Studies: Genome/exome studies have identified the protective association with a loss-of-function variant of NHERF2 (Giri, in IDS). Further, Shiffman (US20170292159, pub. 10/12/2017, of record) indicate association of many genetic polymorphisms and cardiovascular diseases, including myocardial infarction and hypertension, and disclose a method of determining an altered risk for cardiovascular disease in humans following genotype testing to determine presence of single nucleotide polymorphism (SNP), including of SLC9A3R2 (abstract, cl. 1, see table 21 and table 22 for SLC9A3R2). But neither appears to disclose the claimed, elected variant (Arg171Trp-Long).
Non-GWAS studies: A mouse model of spontaneous/genetic hypertensive rats (SHR) was studied for understanding the pathophysiology of hypertension (Kobayashi, 2004, p. 1723). Since it is known that NHE3 has an essential role in sodium reabsorption, Kobayashi studied whether the family of NHERF scaffolding proteins (specifically NHERF1 and NHERF2) play a role in regulating NH3 in SHR (Kobayashi, pg. 1723-1724). In SHR, Kobayashi evaluated the activity of NHE (Na/H exchanger) and NHERF1 and NHERF2 expression levels in the kidney (Abstract). The authors concluded that decreased expression of NHERF1 may be related to the enhanced NHE activity in SHR and that these changes are likely to be genetically determined, whereas the increased NHERF2 expression may be induced as a compensatory mechanism for the genetic abnormality and “increased NHERF2 expression was not induced by hypertension” (Kobayashi, 2004, pg. 1729, 1727). The conclusion raises the question of whether reduction in NHERF2 would treat hypertension in SHR animals.
The level of predictability in the art:
Regarding the lack of studies associated with inhibitory nucleic acid molecules: One skilled in the art understands that considering only the canonical siRNA of 21 nt. for a target of SLC9A3R2 nucleic acid molecule (SEQ ID NO: 3 is identified as a reference sequence and is 2160 nt.) there is a possibility of some 2,139 siRNAs. Gavrilov (2012, Yale J. Biol. Med., 85, pg. 187-200) discloses that siRNA therapeutic is “extremely promising” but needs to overcome a number of intracellular and extracellular barriers, including siRNA stability and targeting, off-target silencing and its activation of immune response, delivery of the siRNA therapeutic to the target cell (pg. 190-192). Although these barriers can be addressed, e.g., by improving stability by modifying the naked siRNA (it is noted that the specification provides a generic modification pattern for modifying a siRNA, see par. 52), identifying a carrier to deliver the siRNA therapeutic, there is still need of further testing. One of skill in the art is aware of many platforms that identify exemplary siRNAs, however, Gavrilov points out that “[o]ff-target silencing cannot be ignored in developing siRNA-based therapeutics, and all potential therapeutic siRNA candidate sequences must be heavily tested for perturbation of normal protein expression profiles” (pg. 191). Thus, the enablement requirement for methods of treatment with siRNAs is not met merely by identifying a functional siRNA. The state of the art calls for further testing to establish therapeutic efficacy. Thus, testing would be required to identify an efficient therapeutic siRNA or even one able to decrease expression of SLC9A3R2 effectively in a subject, and further a therapeutic siRNA would require further testing to potentially overcome the barriers noted above.
Exome sequencing studies – Although genome/exome sequence studies are gaining in prominence due to reduced costs, there are still issues concerning the causal link that is suggested between the genetic variation and a disease phenotype. Burgess et al. (2018, Ann. Rev. of Genomics and Human Genetics, 19, 303-327) disclose that an observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of risk factor will have a causal impact on the outcome (correlation is not causation) (Abstract). It could be an issue of confounders, common determinants of the risk factor and the outcome, that give rise to the association (pg. 305).
Further, even the specification discloses that an initial “low frequency missense variant in SLC9A3R2 (r5139491786, Arg171Trp, MAF=0.7%) was previously identified in a GWAS of blood pressure, but the signal was attributed to the nearby PKD1 gene variant (r5140869992, Arg2200Cys)” (par. 304). Thus, there is also an issue of mis-identifying the signal to a different gene variant.
Disease- As the specification points out, the cause of high blood pressure is unknown, but involves an interplay between many factors, include hormone systems, central-nervous system, stress, physical work and genetic influences/predisposition, and “derailment of one or more [these] systems results in high blood pressure” (par. 3). Thus, although it is potentially possible that targeting a single gene may be sufficient to control blood pressure, but without further studies, there is uncertainty whether suppression of SLC9A3R2 would treat hypertension.
