DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the amendment filed on 07 January 2026. Applicant's arguments and amendments to the claims have been fully considered but do not place the application in condition for allowance. All rejections and objections not reiterated herein are hereby withdrawn.
Claim Status
3. Claims 1, 2, 6, 7, 10-12, 14, 30-32, 34 and 50-51 are pending and have been examined herein. It is noted that claims 10, 14, 30 and 34 encompass non-elected species of PIEZO1 variant nucleic acids other than the elected PIEZO1 nucleic acid variant encoding for a Pro2510Leu / genomic nucleic acid having a nucleotide sequence comprising a thymine at position 69,579 of SEQ ID NO: 2; and claims 7 and 51 encompass the non-elected species of agonists of Jedi1 and Jedi2. Prior to the allowance of the claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Claim Interpretation
4. The specification at para [0049] (note that paragraph numbering herein is with respect to the published application) states “When the subject lacks a PIEZO1 variant nucleic acid molecule encoding a PIEZO1 predicted gain-of-function polypeptide (i.e., the subject is genotypically categorized as PIEZO1 reference), then the subject has an increased risk of developing varicose veins.” Accordingly, the recitation of “a subject that is PIEZO1 reference” is considered to mean a subject that lacks a PIEZO1 variant nucleic acid molecule encoding a PIEZO1 predicted gain-of-function polypeptide.
Maintained Claim Rejections - 35 USC § 101
5. 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 30, 34, 50 and 51 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite “wherein the presence of a genotype having the PIEZOI variant nucleic acid molecule encoding the PIEZO1 predicted gain-of-function polypeptide indicates the subject has a decreased risk of developing varicose veins.” Thus, the claims recite the correlation between the PIEZOI variant nucleic acid molecule encoding the PIEZO1 predicted gain-of-function polypeptide and a decreased risk of developing varicose veins. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The claims recite “obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the PIEZO1 variant nucleic acid molecule encoding the PIEZO1 predicted gain-of-function polypeptide.” These steps do not practically apply the judicial exception.
The claims encompass methods wherein the sequence analysis determines that the subject is homozygous for the PIEZO1 variant nucleic acid encoding a PIEZO1 gain-of-function (GOF) polypeptide. In these instances, the claims do not require performing any additional administering step. In this embodiment encompassed by the claims, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception.
The claims also encompass methods wherein the sequence analysis determines that the subject lacks the PIEZO1 variant nucleic acid / is a PIEZO1 reference and the method further comprises administering or continuing to administer the therapeutic agent that treats or prevents varicose veins in a standard dosage amount to a subject OR the sequence analysis determines that the subject is heterozygous for the PIEZO1 variant nucleic acid, and the method further comprises administering or continuing to administer the therapeutic agent that treats or prevents varicose veins in an amount that is the same as the standard dosage amount. Thus, the claims encompass methods wherein the subject that is PIEZO1 reference is treated in the same manner as a subject that is heterozygous for the PIEZO1 nucleic acid encoding the PIEZO1 GOF polypeptide. Accordingly, In these embodiments encompassed by the claims, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception since subjects with a decreased risk of developing varicose veins are treated in the same manner as subjects at increased risk of developing varicose veins.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. To the extent that the claims encompass methods wherein the subject is one in which a sample was previously obtained from the subject and previously analyzed to determine the PIEZO1 genotype, these claims do not require performing any additional steps in those instances wherein the sequence analysis determines that the subject is homozygous for the PIEZO1 variant nucleic acid. To the extent that the claims encompass methods in which the subject is PIEZO1 reference or is heterozygous for the PIEZO1 variant nucleic acid, the additional administering step is merely an “apply it” step since the administering step encompasses administering any therapeutic agent that treats varicose veins at a standard dosage to a subject that has varicose veins.
To the extent that the claims encompass the embodiment of obtaining a biological sample from the subject and performing a sequence analysis of the sample, these steps were well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification (para [0127]) which discloses that any of the well-known techniques for sequencing can be performed to determine the PIEZO1 genotype.
