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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/07/2026 has been entered.
Status of Claims
Claims 16 and 20-35 are pending following the Reply filed 05/07/2026. Claims 17-19 have been cancelled. Claims 16, 20, 22, 26 and 31-32 have been amended without introducing new matter. Claims 16 and 20-35 have been examined on the merits.
Claim Objections
Claim 31 is objected to because of the following informalities:
For clarity, please amend the phrase “the sample comprising saliva and the sample pad configured to receive the saliva” in lines 3-4 to recite “wherein the sample comprises saliva and the sample pad is configured to receive the saliva”.
Appropriate correction is required.
Withdrawn
The objection to the specification is withdrawn in light of the amendments.
Any objection or rejection of claims 17-19 is moot because the claims have been cancelled.
The objections to claims 22 and 32 are withdrawn in light of the amendments.
The rejection of claims 16 and 21-30 under 35 U.S.C. 112(a) is withdrawn in light of the amendments. In particular, the limitations of cancelled claim 19, which was free of this rejection, have been incorporated into independent claim 16. See Response to Arguments for further discussion.
The rejection of claims 21, 23 and 26 under 35 U.S.C. 101 are withdrawn in light of the amendments. See analysis under 35 U.S.C. 101 for further discussion.
Maintained Rejections and New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112(b)
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.
Claim 26 is 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 26 recites the limitation, “cells containing a nucleic acid vector wherein the cells containing the nucleic acid vector comprises a region encoding a Klotho protein” which renders the claim indefinite, because it is unclear whether (1) the vector comprises the region encoding a Klotho protein or (2) the cells comprise the region encoding the protein. Note that the second interpretation is broader in scope, because the nucleic acid vector is not required to comprise said “region”. Here, the plain meaning of the phrase, “wherein the cells containing the nucleic acid vector comprises a region encoding a Klotho protein” is that the cells comprise the region, which does not require the vector to comprise said region. However, it may be more narrowly interpreted that the purpose of the vector is to comprise the region that encodes the protein. Moreover, the use of the term “comprises” (instead of “comprise” or “comprising”) is grammatically incoherent (i.e., “cells… comprises” or “cells containing…the vector comprises”) which leads to confusion regarding the intended scope of the claim.
Suggestions to obviate the rejection: Applicant may, for example, amend the limitation to recite “administering a therapeutically effective number of cells containing a nucleic acid vector wherein
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 16, 20, 22, 24-25 and 27-30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the observation of a natural phenomenon without significantly more.
Step 1: It must first be determined if the claim is to a statutory category and, if so, proceed to step 2A prong 1. In this case:
Claims 16 and 20-30 are methods and fall within the statutory category of a process.
Step 2A, prong 1: Prong 1 requires the Examiner to evaluate whether the claim recites a judicial exception and, if so, proceed to prong 2. In this case:
Independent claim 16 recites a method for determining a content of Klotho in a patient to determine a health status of the patient and adjust a treatment for the patient, the method comprising a step of measuring a content of Klotho in saliva to determine whether the content of Klotho is at or above a pre-selected threshold.
Similarly, independent claim 20 recites a method for determining a content of Klotho in a patient to determine a health status of the patient and adjust a treatment for the patient, the method comprising a step of measuring a content of Klotho in saliva to determine whether the content of Klotho is at or above a pre-selected threshold.
Thus, the claims are directed to the observation of certain naturally occurring biomarkers (Klotho) in saliva and using this information to “determine” a health status of a patient, which is the observation of a natural correlation/phenomenon which exists in principle apart from any human action and represents a judicial exception.
Step 2A, prong 2: Prong 2 requires the Examiner to evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception and, if not, proceed to step 2B. In order to integrate the recited judicial exception into a practical application, the claim will apply, rely on, or use the judicial exception that imposes a meaningful limit such that the claim is more than a drafting effort to monopolize the judicial exception. Examiners evaluate integration by identifying additional elements in the claim beyond the judicial exception and evaluating those elements individually and in combination to determine whether they integrate the exception in to a practical application. Examples that have been found by the Courts in which the exception was not integrated into a practical application include:
- Mere instructions to implement an abstract idea on a computer
- Adding generic instructions that the judicial exception should be used ("apply it")
- Adding insignificant extrasolution activity to the exception ("mere data gathering")
- Generally linking the use of the exception to a particular technological environment or field of use
In this case:
Independent claims 16 and 20 recite measuring the content of Klotho in saliva “via a diagnostic kit”, which does not affect the inquiry, because the nature of the test itself does not alter the conclusions as to whether the step of measuring Klotho integrates the judicial exception. The Courts have recognized that “mere data gathering” is not a practical integration of a judicial exception. In the instant case, the use of a diagnostic kit is directed to the necessary steps required to observe the judicial exception and represents no more than mere data gathering. See, e.g., MPEP §2106.04(d) and §2106.05(g) for additional discussion, including the indication that determining the level of biomarkers in blood and performing clinical tests are explicitly enumerated examples of “mere data gathering”.
Independent claim 16 further recites a step of “administering at least one treatment to the patient to increase the content of the Klotho to at least the pre-selected threshold”. When determining whether a claim applies or uses a recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, the treatment or prophylaxis limitation must be “particular”, i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). A claim that recites a step of “administering a suitable medication to a patient” is not particular, and is instead merely instructions to “apply” the exception in a generic way. Similarly, the limitation of “administering at least one treatment… to increase the content of the Klotho” is recited at a high level of generality, encompassing essentially any treatment to increase the content of Klotho, and fails to integrate the judicial exception into a practical application. See MPEP 2106(d)(2).
