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 .
Status of Claims
Claims 16-35 are pending following the Reply filed 09/22/2025. Claims 16-30 have been amended and claims 31-35 have been added without introducing new matter. Claims 16-35 have been examined on the merits.
Notice
Upon examination the examiner noted the following error in the amended claim set (filed 09/22/2025):
Amended claim 16 is missing text which appeared in the previous claim set (filed 09/07/2022), failing to indicate the changes made to the previous claims by showing the marked-up text of the deleted matter (i.e., by strike-through). The phrase "determining and/or" which appears in line 1 of the previous claim has been omitted in the currently amended claim without being indicated by mark-up.
Per 37 C.F.R. 1.121 (see section (c)(2)), all claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived.
Since the above-mentioned reply appears to be bona fide, and no other errors or omissions appear in the pending claim set, examination of the claims has proceeded on the merits.
Withdrawn
The objections to claims 28 and 30 are withdrawn in light of the amendments.
The rejection of claims 17-18, 20-25 and 27-30 under 35 U.S.C. 112(b) are withdrawn in light of the amendments.
The rejection of claims 19-20 under 35 U.S.C. 112(a) is withdrawn in light of the amendments. Specifically, the scope of the claims have been narrowed to the monitoring of Klotho levels in patients having specific diseases reported in the prior art as being associated with lowered levels of Klotho.
The rejection of claims 16-18, 21 and 27 under 35 U.S.C. 102 is withdrawn in light of the amendments and Applicant’s arguments. See Response to Arguments below for further discussion.
Specification
The disclosure is objected to because of the following informalities: the specification recites the term “amyothrophic” on page 13, line 16, which appears to be a misspelling of “amyotrophic” in view of the prior art (see, e.g., Tarsio, previously cited, at pg. 6, para. [0047]).
Appropriate correction is required.
Claim Objections
Claim 19 is objected to because of the following informalities: the claim recites “amyothrophic” in line 3, which appears to a misspelling of “amyotrophic” in view of the prior art (see, e.g., Tarsio, previously cited, at pg. 6, para. [0047]). Appropriate correction is required.
Claim 22 is objected to because of the following informalities: for clarity, please amend “wherein the administering of the at least one treatment to the patient comprises causing the patient to undergo muscle training” (Emphasis added) to “wherein the administering of the at least one treatment to the patient comprises subjecting the patient to muscle training”. This claim language is consistent with the previous claim set (see claim 26 in the claims filed 06/26/2025) and is a more definite description than the present limitation. Appropriate correction is required.
Claim 32 is objected to because of the following informalities: for clarity and consistency, please amend “The test kit of claim 31, comprising:” in line 1 to “The test kit of claim 31, further comprising:”. Appropriate correction is required.
Claim 32 is objected to because of the following informalities: the claim recites “a control zone having an antibody that binds to the conjugate of the Klotho specific antibody and also being unable to bind to the Klotho of the sample”. While it is understood that the antibody binds to the conjugate but is unable to bind to the Klotho, the use of a second gerund (“being”) as a transition word leads to confusion. For clarity, “and also being” recited in line 3 can be amended to “and is” or alternatively to “but is”. Appropriate correction is required.
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.
Claims 19 and 26 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 19 recites the limitation “wherein the neurodegenerative disease comprises Morbus Alzheimer, Parkinson disease, amyothrophic lateral sclerosis (ALS) and Huntington’s disease” (Emphasis added). This renders the claim indefinite, because the plain meaning of the limitation would require the patient to have all four of the recited diseases. In view of the specification, neurodegenerative diseases for which a Klotho level can be determined by the method “include” the recited diseases (see pg. 13, lines 13-16) and there is no suggestion that a patient would have to be co-morbid with all four conditions for the claimed method. Furthermore, while there are no teachings in the prior art of record to suggest that a patient cannot be co-morbid with all four conditions, no prior art has been found which discloses such a diagnosis. As such, one may interpret the limitation to include patients having any “one or more” of the recited diseases. Hence, it is unclear whether the recitation of “comprises… A, B, C and D” is due to a drafting error or reflects the scope intended by the applicant.
Suggestion to obviate the rejection: Applicant may, for example, amend the claim to read, “wherein the neurodegenerative disease comprises Morbus Alzheimer, Parkinson disease, amyotrophic lateral sclerosis (ALS) or Huntington’s disease” which is similar to the language used in claim 20. In the interest of compact prosecution, the claim is interpreted accordingly.