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims encompass analyzing the sequence of a particular gene - i.e., PIEZO1, the identity of the gene is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence so as to add something ‘significantly more’ to the recited judicial exceptions.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Response to Remarks:
The response asserts that the claims are written in the “Vanda style format.” It is stated that “Applicant reminds the Office that Applicant has not invented a new therapeutic compound, but has rather identified a new portion of the population that can be treated with the recited agents. Indeed, no such association has been previously reported prior to Applicant's filing date. This presents a novel and non-obvious set of subjects to be treated.” It is also stated that the additional elements integrate the judicial exception into a practical application.
These arguments have been fully considered but are not persuasive. As discussed in detail in the rejection, the claims encompass the embodiment of determining that the subject has two copies of the PIEZO1 variant nucleic acid. The claims do not recite that a subject homozygous for the PIEZO1 variant nucleic acid is treated by administering any particular compound. Thereby, the claims encompass methods comprising determining that a subject is homozygous for the PIEZO1 variant nucleic acid and then no administering step is performed. Note that the claims require an administering step only if the subject is PIEZO1 reference or if the subject is heterozygous for the PIEZO1 variant nucleic acid. Accordingly, the claims are not in fact similar to those in the Vanda decision since the claims encompass methods that do not include a final administering step.
Further, the fact pattern herein is not the same as that in Vanda because the claims do not require that the subject is treated differently based on the results of the detecting / determining step so as to practically apply the recited judicial exception of a law of nature. The claims in Vanda required administering 12mg/day or less of iloperidone to subjects having a CYP2D6 poor metabolizer genotype and administering more than 12mg/day, up to 24mg/day, of iloperidone to subjects that do not have a CYP2D6 poor metabolizer genotype. Thereby, the two groups of patients were clearly treated in different manners based on the determined CYP2D6 genotype. In contrast, the present claims encompass the embodiment in which patients determined to have PIEZO1 reference and patients heterozygous for the PIEZO1 variant nucleic acid (at decreased risk for varicose veins) are treated in the same manner. That is, the claims encompass a method that comprises administering or continuing to administer the therapeutic agent that treats or prevents varicose veins in an amount that is the same as the standard dosage amount if the subject is identified as having PIEZO1 reference (at a normal risk for varicose veins) OR if the subject is heterozygous for the PIEZO1 variant nucleic acid (at decreased risk for varicose veins). In these embodiments encompassed by the claims, the administering step is an “apply it” limitation and the claims do not recite a practical application of the judicial exception.
The response argues that the steps of the claim “are concrete steps that are NOT abstract.”
This argument is not understood in the context of the rejection since the rejection does not assert that the claims recite an abstract step. Rather, the rejection states that the claims recite the judicial exception of a law of nature of the correlation between the PIEZOI variant nucleic acid molecule encoding the PIEZO1 predicted gain-of-function polypeptide and a decreased risk of developing varicose veins. For instance, the claims recite “wherein the presence of a genotype having the PIEZOI variant nucleic acid molecule encoding the PIEZO1 predicted gain-of-function polypeptide indicates the subject has a decreased risk of developing varicose veins.” Thus, the claims recite the correlation.
New Claim Rejections - 35 USC § 112(b)
6, 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 14 and 34 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 14 is dependent on canceled claim 13 and claim 34 is dependent on canceled claim 33. Therefore claims 14 and 34 are “incomplete.” See MPEP 608.01(n)(V).
Maintained / Modified Claim Rejections - 35 USC § 112(a) – Written Description
7. 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, 6, 10-12, 14, 30-32, 34 and 50 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description rejection.
In analyzing the claims for compliance with the written description requirements of 35 U.S.C. 112, first paragraph, a determination is made as to whether the specification contains a written description sufficient to show they had possession of the full scope of their claimed invention at the time the application was filed.
For claims drawn to a genus, MPEP § 2163 states:
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").”
MPEP § 2163 goes on to state:
“An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004).”
Claims 1, 2, 6, 10-12, 14, 30-32, 34 and 50 encompass methods of administering a PIEZO1 agonist to a subject to treat varicose veins or to also prevent varicose veins. Claims 6 and 50 limit the agonist to a small molecule.
The claims do not define the required PIEZO1 agonists in terms of a specific structure. The agonist may be any small molecule (claims 6 and 50) or any antibody, enzymes, cyclic peptide or other type of polypeptide, any nucleic acid, including any gene therapy polynucleotide, or any aptamer, antisense RNA, siRNA, shRNA, miRNA, or ribozyme, or any other organic or inorganic molecule.