Conversely, Claim 20 does not recite a further method step, and the method ends after the observation of the natural phenomenon. This is similar to the decision in Mayo (566 U.S. 66 (2012)) where the claims also ended after the observation and was considered no more than “informing the doctor that metabolite concentrations above or below these thresholds ‘indicate a need’ to decrease or increase (respectively) the drug dosage”. Hence, claim 20 does not recite any additional elements sufficient to integrate the judicial exception into a practical application.
Claim 22 recites the method of claim 16, wherein the administering of the at least one treatment to the patient comprises subjecting the patient to muscle training. However, the broadest reasonable interpretation of “subjecting the patient to muscle training” would include any amount of muscle training. A person of skill would recognize that all living organisms comprising muscle tissue are naturally subjected to some degree of muscle training, because this is a natural function of having and using muscles. Hence, the further limitation of the claim does not provide a particular treatment or impose a meaningful limit on the judicial exception in order to integrate the exception under MPEP 2106(d)(2).
Conversely, claims 21, 23 and 26 recite the method wherein the administering step comprises “injecting stem cells that express Klotho”, “subjecting the patient to muscle training”, “administering a therapeutically effective number of mesenchymal stem cells that produce Klotho”, and “administering a therapeutically effective number of cells containing a nucleic acid vector… [comprising] a region encoding a Klotho protein”, respectively. In this case, these limitations (a) are particular, (b) have a significant relationship to the exception, and (c) and impose a meaningful limit on the judicial exception (see MPEP 2106(d)(2)). Therefore, the additional elements of claims 21-23 and 26 integrate the judicial exception into a practical application, and these claims are excluded from further analysis.
The claims also recite wherein the diagnostic kit comprises an immune assay having at least one antibody or aptamer that binds to Klotho (claim 28), a double antibody sandwich assay or a competitive assay (claim 29), or a lateral flow assay (claim 30). However, all of these additional elements are insignificant extra-solution activities. The Courts have recognized that “mere data gathering” is not a practical integration of a judicial exception. These additional elements are all directed to the necessary steps required to observe the judicial exception and represent no more than mere data gathering. See, e.g., MPEP §2106.04(d) and §2106.05(g) for additional discussion, including the indication that determining the level of biomarkers in blood and performing clinical tests are explicitly enumerated examples of “mere data gathering”.
Step 2B: Where a claim does not integrate the exception, a claim may nevertheless be patent eligible, for example where additional elements are “significantly more” than the exception such that the additional elements were unconventional in combination. Considerations include whether or not the claim adds a specific limitation or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; or simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may not be present. In this case:
Independent claim 16 further recites a step of “administering at least one treatment to the patient to increase the content of the Klotho to at least the pre-selected threshold”. This further limitation is recited at a high level generality, encompassing essentially any treatment to raise Klotho content, without any limitation as to how the recited effect of the treatment may be accomplished. Therefore, this limitation merely indicates a field of use in which to apply the judicial exception and does not amount to an inventive concept or significantly more than the exception itself.
Claim 28-30 recite the claimed method, wherein the diagnostic kit comprises an immune assay having at least one antibody or aptamer that binds to Klotho (claim 28), a double antibody sandwich assay, a competitive assay (claim 29), or a lateral flow assay (claim 30), which are well-understood, routine, and conventional activities in the field of biological testing. For example, Cox et al. (previously cited) teach that immunoassays are used to quantify molecules of biological interest based on the specificity and selectivity of antibody reagents generated (see Abstract), that immunoassays are used when an unknown concentration of an analyte within a sample needs to be quantified (see pg. 3, para. 2), and that sandwich assays tend to be more sensitive and robust and therefore tend to be the most commonly used (see pg. 7, para. 6). According to Koczula et al. (previously cited), lateral flow assays are the technology behind low-cost, simple, rapid and portable detection devices popular in biomedicine, agriculture, food and environmental sciences (see Abstract), and are widely used in hospitals, physicians offices and clinical laboratories, wherein a variety of biological samples can be tested, including saliva and serum (see pg. 111, para. 1). Thus, once informed of the relevance of determining Klotho content in a biological sample, those in the art at the time of filing would have thought to use the well-understood and routine activity of an immunoassay, including the examples recited in the claim, which conventionally includes at least one antibody which specifically binds to the molecule of interest (in this case, Klotho).
The Court in Ameritox v Millennium 88 F.Supp.3d 885 (2015) determined that while the decision in Mayo tied the notion of well-understood and conventional steps to "activity already engaged in by the scientific community", the Court when deciding Myriad v Ambry couched the question as "techniques that a scientist would have thought" to use. Thus, the relevant question when determining whether or not a technique was routine and conventional is not necessarily that the steps were strictly practiced in the art prior to the invention as in Mayo, but whether the techniques are those that would have been thought of by the artisan given the relevant information. This conclusion is supported not only by the Ameritox case, but also by the decision in Ariosa v Sequenom, where the sample was clearly unconventional (maternal plasma had routinely been disregarded as medical waste) but when provided with information regarding the natural relationship between cffDNA in maternal plasma and a diagnosis, the remaining portion of the claim was drawn to no more than "known laboratory techniques".
Thus, there is simply no argument that any portion of the claims, other than the judicial exception itself (what the Klotho indicates) was not routine, well-known, or conventional. Whether or not Applicant discovered that this particular biomarker existed in saliva and whether or not Applicant discovered the importance of those levels is immaterial to a step 2B analysis because they are part of the judicial exception, and an inventive concept “cannot be furnished by the unpatentable law of nature (or natural phenomenon) itself” (MPEP §2106.05).