All these issues in this section point to unpredictability in the art: NHERF2 is not clearly associated with hypertension and as Kobayashi demonstrated that the increased NHERF2 expression may be induced as a compensatory mechanism; and although siRNAs targeting NHERF2 are known, that does not equate to a predictable efficient therapeutic siRNA without carrying out further tests as pointed out by Gavrilov; association from genome wide studies are not causal but a correlative one as pointed out by Burgess; and on rare occasion, the positive signal is from a different gene, thus introducing another unpredictable factor based on the platform used to identify the association.
The amount of direction provided by the inventor/existence of working examples: The specification discloses an exome sequencing study of some ~450, 000 participants, where “a novel association was identified between a lower risk of hypertension and a burden of rare pLoFs and deleterious missense variants in SLC9A3r2)” (par. 303). Table 2 provides analysis of the association of deleterious missense variants of SLC9A3R2, which are the recited claimed subject matter.
MPEP 2164.03 indicates that more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling.
Here, the specification fails to, first, disclose a single, functional therapeutic claimed inhibitory nucleic acid molecule that hybridizes to SLC9A3R2 and inhibits its expression in a subject, second, fails to disclose an example of a method of treating a subject with claimed conditions or at risk of claimed conditions by administering claimed inhibitory nucleic acid molecule, wherein the subject is SLC9A3R2 reference (lacks claimed SCL9A3R2 missense variant) or is heterozygous for a claimed SCL9A3R2 missense variant; and third, fails to disclose an example demonstrating that one of the claimed variants is protective in a subject with the claimed conditions or in a cellular model. Further, even the specification indicates identification of “[a] burden of rare putative loss-of-function (LOF) and deleterious missense variants in the SLC9A3R2 gene associated with decreased risk of developing hypertension” (pg. 7, line 29-30). Thus, due to its rarity and being a putative LoF variant indicates a certain level of unpredictability and further information is required, such as whether the claimed variant(s) when expressed is indeed a LoF variant or whether its expression results in the indicated protective features. Data from suggested studies would provide information that would aid in removing unpredictability of the claimed subject matter. The lack of information noted above results in the art of the claimed subject matter being unpredictable, and consequently, the specification does not disclose sufficient enabling guidance of making claimed inhibitory nucleic acid molecule targeting SLC9A3R2 and using an inhibitory nucleic acid molecule of SCL9A3R2 in treating hypertension in a subject carrying SLC9A3R2 reference or its recited heterozygous variant(s).
The quantity of experimentation: Here the specification does not provide if a) predicted loss of function (pLoF) is an actual a loss-of-function mutation, i.e. a shortened mutant polypeptide; b) any functional studies demonstrating a causal link between the genetic variants and their protective nature, either in vivo or in vitro; c) or how the mutations are able to lower the risk of hypertension or hypertension, including studies to demonstrate suppression of SLC9A3R2 reduces hypertension or risk of hypertension; d) the specification also fails to identify an optimal or any inhibitory nucleic acid molecule that inhibits SLC9A3R2 in vivo or in vitro. Thus, there would be a need to conduct numerous undue experiments to practice the recited claims.
Thus, here the method of treating a subject by reducing the expression of SLC9A3R2 in a subject having hypertension or at risk of developing hypertension, the method comprising administering SLC9A3R2 inhibitor comprising a modified, inhibitory nucleic acid molecule, where in the subject is SLC9A3R2 reference or is heterozygous for claimed SLC9A3R2 variant recited in claimed subject matter would require unreasonable experimentation.
Response to Arguments
Applicant's arguments filed 04/08/2026 (“the Remarks”) have been fully considered but they are not persuasive. Only the Remarks addressing the enablement rejection are addressed. The withdrawal of finality rejection was addressed in Advisory Action of 04/24/2026.
The Remarks makes several arguments against the comments of the Advisory Action:
The Remarks argue that the claim amendments directed to the nucleic acid inhibitory molecule hybridizing to and decreasing the expression of target transcript should overcome the enablement rejection (pg. 11).
The Remarks, again, raise the argument that siRNA is well known in the arts, noting the following: a) provides a reference of Wong & Goldberg for determining dosing for therapeutic antisense nucleic acid molecule and associated clinical trials (pg. 11); b) availability of software to generate a siRNA, providing a commercial manufacturer (pg. 12); c) notes Khvorova reference, which provides for algorithms for cost-effective selection of optimized siRNA that is not sequence or species specific (pg. 12); d) notes a Rondinone reference, which describes successful introduction of siRNA into cells by IV injection (pg. 12). Thus, since the siRNA art is mature as of the application’s filing date, “there is no reason to believe that one skilled in the art would be required to perform undue experimentation to make and use the claimed subject matter” (pg. 12-13).