However, the specification discloses only the PIEZO1 agonists of Yoda1, Jedi1, and Jedi2, which are small molecules and known in the prior art.
The specification does not describe in terms of their complete structure or other relevant identifying characteristics other PIEZO1 agonists, including agonists that are not small molecules. There is also no disclosure that a representative number of other PIEZO1 agonists are known in the prior art.
Accordingly, the claims encompass administering a significantly large genus of possible PIEZO1 agonists. The variation encompassed by the presently claimed genus of PIEZO1 agonists is large and the specification does not establish that the 3 small molecules described therein is representative of the claimed genus. Nor does the disclosure provide any evidence to establish that there is a common structure shared by the diverse PIEZO1 agonists. The disclosure therefore does not show that Applicant was in possession of the necessary common attributes or features possessed by the members of the claimed genus of PIEZO1 agonists that are to be administered to subjects to treat or prevent varicose veins. Accordingly, the skilled artisan would not recognize that Applicant was in possession of the invention as broadly claimed at the time the application was filed.
Note that the purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 48 USPQ2d 1398 (CAFC 1997).
Additionally, the Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties, “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a polypeptide is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877- 78 (Fed. Cir. 2011).
Additionally, Cf. University of Rochester v G.D. Searle & Co., Inc., Monsanto Company, Pharmacia Corporation, and Pfizer Inc., No. 03-1304, 2004 WL 260813 (Fed. Cir., Feb. 13, 2004) held that:
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.
As noted in Vas-Cath Inc. v. Mahurkar (19 USPQ2d 1111, CAFC 1991), the Federal Circuit concluded that:
"...applicant must also convey, with reasonable clarity to those skilled in art, that applicant, as of filing date sought, was in possession of invention, with invention being, for purposes of "written description" inquiry, whatever is presently claimed."
With respect to the present invention, there is no record or description which would demonstrate conception of a representative number of the diverse PIEZO1 agonists required by the claims. Therefore, the claims fail to meet the written description requirement because the claims require a significantly large genus of PIEZO1 agonists which are not described in the specification. Response to Remarks:
It is first noted that those aspects of the prior rejection as they pertained to the PIEZO1 variant nucleic acid encoding a PIEZO1 predicted gain-of-function polypeptide have been obviated by the amendment to claims 10-12, 30-32, 50 and 51 to recite “a PIEZO1 variant nucleic acid molecule encoding a PIEZO1 predicted gain-of-function polypeptide encoding PIEZO1 Pro2,510Leu, Pro2,024Leu, Pro2,079Leu, or Pro92Leu.”
Regarding the claimed genus of PIEZO1 agonists, the response argues:
“Applicant's specification identifies PIEZO1 agonists, including but not limited to Yodal, Jedi 1, and Jedi2 (see, paragraph [0044]). These examples are known in the art and were already characterized as PIEZO1 activators at the time of filing. All identified agonists share a unifying functional property - activation of PIEZO1resulting in modulation of vascular tone and mechanotransduction signaling. These mechanistic commonalities, not their chemical bone, defines the genus and provides a clear objective boundary to the claimed subject matter.”
These arguments have been fully considered but are not persuasive. First, while the specification at para [0044] states “Examples of PIEZO1 agonists include, but are not limited to, Yoda1, Jedi1, and Jedi2,” the specification does not teach any additional PIEZO1 agonists. The response does not point to any additional PIEZO1 agonists disclosed in the specification or in the prior art. Further, while PIEZO1 agonists may have a common function, they do not have a common structure associated with that function, particularly given the breadth of the claims which encompass agonists that are any antibody, enzymes, cyclic peptide or other type of polypeptide, any nucleic acid, including any gene therapy polynucleotide, or any aptamer, antisense RNA, siRNA, shRNA, miRNA, or ribozyme, or any other organic or inorganic molecule, as well as any small molecule that activates a PIEZO1 receptor. As set forth in the rejection, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus.
It is maintained that the disclosure in the specification (and prior art) of 3 PIEZO1 agonists that are small molecules - i.e., Yoda1, Jedi1, and Jedi2 - does not constitute a representative number of species within the broadly claimed genus of any PIEZO1 agonist.