Accordingly, the remainder of the claims which are more broadly drawn to essentially any testing method via a diagnostic kit, and a generically recited administration step encompassing any suitable treatment for raising Klotho levels, do not require any additional elements that are unconventional in combination. Furthermore, the instant method of these claims is recited at such a high level of generality (i.e., the measuring of Klotho content in saliva by essentially any means possible) that the method covers most known methods of detecting a protein in a sample, and what this measurement indicates is necessarily directed to the judicial exception without significantly more.
Taken as a whole and following current guidance for patent eligibility, the claims fail to meet the standard for patent eligibility as the claims are directed to a judicial exception without significantly more. The claims amount to a drafting effort to monopolize observation of a natural phenomenon by warning others as to what that phenomenon indicates, which is what the judicial exceptions criticize and are in place to prevent.
Therefore, claims 16, 20, 22, 24-25 and 27-30 are not patent eligible.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 16 and 20-30 are rejected under 35 U.S.C. 103 as being unpatentable over Tarsio (US 20190169593 A1; cited in the IDS filed 06/16/2025), and further in view of Dubal et al. (US 20230123357 A1; effectively filed 03/04/2020; cited on Form 892), hereafter, “Dubal 2023”.
Regarding claim 16, Tarsio teaches methods of detecting, monitoring, and quantifying Klotho protein levels, particularly soluble alpha Klotho protein levels, in a mammalian blood sample, methods of diagnosing Klotho protein deficiency, and methods of increasing Klotho protein levels or production in a human or non-human mammalian subject (see Abstract). Tarsio teaches that circulating levels of soluble Klotho proteins in mammals, including humans, are thought to decrease with age, and Klotho has been implicated in a number of cellular processes related to aging (see pg. 1, para. [0006]). Tarsio teaches that the aging of the human body, for instance, is associated with the decline of cellular function, which can lead to the development of a variety of a diseases (see pg. 1, para. [0007]). Tarsio teaches that the population of aging individuals is rapidly increasing globally, and recombinant klotho proteins may provide promising therapeutic agents to counter age-related health conditions (see pg. 1, para. [0008]). Tarsio teaches a need for a product or method for efficiently, reliably, reproducibly, practically, and/or economically monitoring soluble alpha Klotho protein levels or protein variant levels and for diagnosing Klotho protein deficiency in human and non-human animals (see pg. 2, para. [0011]).
Tarsio teaches a method that includes determining the serum soluble Klotho protein concentration of a subject, calculating a pharmaceutically effective amount of a composition to raise soluble Klotho protein levels, and administering the composition to the subject (see pg. 6, para. [0044]) in order to treat one or more aging-related conditions (see pg. 6, para. [0046]). Tarsio teaches embodiments that include a kit for detecting and quantifying Klotho protein levels, particularly, endogenous and/or exogenous soluble alpha Klotho protein levels (see pg. 13, para. [0145]), such as a lateral flow test with a quantification/measurement indicator (see pg. 13, para. [0144]). Tarsio teaches that such conditions include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and/or multiple sclerosis (MS) (see pg. 6, para. [0047]). Tarsio also teaches that the method can be useful in treating cancer and in reversing or attenuating age-related therapy resistance in melanoma or other cancers (see pg. 7, para. [0048]).
Tarsio does not teach the method wherein the sample collected from the patient for testing is saliva.
However, Tarsio teaches that venous blood draws typically require a professional phlebotomist and are “inconvenient and painful to the patient” (see pg. 13, para. [0141]), and “there is not currently a product (e.g., kit or system) or method for efficiently, reliably, reproducibly, practically, and/or (commercially or economically) viably monitoring Klotho protein levels” (see pg. 2, para. [0011]). Thus, Tarsio teaches there to be a design need for more efficient, practical and convenient methods and kits for measuring Klotho, and a person of ordinary skill would have been motivated to reach another workable product or process.
Dubal 2023 teaches methods of monitoring Klotho activity (see Abstract) in an animal, such as a human, wherein the Klotho activity is measured either before administration (e.g., to identify how likely an animal will be responsive to Klotho) or after administration of Klotho to measure Klotho’s effect on downstream intermediates (see pg. 3, para. [0028]). Dubal 2023 teaches obtaining a sample from the animal to measure a quantity or activity, comparing the quantity or activity to a control value, and then administering an effective dose of a Klotho polypeptide (see pg. 1, para. [0005]). Dubal 2023 teaches that the biological sample obtained from the patient may include saliva (see pg. 11, para. [0032]). Dubal 2023 teaches that a number of immunoassay formats are known and can be used, such as a direct or competitive immunoassay (see pg. 11, para. [0030]).