Claim 26 recites the limitation, “wherein the administering… comprises administering a therapeutically effective number of mesenchymal stem cells which produce Klotho, a therapeutically effective number of cells containing a nucleic acid vector…” which renders the claim indefinite. The limitation appears to have the form of “comprises A, B” wherein the absence of a transition word (“and”, “or”, or “wherein”) leads to confusion. Hence, it is not clear whether this limitation comprises (1) administering a therapeutically effective number of mesenchymal stem cells AND cells containing a nucleic acid vector, (2) administering a therapeutically effective number of mesenchymal stem cells OR a therapeutically effective number of cells containing a nucleic acid vector, or (3) administering a therapeutically effective number of mesenchymal stem cells WHEREIN the cells contain a nucleic acid vector.
Suggestions to obviate the rejection: (1) Use a transitional phrase to connect “A” and “B” as described above. (2) Examiner notes that the first limitation of administering “mesenchymal stem cells” is already recited in claim 23. Hence, Applicant may alternatively remove the phrase, “a therapeutically effective number of mesenchymal stem cells which produce Klotho,” which would also obviate the rejection.
In the interest of compact prosecution, the claim is given its broadest reasonable interpretation: “The method of claim 16, wherein the administering the at least one treatment to the patient comprises administering a therapeutically effective number of mesenchymal stem cells which produce Klotho or a therapeutically effective number of cells containing a nucleic acid vector…”
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 16-18 and 21-30 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 monitoring a content of Klotho in a patient having a certain disease or condition in order to adjust a treatment for said patient, does not reasonably provide enablement for any patient having any health status, disease or condition. 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.
Enablement requires that the specification teaches those in the art to make and use the
invention without undue experimentation. Factors to be considered in determining whether a
disclosure would require undue experimentation include (1) the nature of the invention, (2) the state of the prior art, (3) the predictability or lack thereof in the art, (4) the amount of direction or guidance present, (5) the presence or absence of working examples, (6) the quantity of experimentation necessary, (7) the relative skill of those in the art, and (8) the breadth of the claims.
Summary of the problem – The claims are directed to a method for monitoring the content of Klotho in a patient and for adjusting a treatment for the patient based on the Klotho content measured in saliva, wherein the patient is administered at least one treatment to increase the content of Klotho if the content of Klotho is below a pre-selected threshold. The patient of the claimed method is interpreted as including any patient (any animal, mammal, human, etc. regardless of age, sex, medical history, etc.) having any previous or existing disease or condition, including cancer, neurodegenerative disease, autoimmune disease, sepsis, premature aging, etc. However, there is a lack of guidance and exemplification provided in the specification as filed which would reasonably enable one to be able to monitor and determine a treatment for any individual with any health status by merely measuring the content of Klotho in saliva.
As set forth below, numerous pertinent factors, to which the specification provides little to no guidance regarding, are required in order for even a skilled artisan to be able to make and use the invention as claimed, such that any attempt to do so warrants undue experimentation without a reasonable expectation of success.
The nature of invention and the breadth of the claims – Claims 16 and 21-30 are directed to a method of monitoring any health status in an individual by measuring the content of Klotho in saliva. Claim 17 is directed to the method wherein the patient has any existing or previous disease or condition. Claims 18 is directed to the method wherein the disease or condition is selected from numerous diseases or conditions (e.g., organ fibrosis, erectile dysfunction, sepsis, arteriosclerosis, etc.), including several broad categories of disease (e.g., cancer, inflammatory diseases, autoimmune diseases). Hence, the claims reasonably encompass a vast and varied genus of health statuses, diseases, and physiological conditions, each of which must be effectively treated in response to Klotho being below a certain pre-determined threshold.
The state of the prior art – Hu et al. (previously cited; published in 2012; hereafter, “Hu”) investigate the emerging role of Klotho in clinical nephrology and, specifically, its use as an indicator of acute kidney injury (AKI) and chronic kidney disease (CKD) (see Abstract). Hu teaches that compared with NGAL, KIM and IL-18, all of which are entering the clinical realm, Klotho measurement in AKI and CKD patients is still in its infancy (see pg. 2654, col. 2., para. 4). Hu teaches that, hopefully, Klotho measurement may provide the following clinical applications in AKI and CKD: (i) early detection of the presence of AKI, (ii) identification of risk of progression post-AKI to CKD, (iii) early detection of the presence of CKD and (iv) prediction of progression, extra-renal complications and mortality in CKD (see pg. 2654, col. 2., para. 4). Hu teaches that these potential applications are all based on preclinical data at the moment, and there are many critical questions to answer, such as: “What is the normal range of plasma and urinary-soluble Klotho levels in humans? Are there age, gender, ethnic and dietary dependence and adjustments? What kind of assay for plasma and urine-soluble Klotho is ideal and how should this be validated?” (See pg. 2654, col. 2, para. 4).