Maintained / Modified Claim Rejections - 35 USC § 112(a) - Enablement
8. Claims 1, 2, 6, 7, 10-12, 14, 30-32, 34, 50 and 51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of treating a subject at increased risk of having or developing varicose veins, the method comprising: a) determining whether the subject has a Piezo Type Mechanosensitive Ion Channel Component 1 (PIEZO1) variant nucleic acid molecule that encodes for a PIZEO1 polypeptide having a Pro2501Leu substitution by: (i) obtaining or having obtained a biological sample from the subject; and (ii) performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the PIEZO1 variant nucleic acid molecule encoding the PIEZO1 polypeptide having the Pro2501Leu substitution; b) determining that the subject lacks the genotype comprising the PIEZO1 variant nucleic acid molecule encoding the PIEZO1 polypeptide having the Pro2501Leu substitution; and c) following step b), administering to the subject a therapeutic agent that treats varicose veins, wherein the therapeutic agent is a flavonoid or an anti-inflammatory agent,
does not reasonably provide enablement for methods that treat or prevent varicose veins comprising administering any PIEZO1 agonist or the particular PIEZO1 agonists of Yoda1, Jedi1 or Jedi2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
Claims 1, 2, 6-7, 10-12, 14, 30-32, 34 and 50-51 encompass methods of administering a PIEZO1 agonist to a subject to treat varicose veins or to also prevent varicose veins (claims 30-32, 34 and 50). Claims 6 and 50 limit the PIEZO1 agonist to a small molecule. With respect to the elected species, claims 7 and 51 limit the PIEZO1 agonist to Yoda1; claims 7 and 51 also recite the non-elected species of Jedi1 and Jedi2.
The specification discloses only the PIEZO1 agonists of Yoda1, Jedi1, and Jedi2, which are small molecules and known in the prior art.
However, there is no evidence of record to establish that it was conventional in the prior art to treat varicose veins by administering a PIEZO1 agonist. The specification does not provide any examples in which a PIEZO1 agonist is administered to a subject to treat or prevent varicose veins. Rather, in discussing the PIEZO1 Pro2051leu mutation, the specification (p. 100) states:
“The new protective association with rs61745086:A, which replicated in the GHS cohort (2,243 carriers; OR=0.66, 95% Cl 0.47 to 0.93, P=0.017), suggests that this missense variant likely has a gain-of-function effect. This is important because it suggests that activation of PIEZO1 may provide a therapeutic pathway for a common condition with no available pharmacological interventions.”
Yet, there is no evidence of record to support the hypothesis that treatment with a PIEZO1 agonist in subjects that do not have a PIEZO1 nucleic acid variant encoding for any gain-of-function PIEZO1 mutation will alleviate or prevent varicose veins. Nor is there any evidence of record to support the contention that administration of a PIEZO1 agonist to subjects having any PIEZO1 genotype (as encompassed by claims 1, 2, 6, and 7) or subjects having the PIEZO1 variant encoding for a gain of function PIEZO1 polypeptide (as encompassed by claims 10-12, 14, 30-32, 34, 50 and 51) will treat or prevent varicose veins.
In the absence of any evidence establishing the effect of a PIEZO1 agonist on varicose veins or the development of varicose veins in subjects having any PIEOZ1 genotype, or having a PIEOZ1 nucleic acid variant encoding for a gain-of-function mutation or a genotype that lacks a PIEZO1 nucleic acid variant encoding for a gain-of-function mutation, there is a high level of unpredictability in the art as to whether such agonists can be used to treat varicose veins or prevent the occurrence of varicose veins.
The unpredictability in the art is supported by the post-filing date teachings of Zhao et al (Molecular and Cellular Biochemistry (2025) 480:2423–2435). Zhao teaches that PIEZO1 expression was significantly increased in vein tissue from human subjects having varicose veins as compared to non-varicose vein tissue / normal vein tissue (p. 2426, col. 1). Zhao (p. 2426, col. 2) states:
“Further analysis revealed that the mRNA abundance of PIEZO1 was more than tenfold higher than that of PIEZO2 in clinical VVs, highlighting the potential role of PIEZO1 in VVs disease (p<0.05, Fig. 1B). We also investigated the Piezo1 abundance in mouse veins. Similarly, higher mRNA abundance of Piezo1 also was observed in mouse compared to Piezo2 and Casz1 (p<0.05, Fig. 1C).”