Dubal 2023 teaches that the Klotho protein has been described for use in various clinical settings, including for improving cognition and kidney disease among other diseases (see pg. 1, para. [0003]). Dubal 2023 teaches that in mice, transgenic overexpression of klotho extends lifespan and associates with better cognitive functions in the normal and diseased brain, and increased Klotho secretion has been shown to promote longevity and is associated with better baseline cognitive functions in aging populations (see pg. 14, para. [0039]). Dubal 2023 teaches that individuals in need of improved cognitive function include those with age-related cognitive decline, a neurodegenerative disease, or a brain injury due to brain cancer, radiation or chemotherapy (see pg. 2, para. [0014]).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Tarsio and Dubal 2023 because both disclosures teach methods for monitoring a content of Klotho in a patient to determine a health status and to adjust a treatment for said patient. One would have recognized from both disclosures that diagnostic kits can be used to determine whether the content of Klotho is at or above a control level (i.e., a pre-selected threshold) to determine a pharmaceutically effective amount of a composition for administering to the patient to increase Klotho protein levels. One would have been motivated to combine these teachings, because both disclosures teach that multiple conditions associated with aging may be monitored and treated by using Klotho, such as neurodegenerative diseases, and Tarsio teaches a need in the art for better methods to monitor and treat such conditions due to the rapidly increasing global population of aging individuals. Hence, one would have been motivated to seek alternative methods to detect and/or monitor Klotho levels, and would have recognized from Dubal 2023 that the quantity or activity of Klotho can be determined using saliva, which is more convenient and less painful than previous methods. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103). Furthermore, there would have also been a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g. MPEP 2121(I)) for all that it discloses (see, e.g., MPEP 2123(I)-(II)).
Regarding claim 20, Tarsio teaches the method wherein the aging-related condition that can be effectively treated by raising soluble Klotho protein levels includes multiple sclerosis (MS) (see pg. 6, para. [0047]). Hence, it would have been obvious to have measured a content of Klotho in saliva of a patient having this condition for the same reasons discussed regarding claim 16.
Regarding claim 21, Tarsio teaches suitable routes of administration include injection (see pg. 74, para. [0414]). Tarsio teaches the composition for administering to the individual to include a cell suspension culture comprising one or more cells that each express a recombinant human alpha soluble Klotho protein (see pg. 2, para. [0015]). Tarsio also teaches a combination product, comprising a therapeutic recombinant Klotho protein in combination with human stem cells (see pg. 85, para. [0519]), the administration of which provides synergistic outcomes for subjects in need thereof (see pg. 85, para. [0518]). Hence, it would have been obvious for the step of administering to comprise injecting stem cells expressing Klotho into the patient.
Regarding claim 22, Tarsio teaches that serum Klotho protein levels may also enhance or support muscle regeneration in athletes and other patients; accordingly, embodiments can include administering a composition prophylactically (pre-workout) and/or following exercise (see pg. 79, para. [0461]). Hence, as Tarsio teaches embodiments which include subjecting the patient to exercise before and/or after being administered a treatment to increase Klotho levels, it would have been obvious to subject the patient to muscle training.
Regarding claim 23, Tarsio teaches the composition administered to the patient is a cell suspension culture comprising one or more cells that each express a recombinant human alpha soluble Klotho protein (see pg. 2, para. [0015]). Tarsio also teaches a combination product, comprising a therapeutic recombinant Klotho protein in combination with human stem cells (see pg. 85, para. [0519]), the administration of which provides synergistic outcomes for subjects in need thereof (see pg. 85, para. [0518]). Tarsio teaches that the stem cells can comprise mesenchymal stem cells (see pg. 85, para. [0520]). Hence, it would have been obvious for the step of administering to comprise administering a therapeutically effective number of mesenchymal stem cells that produce Klotho.
Regarding claim 24, Tarsio teaches a pharmaceutically effective and/or sufficient amount of purified recombinant S-klotho protein can be administered so as to raise the serum soluble Klotho protein concentration of the subject to any suitable level, such as equal to 100 pg/mL (see pg. 75, para. [0420]).
Regarding the limitation “at a ratio of Klotho content in serum to Klotho content in saliva of 3.6:1”, this ratio is presumed to be a natural and inherent property of Klotho content in serum versus saliva. Moreover, when determining the Klotho content of serum and saliva in the patient, a person of ordinary skill would have necessarily arrived at this ratio through no more than routine optimization. This is similar to Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989), wherein “the claimed ratios were obvious as being reached by routine procedures and producing predictable results” (see MPEP 2144.05(II)(A)). In the instant case, one would have only needed to compare the levels of Klotho in a patient’s serum and saliva to have arrived at the claimed ratio.
Furthermore, Tarsio provides a known result-effective variable for Klotho protein concentration in serum, which would have provided sufficient motivation for the ordinary artisan to determine the corresponding value in saliva. See MPEP 2144.05(II)(B) which states that “a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation” while “the Supreme Court held that ‘obvious to try’ was a valid rationale for an obviousness finding, for example, when there is a ‘design need’ or ‘market demand’ and there are a ‘finite number’ of solutions”.
In the instant case, the disclosures of Tarsio and Dubal 2023 disclose a finite number of solutions (i.e., biological materials which can be tested, such as serum and saliva), while Tarsio provides a result-effective variable (i.e., Klotho concentration in serum). Tarsio also teaches that venous blood draws typically require a professional phlebotomist and are “inconvenient and painful to the patient” (see pg. 13, para. [0141]), and “there is not currently a product (e.g., kit or system) or method for efficiently, reliably, reproducibly, practically, and/or (commercially or economically) viably monitoring Klotho protein levels” (see pg. 2, para. [0011]). Thus, Tarsio teaches there to be a design need for more efficient, practical and convenient methods and kits for measuring Klotho, and a person of ordinary skill would have been motivated to reach another workable product or process. Hence, it would have been obvious to have determined the correlation between serum Klotho levels and saliva Klotho levels in order to apply the result-effective variable taught by Tarsio for the testing of saliva.