The argument is not persuasive.
Addressing 1 and 2, the Examiner appreciates the fact that generally the field of siRNAs is mature (i.e. there are a handful siRNAs/ASOs that are FDA approved, see Zhang 1/2021, Biochemical Pharmacology, 189, 1-12), but that does not equate to the art of the subject matter claimed is mature or that identifying a rare variant, which is a “rare” variant expressing a putative Lof, in human subjects correlating with a decreased risk of certain cardiovascular conditions in a GWAS study does not equate to decreasing the wild-type version of the transcript will provide similar outcome, i.e. treating or decreasing risk of hypertension/cardiovascular condition, in a subject, especially when sufficient, corroborative studies have not been disclosed in the specification. None of the references noted provide a nucleic acid inhibitor to SLC9A3R2.
The claim amendment does not overcome the enablement rejection, since the claims still require hybridization of the nucleic acid inhibitor to the target transcript and sufficient, consequential decrease in the target transcript to result in a desired physiological outcome (i.e. treating hypertension) in a subject or in a cell in a subject. Any nucleic acid inhibitor will not inhibit the target transcript sufficiently to exhibit the desired physiological outcome in a subject. Despite availability of siRNA/ASO designing software, testing to identify the one(s) that actually inhibit in a subject is still required. Even Khvorova’s publication provided extensive exemplary studies and, as noted in prior Response to the Remarks, “Khvorova’s disclosure of designing siRNA is not a simple “plug and play,” e.g., the seventh embodiment (par. 60) requires “measuring the gene silencing ability of each siRNA from said set” (par. 60, (b); see also cl. 14) and then determining the amount of improved functionality by the presence or absence of at least one variable noted (par. 60)” (pg. 12 of 02/09/2026 Action).
The issue is not of dosing, as alluded by citing Wong, but rather whether reduction of the claimed transcript will actually treat the elected hypertension condition based on the disclosure of the specification and what is known in the prior art and there is sufficient uncertainty that undue experimentation will be required.
Further, even regarding the siRNA therapeutics in the market, Zhang (1/2021, Biochemical Pharmacology, 189, 1-12) indicates, despite noting some promising possibilities with siRNA drugs, that “[d]espite inclisiran’s projected success, however, some experts caution that it may not live up to expectations,” that although it decreased the target gene’s expression level, it did not achieve desired outcome, i.e. an improved cardiovascular outcome (pg. 8). Thus, it is unpredictable that inhibiting a transcript’s expression at its optimal level will result in desired physiological outcome, here it is unpredictable whether inhibiting expression of SLC9A3R2 in a subject with SLC9A3R2 reference/heterozygous will treat hypertension. Thus undue experimentation will be required.
Thus the examined claims are rejected.
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.
Claim 102 is rejected under 35 U.S.C. 101 because the claimed invention is directed to natural law/phenomenon or an abstract idea without significantly more. The claims recites “a method of identifying a subject having an increased risk of developing hypertension . . . the method comprising determining or having determined the presence or absence of a SLC9A3R2 missense variant nucleic acid molecule encoding an SLC9A3R2 predicted loss-of-function polypeptide in a biological sample obtained from the subject, wherein: when the subject is SLC9A3R2 reference, the subject has an increased risk of developing hypertension . . . and when the subject is heterozygous or homozygous for an SLC9A3R2 missense variant nucleic acid molecule encoding the SLC9A3R2 predicted loss-of-function polypeptide, then the subject has a decreased risk of developing hypertension.”
A correlation that preexists in the human is an unpatentable phenomenon. The last two steps of the claim (“when” clauses) are an association between genetic variations and risk of hypertension and is a law of nature/natural phenomenon.
The “having determined” is no more than a mental step. The “determining or having determined” adds nothing more than looking at a piece of paper or computer screen with a result, i.e. reading the genotype sample of a subject. This mental step falls under the unpatentable category of an abstract idea.
This judicial exception is not integrated into a practical application. The embodiment where the mutation has been determined does not include any elements in addition to the judicial exceptions. Thus, the claim is not integrated into a practical application. Even if the determining is carried out, this step is a mere data gathering step that amounts to insignificant extra solution activity in order for one to make the correlation.
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. The embodiment where the mutation has been determined does not include any elements in addition to the judicial exceptions. Thus, the claim is not directed to significantly more than the judicial exception. Even if the determining is carried out, this step constitutes of sequencing a gene (presumably, the purpose of obtaining the sample) to identify a mutation, which was well known in the art, routine, and conventional at the time of the application filing (see Shiffman, US20170292159, in IDS, e.g., par. 149, 361).
Allowable Subject Matter
No claim allowed.
Conclusion
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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