This supports the position that it is unpredictable as to whether increasing the level of PIEZO1 (by administering a PIEZO1 agonist) would alleviate the symptoms of or prevent varicose veins.
Zhao further teaches administering the PIEZO1 agonist Yoda1 to mice (p. 2426 col. 2 to p. 2427, col. 1). Zhao (p. 2426 col. 2 to p. 2427, col. 1) reports that:
“The laser speckle imaging system showed that Yoda1 administration increased the blood perfusion ratio caused by VVs compared to the vehicle group, which leading exacerbated varicose vein after iliac occlusion (p < 0.05, Fig. 3B&C). Further immunofluorescence staining showed that VVs induced CD45+ leukocyte and CD68+ macrophage infiltration, which was aggravated by Yoda1 administration (Fig. 3D). This suggested that pharmacological activation of PIEZO1 exacerbated VVs in mice by promoting inflammatory cell infiltration.”
Zhao discusses the discrepancies between their work and results reported in the prior art, stating:
“the activation of leukocytes may be responsible for the effect of Yoda1 on the aggravation of experimental VVs [36]. Third, although causal genes PIEZO1 with VVs have been demonstrated by the above researches, polypeptide-truncating variants and LOF variants of PIEZO1 in these cases are rare (MAF<1%) [9, 14]. Therefore, further studies are needed to determine how Piezo1 works to regulated VVs” (p. 2433, col. 1).
Further, the specification does not provide sufficient guidance as to how to make and use a representative number of the broadly claimed agonists of PIEZO1.
The specification does not describe in terms of their complete structure or other relevant identifying characteristics other PIEZO1 agonists, including agonists that are not small molecules. There is also no disclosure that a representative number of other PIEZO1 agonists are known in the prior art.
With the exception of claims 7 and 51, the claims encompass administering a significantly large genus of possible PIEZO1 agonists. The agonist may be any small molecule (claims 6 and 50) or any antibody, enzymes, cyclic peptide or other type of polypeptide, any nucleic acid, including any gene therapy polynucleotide, or any aptamer, antisense RNA, siRNA, shRNA, miRNA, or ribozyme, or any other organic or inorganic molecule.
The variation encompassed by the presently claimed genus of PIEZO1 agonists is large and the specification does not establish that the 3 small molecules described therein is representative of the claimed genus. Nor does the disclosure provide any evidence to establish that there is a common structure shared by the diverse PIEZO1 agonists. It is highly unpredictable as to what would be the structure of additional PIEZO1 agonists, in the absence of a common structure for the agonists.
In the absence of specific guidance as to the identity of such PIEZO1 agonists (e.g., their structure, biological activity and route of administration), in vivo therapies are highly unpredictable. For example, regarding polypeptide pharmaceuticals, such therapies are unpredictable for the following reasons: (1) the polypeptide maybe inactivated before producing an effect, i.e. such as proteolytic degradation, immunological inactivation or due to an inherently short half-life of the polypeptide: (2) the polypeptide may not reach the target area because, e.g., the polypeptide may not be able to cross the mucosa or the polypeptide may be adsorbed by fluids, cells and tissues where the polypeptide has no effect; and (3) other functional properties, known or unknown, may make the polypeptide unsuitable for in vivo therapeutic use, such as adverse side effects prohibitive to the use of such treatment. Therefore, for each polypeptide, one must develop de novo the appropriate set of parameters for in vivo function and delivery.
As stated in MPEP 2164.03:
“The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The 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. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) (‘Nascent technology, however, must be enabled with a ‘specific and useful teaching.’ The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee’s instruction. Thus, the public’s end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology.’ (citations omitted)).”
Further, as set forth in Rasmusson vs. SmithKIine Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention. Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
In the present situation, the art of small molecule, polypeptide, antibody and nucleic acid therapeutics to treat cancer is highly unpredictable. Yet, the specification does not provide any specific guidance as to how to make and use a representative number of the diverse types of PIEZO1 agonist therapies for treating or preventing varicose veins.