Regarding claim 25, Tarsio teaches a pharmaceutically effective and/or sufficient amount of purified recombinant S-klotho protein can be administered so as to raise the serum soluble Klotho protein concentration of the subject to any suitable level, such as between 100 and 250 pg/mL (see pg. 75, para. [420]). Hence, the claimed value of 200 pg/mL is included within the broader range taught by Tarsio. "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). Further, there is no evidence in Applicant’s disclosure to support the claimed value being critical. See MPEP 2144.05(II)(A) which states:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). (Emphasis added)
See also MPEP III 2144.05(III)(A) which states:
"The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). (Emphasis added)
In the instant case, the claimed value falls within the prior art range, and, without any evidence of the claimed value being critical to the claimed invention (i.e., achieves unexpected results), it would have been prima facie obvious for a person of ordinary skill to have selected a value of 200 pg/mL in serum in view of Tarsio. Regarding the limitation of “a ratio of Klotho content in serum to Klotho content in saliva of 3.6:1”, the claimed ratio would have been obvious for the same reasons discussed regarding claim 24.
Regarding claim 26, Tarsio teaches the composition for administering to the individual to include a cell suspension culture comprising one or more cells that each (i) contain a nucleic acid construct or vector that encodes a recombinant human alpha soluble Klotho protein and (ii) express a recombinant human alpha soluble protein (see pg. 2, para. [0015]), wherein the nucleic acid can also include or encode a promoter associated with the transgene (see pg. 3, para. [0020]). Hence, it would have been obvious for the treatment to comprise a therapeutically effective number of cells containing a nucleic acid vector comprising a region encoding a Klotho protein wherein said region is operably linked to a promoter.
Regarding claim 27, the claim recites a functional limitation of the diagnostic kit recited in claim 16. Here, no further method step is recited in the present claim, and neither claim recites any structure regarding the diagnostic kit. Hence, the measuring of the content of Klotho via the diagnostic kit taking “less than or equal to 15 minutes” is an inherent property of the kit selected to perform the measurement. In view of the specification, this measurement can be performed using a lateral flow immunoassay which “generally produce a result within 15 minutes” (see pg. 22, lines 7-8). Tarsio teaches that lateral flow assays with a quantification/measurement indicator provide a substantial benefit over existing methods and products (see pg. 13, para. [0144]). “When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process” In re King, 801 F.2d 1324, 231 USPQ 136 (Fed. Cir. 1986). Hence, it would have been obvious for a person of ordinary skill to have conducted this measurement using a lateral flow assay in view of Tarsio, and the time taken to obtain a result would have been an inherent effect of using the lateral flow assay.
Regarding claim 28, Tarsio teaches embodiments that include a kit for detecting and quantifying Klotho protein levels (see pg. 13, para. [0145]), and that low soluble Klotho serum levels can be determined in an individual using an ELISA immunoassay (see pg. 74, para. [0411]), which can include performing ELISA using an antibody configured to bind the soluble Klotho protein (see pg. 7, para. [0055]). Hence, it would have been obvious for the diagnostic kit to have comprised an immune assay having at least one antibody that binds to Klotho.
Regarding claim 29, Dubal 2023 teaches that a number of immunoassay formats are known and can be used, such as a direct or competitive immunoassay (see pg. 11, para. [0030]). Hence, it would have been obvious for the diagnostic kit to have comprised a competitive assay.
Regarding claim 30, Tarsio teaches embodiments that include a kit for detecting and quantifying Klotho protein levels (see pg. 13, para. [0145]), such as a lateral flow assay with a quantification/measurement indicator (see pg. 13, para. [0144]). Hence, it would have been obvious for the diagnostic kit to have comprised a lateral flow assay.
Claims 31-35 are rejected under 35 U.S.C. 103 as being unpatentable over Tarsio and Dubal 2023, as applied to claims 16 and 20-30 above, and further in view of Koczula et al. (previously cited), hereafter, “Koczula”.
Regarding claim 31, Tarsio, as discussed above, teaches a kit for detecting and quantifying Klotho levels, particularly soluble alpha Klotho levels, including lateral flow assays featuring a quantification/measurement indicator. Dubal 2023, as discussed above, teaches that the measuring of the quantity or activity of Klotho in a sample can be conducted via an immunoassay and further involves comparing said quantity or activity to a control value (i.e., a pre-selected threshold).
Tarsio and Dubal 2023 do not explicitly teach a kit comprising a solid phase, the solid phase comprising:
a) a sample pad for application of a sample to be tested, the sample comprising saliva and the sample pad configured to receive the saliva;
b) a conjugate or reagent pad comprising a conjugate of a Klotho-specific antibody;
c) a reaction or capture zone on which the Klotho specific antibody is immobilized;
d) a wick or waste reservoir positioned to collect excess saliva;
wherein the reaction or capture zone is configured to provide a visible indication in response to the sample having more than a pre-selected threshold for a content of Klotho in the sample.
Koczula teaches lateral flow assays are the technology behind low-cost, simple, rapid and portable detection devices popular in biomedicine, agriculture, food and environmental sciences (see Abstract), and are widely used in hospitals, physicians offices and clinical laboratories, wherein a variety of biological samples can be tested, including saliva and serum (see pg. 111, para. 1). Koczula teaches that this type of assay has recently attracted considerable interest because of its potential to provide instantaneous diagnosis directly to patients (see Abstract). Koczula teaches that while the principle of the method has remained unchanged for decades, there have been continuous improvements of LFA techniques leading to increased sensitivity and reproducibility, and the simultaneous detection of several analytes (see pg. 117, para. 2). Koczula teaches these assays can now be effectively performed outside the laboratory, providing great advantages for use in developing countries and at the point-of-care, whether in the field or in more traditional clinical settings (see pg. 117, para. 2). Koczula teaches that the lateral flow assay (LFA) is a paper-based platform for the detection and quantification of analytes in complex mixtures, where the sample is placed on a test device and the results are displayed within 5–30 min (see pg. 111, para. 1). Koczula teaches the typical configuration of a lateral flow immunoassay test strip as shown in Figure 2, which is provided below:
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Regarding part a), Koczula teaches that the sample is applied at one end of the strip, on the adsorbent sample pad (see pg. 112, lines 4-7).
Regarding part b), Koczula teaches that the sample migrates through the conjugate release pad, which contains antibodies that are specific to the target analyte and are conjugated to colored or fluorescent particles (see pg. 112, lines 8-10). Koczula teaches fluorescent particles to be an example of a label (see the description of Table 1 on pg. 116).
Regarding part c), Koczula teaches that the sample, together with the conjugated antibody bound to the target analyte, then migrates along the strip into the detection zone, which contains immobilized antibodies which react with the analyte bound to the conjugated antibody (see pg. 112, lines 10-13). Koczula teaches that recognition of the sample analyte results in an appropriate response on the test line (see pg. 112, line 13). Hence, the detection zone taught by Koczula is equivalent to the “reaction or capture zone” of the claim.
Regarding step d), Koczula teaches that an absorbent pad is attached at the end of the strip, which is to wick the excess reagents and prevent backflow of the liquid (see pg. 112, lines 21-23). Hence, the absorbent pad is equivalent to the “wick or waste reservoir positioned to collect excess saliva”.
Regarding the limitation, “[wherein] the sample [comprises] saliva and the sample pad [is] configured to receive the saliva”, while the instant specification generally summarizes lateral flow assays (see pgs. 17-18), there is no disclosure of any particular structure(s) that are required to “configure” the sample pad for receiving saliva, as opposed to other sample types. Because apparatus claims are interpreted as what a device is, rather than what it does, merely reciting a function does not distinguish the structure from the prior art. See MPEP 2114(II). In the instant case, Koczula teaches that the sample pad is usually impregnated with buffer salts, proteins, surfactants and other liquids to control the flow rate of the sample and to make it suitable for the interaction with the detection system, and the pores of the sample pad can act as a filter in order to remove redundant materials (see pg. 114, “Sample pad”). Koczula also discloses that the use of LFAs to test saliva is known in the prior art (see pg. 111, para. 1; pg. 118, Reference 6). Therefore, Koczula teaches that LFAs can be configured to test saliva, and it was within the ordinary skill in the art to have configured the sample pad to receive saliva.
Regarding the limitation “wherein the reaction or capture zone is configured to provide a visible indication…”, Koczula teaches that the detection zone is configured such that recognition of the sample analyte results in an appropriate response on the test line (see pg. 112, line 13) to indicate a positive result (see pg. 112, para. 2). Dubal 2023 further teaches that the measuring of the quantity or activity of Klotho in a sample further involves comparing said quantity or activity to a control value (i.e., a pre-selected threshold), as discussed above.
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Tarsio and Dubal 2023 with that of Koczula to provide a test kit suitable for a lateral flow assay as described in the claim. In view of Koczula, the methodology of the claimed test kit is well-known and commonly-used in the art, and furthermore, these kinds of tests are popular due to being low-cost, simple to use, rapid, and portable. Hence, one of ordinary skill would have recognized the advantages of using such a methodology when applying the teachings of Tarsio and Dubal 2023. One would have also recognized that Tarsio teaches the use of immunoassays, including lateral flow assays, to be used in test kits to detect Klotho, and Koczula merely provides further detail and guidance in the design of this widely known methodology. As Koczula teaches these assays to be commonly used for their effectiveness and convenience in the detection and quantification of many different analytes in complex mixtures derived from a variety of biological sources, one would have immediately recognized that the results of using this methodology would have been predictable and to have a reasonable expectation of success. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 32, Koczula teaches a response on the control line indicates proper liquid flow through the strip (see pg. 112, line 14), and the control line contains antibodies that are specific for the antibody in the particular conjugate (see pg. 112, para. 2) and should be visible independently of the test result (see pg. 113, para. 1). Hence, the control line taught by Koczula is equivalent to the “control zone” of the claim, wherein antibodies (“an antibody”) are specific for (“binds to… but not to the Klotho of the sample”) the antibody in the particular conjugate (“the conjugate of the Klotho specific antibody”).
Regarding claim 33, Koczula teaches that the sample, together with the conjugated antibody bound to the target analyte, then migrates along the strip into the detection zone, which contains immobilized antibodies which react with the analyte bound to the conjugated antibody (see pg. 112, lines 10-13). Hence, it is understood that the immobilized antibodies are “analyte specific” (e.g., Klotho specific antibodies). Koczula teaches that the detection zone comprises a test line (see pg. 112, line 13). As shown in Figure 2 above, the test line runs across the width of the solid phase.
Regarding claim 34, it would have been obvious to have selected a pre-selected threshold of 200 pg/mL and to have arrived at the claimed ratio for the same reasons discussed regarding claim 25.
Regarding claim 35, it would have been obvious to have selected a pre-selected threshold of 100 pg/mL and to have arrived at the claimed ratio for the same reasons discussed regarding claim 24.
Response to Arguments
In response to the scope of enablement rejection under 35 U.S.C. 112(a), Applicant argues that the rejection is based on a contention that a detected level of Klotho was used to identify a particular type of disease or condition, and the claims as amended herein resolve the issues raised in the Office Action and are enabled.