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Response to Remarks:
It is first noted that those aspects of the prior rejection as they pertained to the PIEZO1 variant nucleic acid encoding a PIEZO1 predicted gain-of-function polypeptide have been obviated by the amendment to claims 10-12, 30-32, 50 and 51 to recite “a PIEZO1 variant nucleic acid molecule encoding a PIEZO1 predicted gain-of-function polypeptide encoding PIEZO1 Pro2,510Leu, Pro2,024Leu, Pro2,079Leu, or Pro92Leu.”
Regarding those aspects of the prior rejection pertaining to treatment of varicose veins with a PIEZO1 agonists, the response argues:
“The specification identifies PIEZO1 agonists, including but not limited to Yodal, Jedi1, and Jedi2 (see, paragraph [0044]). These examples are known in the art and were already characterized as PIEZO1 activators at the time of filing. All identified agonists share a unifying functional property - activation of PIEZO1 resulting in modulation of vascular tone and mechanotransduction signaling. These mechanistic commonalities, not their chemical bone, defines the genus and provides a clear objective boundary to the claimed subject matter. Because these compounds and their activity as PIEZO1 agonists were well established in scientific literature, a person of ordinary skill in the art would have readily understood that administration of any such PIEZO1 agonists to subjects exhibiting PIEZO1-related dysfunction or risk factors would produce the intended protective or therapeutic effects against varicose veins.”
These arguments have been fully considered but are not persuasive. First, contrary to Applicant’s assertion, the disclosure of 3 small molecules (i.e., Yoda1, Jedi1, and Jedi2) in the prior art that are PIEZO1 agonists does not constitute a representative number of species in the genus of PIEZO1 agonists required by the claims. Secondly, the specification does not in fact establish that treatment with a representative number of PIEZO1 agonists results in modulation of vascular tone and that such agonists can be used to treat or prevent varicose veins in any subject, including subjects which have wildtype / reference PIEZO1, or loss of function PIEZO1 or gain of function of PIEZO1, as encompassed by claims 1, 2, 6, and 7. Lastly, the administration of PIEZO1 agonists to treat any condition was not in fact readily understood in the prior art, particularly in the context of the treatment or prevention of varicose veins.
The response further argues:
“by disclosing representative species (such as Yodal, Jedi1, and Jedi2) and the underlying mechanism of PIEZO1 activation, the present application provides sufficient functional guidance to a person skilled in the art to enable the claimed methods. The state of art already provided extensive information about PIEZO1 activation assays and vascular mechanotransduction pathways, eliminating the need for undue experimentation. When considered in the light of the specification and the art-recognized function of PIEZO1 agonists, the claims are fully enabled. Moreover, the Office's reliance on Zhao (Mol. Cell. Biochem., 2025, 480, 2423-2435) does not support the conclusion of unpredictability. Rather, Zhao confirms the established role of PIEZO1 in vascular remodeling and mechanosensitive signaling, which directly supports the mechanistic basis of the present application.
These arguments have been fully considered but are not persuasive. Disclosing the function of an agonist is not sufficient to describe the genus of agonists and does not establish that the artisan can make and use a representative number of PIEZO1 agonists to treat or prevent varicose veins without undue experimentation.
Regarding the Zhao reference, this reference does not in fact “directly supports the mechanistic basis of the present application,” as argued by Applicant. Zhao teaches the opposite result because Zhao teaches that the PIEZO1 agonists of Yoda1 (recited in claims 7 and 51) exacerbated varicose veins in mice ((p. 2426 col. 2 to p. 2427, col. 1). The teachings of Yoda also support the finding of unpredictability in the art of treating a subject with a PIEZO1 agonist because Zhao teaches that “the mRNA
abundance of PIEZO1 was more than tenfold higher than that of PIEZO2 in clinical VVs, highlighting the potential role of PIEZO1 in VVs disease” (p. 2426, col. 2). This finding of Zhao supports the position that it is unpredictable as to whether increasing the level of PIEZO1 (by administering a PIEZO1 agonist) would alleviate the symptoms of or prevent varicose veins.
The enablement rejection is maintained for the reasons set forth above.
Conclusion
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.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682