Applicant’s arguments have been fully considered and are persuasive. In particular, the scope of the claimed method has been narrowed to the monitoring of Klotho levels in patients having existing or previous diseases that are known in the prior art to be associated with lowered levels of Klotho. Therefore, the claims are no longer drawn to identifying any disease or condition in any patient, but are specific to monitoring Klotho levels in individuals having or previously having a specific disease or condition that is known to be associated with low Klotho levels. Accordingly, the rejection has been withdrawn.
In response to the patentable subject matter rejection under 35 U.S.C. 101, Applicant argues that the claims as amended herein are directed to a tangible, concrete process that includes use of a device -- e.g. a diagnostic kit as well as providing a
concrete result (e.g. administering a treatment to increase Klotho content in a patient). See OA at 21 (contending that the administering step of previously presented claim 16
was not considered a limitation of the claim). Thus, the pending claims are all directed to patentable subject matter.
Applicant’s arguments have been fully considered but are not persuasive for the following reasons:
(1) As discussed under the present rejection, the use of a device, e.g., a diagnostic kit does not affect the inquiry under Step 2A, prong 2 (adding insignificant extrasolution activity to the exception, “mere data gathering”). Applicant’s argument fails to address this finding, which was also made in the previous office action. See MPEP 2106.04(d)(I) which states, “mere physicality or tangibility of an additional element or elements is not a relevant consideration in Step 2A Prong Two” and “a specific way of achieving a result is not a stand-alone consideration in Step 2A Prong Two.” As the Supreme Court explained in Alice Corp., mere physical or tangible implementation of an exception does not guarantee eligibility. Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 573 U.S. 208, 224, 110 USPQ2d 1976, 1983-84 (2014). In the case of the claimed method, determining the level of biomarkers in a biological sample is an explicitly enumerated example of “mere data gathering” (see MPEP 2106.04(d) and MPEP 2106.05(g)), and the use of a device is directed to the necessary steps to observe the judicial exception. As the Supreme Court explained in Alice Corp., mere physical or tangible implementation of an exception is not in itself an inventive concept and does not guarantee eligibility:
The fact that a computer "necessarily exist[s] in the physical, rather than purely conceptual, realm," is beside the point. There is no dispute that a computer is a tangible system (in § 101 terms, a "machine"), or that many computer-implemented claims are formally addressed to patent-eligible subject matter. But if that were the end of the § 101 inquiry, an applicant could claim any principle of the physical or social sciences by reciting a computer system configured to implement the relevant concept. Such a result would make the determination of patent eligibility "depend simply on the draftsman’s art," Flook, supra, at 593, 98 S. Ct. 2522, 57 L. Ed. 2d 451, thereby eviscerating the rule that "‘[l]aws of nature, natural phenomena, and abstract ideas are not patentable,’" Myriad, 133 S. Ct. 1289, 186 L. Ed. 2d 124, 133).
(2) As discussed under the present rejection, the use of a diagnostic kit (e.g., in the form of an immune assay, lateral flow assay, double sandwich immunoassay, etc.) to measure the Klotho content of a sample is considered to be a well-understood, routine, and conventional activity under Step 2B. Applicant’s argument fails to address this finding, which was also made in the previous office action.
(3) As discussed under the present rejection, the administration step of claim 16 fails to integrate the judicial exception into a practical application under Step 2A, prong 2, because this treatment limitation is recited at a high level of generality and is not “particular”. Further, this limitation merely indicates a field of use in which to apply the judicial exception and does not amount to an inventive concept or significantly more than the exception itself under Step 2B. See MPEP 2106.04(d)(2) and 2106.05(d-h).
In response to the Obviousness rejections under 35 U.S.C. 103, Applicant argues that Dubal (US 2018/0015151 A1) does not discuss saliva, and there is no disclosed use of any type of diagnostic kit to obtain any type of patient sample nor any administration of a treatment based on that testing. Applicant further argues that Dubal relates to the monitoring of how a patient’s cognitive ability is progressing and there are no body samples of a patient that are evaluated. Applicant further argues that the modification of Tarsio based on Dubal is contrary to Dubal’s explicit disclosure and its fundamental principle of operation.
Applicant’s arguments have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The matters specifically challenged in this argument are addressed in the new ground of rejection based on Dubal 2023 (US 2023/0123357 A1) which teaches the testing of saliva and the use of immunoassays (“diagnostic kit”), as discussed in the present rejection. Dubal 2023 teaches obtaining a sample from an animal to measure a quantity or activity of Klotho, comparing the quantity or activity to a control value, and then administering an effective dose of a Klotho polypeptide, as discussed in the present rejection.
In response to the Obviousness rejections of claims 24-25 and 27 under 35 U.S.C. 103, Applicant argues that the cited art also fails to teach or suggest any use of a pre-selected threshold that corresponds to a value of 100 pg/mL in serum at a ratio of Klotho content in serum to Klotho content in saliva of 3.6: 1 as recited in claim 24. The cited art also fails to teach or suggest any use of a pre-selected threshold that corresponds to a value of 200 pg/mL in serum at a ratio of Klotho content in serum to Klotho content in saliva of 3.6:1 as recited in claim 25.
Applicant’s arguments have been fully considered but they are not persuasive.
As discussed in the present rejection of these claims: (1) Tarsio teaches raising serum Klotho levels to 100 pg/mL; (2) Tarsio provides a result-effective variable in serum which could have been used to arrive at the claimed ratio through no more than routine optimization; (3) the claimed value of 200 pg/mL is within the range taught by Tarsio where no evidence has been presented to support the criticality of the claimed value; (4) Dubal 2023 teaches the testing of Klotho activity in saliva; and (5) Tarsio teaches a diagnostic kit for measuring Klotho.
Applicant further argues that the ratio of a Klotho content in serum to Klotho content in saliva of 3.6:1 is not a “natural or inherent property” as stated in the office action, and this ratio can depend on the testing device’s precision and other parameters. There is no natural or inherent property.
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant fails to present sufficient evidence to support the argument that the ratio of Klotho content in serum compared to Klotho content in saliva is not a natural or inherent property. The instant specification only discloses that “Figure 1 shows the relation between Klotho in serum and saliva measured by the TRF method (time resolved fluorescence immunoassay) to be about 3.6 to 1” (see pg. 22, lines 21-23). There is no disclosure of what “precision”-based factors or “other parameters” were required to obtain this result, and, if other ratios were possible, it is unclear how this would affect the claims, which do not require the use of the TRF method. Furthermore, it must be presumed that in order to successfully determine the content of Klotho in serum by using the claimed ratio, this correlation must relate to a natural and inherent property of Klotho’s presence in the saliva and serum of the patient. In other words, it is unclear how this ratio could be relied upon to practice the claimed invention if it was not an inherent property, and there is no evidence to suggest that the level of Klotho detected in the saliva and/or serum of a patient having a particular disease or condition is not directed to a naturally-occurring phenomenon, as discussed under 35 U.S.C. 101.
Applicant further argues that the cited art fails to teach or suggest use of a diagnostic kit that results in an evaluation of saliva to detect the presence of Klotho that is at or below a pre-selected threshold within 15 minutes.
Applicant’s arguments have been fully considered but they are not persuasive.
The functional limitation of the diagnostic kit taking less than or equal to 15 minutes to obtain a result is an inherent property of the kit, such as the lateral flow assay taught by Tarsio. Further, Koczula explicitly teaches that in lateral flow assays the sample is placed on a test device and the results are displayed within 5–30 min (see pg. 111, para. 1), which is further evidence that the time required to obtain a result is a common and inherent property of using such an assay.
Regarding claims 31-35, Applicant argues that Claim 31 is directed to a test kit and recites the limitations of the claim. Applicant argues that claims 32-35 depend from claim 31 and also include these features. Applicant alleges that “The cited art is silent with respect to such a test kit. For example, none of the cited art teaches or suggests any type of device configured to utilize saliva and react to the saliva to provide a visible indication in response to a sample of the saliva having more than a pre-selected threshold for a content of Klotho in the sample.”
Applicant’s arguments have been fully considered but they are not persuasive.
As discussed in the present rejection, the prior art of Koczula teaches such devices are well-known in the art and can be used to detect proteins in both saliva and serum, while the prior art of Tarsio teaches such devices are useful for detecting Klotho.
Applicant further argues that the Office Action improperly ignored claimed limitations. For instance, there must be a sample pad for application of a sample to be tested, the sample comprising saliva and the sample pad configured to receive the saliva and there must also be a wick or waste reservoir positioned to collect excess saliva. None of the cited art has such features.
Applicant’s arguments have been fully considered but they are not persuasive.
The argument presented by the applicant is clearly not based on a factual conclusion, because Koczula explicitly teaches every feature recited in the argument, as discussed in the present rejection.
Applicant further argues that the Office Action contended that the kit of claim 31 did not have to be configured for use with saliva. (OA at 37)
Applicant’s arguments have been fully considered but they are not persuasive.
No recitation of “configured for” was present in the claim at the time of the previous office action, and there is no discussion of a limitation reciting this phrase in the office action on page 37. Therefore, there is simply no factual basis for Applicant’s argument.
Amended claim 31, which now recites the limitation, “and the sample pad configured to receive the saliva”, is fully addressed in the present rejection.
Applicant further argues that none of the cited art teaches or suggests any device configured for evaluation of a sample of saliva.
Applicant’s arguments have been fully considered but they are not persuasive.
Koczula teaches the use of a lateral flow assay which can be configured for evaluation of a sample of saliva, as discussed in the present rejection.
Applicant further argues that Claim 34 requires the pre-selected threshold is a value that corresponds to a value of 200 pg/ml in serum at a ratio of Klotho content in serum to Klotho content in saliva of 3.6: 1 and claim 35 requires the pre-selected threshold is a value that corresponds to a value of 100 pg/m I in serum at a ratio of Klotho content in serum to
Klotho content in saliva of 3.6: 1 for the reaction or capture zone to provide a visible
indication in response to the sample having more than the pre-selected threshold for the
content of Klotho in the sample. As can be appreciated from the above discussion of
the independent allowability of claims 24-25, the cited art fails to teach or suggest such
features.
Applicant’s arguments have been fully considered but they are not persuasive.
As discussed in the present rejection of claims 24-25: (1) Tarsio teaches raising serum Klotho levels to 100 pg/mL; (2) Tarsio provides a result-effective variable in serum which could have been used to arrive at the claimed ratio through no more than routine optimization; (3) the claimed value of 200 pg/mL is within the range taught by Tarsio where no evidence has been presented to support the criticality of the claimed value; (4) Dubal 2023 teaches the testing of Klotho activity in saliva; and (5) Tarsio teaches a diagnostic kit for measuring Klotho.
Therefore, the further limitations of claims 34-35 are obvious for the same reasons, as discussed in the present rejection.
Conclusion
No claims are allowed.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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