Pedersen et al. (previously cited; published in 2013; hereafter, “Pedersen”) teach that when comparing two different immunoassays using patient samples, no correlation between the measured serum Klotho values was found, and the levels of serum differed with a factor 1000 between the assays suggesting that the two assays recognize different forms of Klotho in serum (see pg. 1081, col. 2, para. 9). Pedersen teaches that since the ELISA from Immuno-Biological laboratories (IBL) utilizes monoclonal antibodies, this assay might only recognize one form of soluble Klotho whereas the TRF assay, utilizing polyclonal and/or monoclonal antibodies, might recognize several different soluble Klotho forms (see pg. 1080, col. 1, para. 4; pg. 1082, col. 1, para. 2). Pedersen teaches that from Western blot analysis it is known that a 130 kDa Klotho protein is present in human serum and spinal fluid; however, several other studies have shown that soluble secreted Klotho derives from several different pathways and the total sum of Klotho protein present in serum is therefore likely to consist of different forms, lengths and with a varying degree of posttranslational modifications (see pg. 1082, col. 2, para. 1). Pedersen teaches that there are at least three different pathways for generation of Klotho protein in the circulation system, but it is still not known which of the three suggested mechanisms is the major source nor is it known how many forms of Klotho are present in serum. (see pg. 1082, col. 2, para. 1).
Pedersen teaches that the IBL ELISA showed a negative correlation between serum Klotho and age, creatinine, and FGF23 in a healthy population (see pg. 1082, col. 2, para. 2). In the present study, Pedersen confirmed a negative correlation of serum Klotho (IBL) with age, while the negative correlation with age was much more pronounced in a Japanese study (see pg. 1083, col. 1, para. 1). In contrast, Pedersen could not confirm the correlations between serum Klotho and the other biomarkers of kidney function previously reported (see pg. 1083, col. 1 para. 1). Pedersen also found a significant difference in serum Klotho levels between males and females and a negative correlation of serum Klotho with height, weight and eGFR, calcium × phosphate, and weekly cola intake (see pg. 1083, col. 1, para. 2). Pedersen concludes that these results suggest that the soluble serum Klotho as measured by the two different immunoassays is possibly compromised by at least two different forms of the Klotho protein which need to be considered as independent factors and whose role and potential value as biomarkers must be evaluated separately (see pg. 1083, col. 2, para. 2).
Xu et al. (previously cited; published in 2015; hereafter, “Xu”) teach that experimental research on α-Klotho has been slow due to: 1) the lack of efficient, specific inhibitors to block α-Klotho activity in vivo and in vitro; and 2) the lack of specific methods to distinguish the different forms of α-Klotho (see pg. 186, col. 1, para. 5). Xu teaches that the full-length α-Klotho protein is expressed primarily in the kidneys and the brain choroid plexus, which does not explain the extensive role of Klotho in other organs and tissues (see pg. 186, col. 2, para. 2). Xu teaches that circulating Klotho has direct effects on tissues and cells that do not express Klotho, which partially explains why a mutation to the Klotho gene causes such extensive aging phenotypes (see pg. 186, col. 2, para. 2). Xu teaches that circulating Klotho may be generated by alternative RNA splicing (secreted Klotho) and/or via the proteolytic cleavage of the transmembrane form of Klotho (soluble Klotho) and Klotho may therefore function as a hormone (see pg. 186, col. 2, para. 2). Xu teaches, however, the binding sites or the receptors for Klotho remain unknown, and it will therefore be important in future studies to identify and characterize Klotho receptors and investigate its downstream signaling (see pg. 186, col. 2, para. 2).
Donate-Correa et al. (previously cited; published in 2015; hereafter, “Donate”) teach that the major interest in the clinical application of Klotho research is related to chronic kidney disease (CKD), where FGF23 and Klotho have also been linked with cardiovascular morbidity and mortality independently of phosphatemia, and these associations remain in populations without impaired kidney function (see pg. 354, col. 2, para. 6). Donate teaches that thus far, measurements of vascular Klotho mRNA and protein in humans have been limited, and it is unknown if vascular expression is also lowered in advanced CKD stages or remains at physiologic levels (see pg. 355, col. 1, para. 1). Donate teaches that what we do know is that vascular expression of Klotho, along with blood soluble levels, are decreased in coronary artery disease (CAD) patients without renal disease (see pg. 355, col. 1, para. 1). (emphasis added)
Torbus-Paluszczak et al. (previously cited; published in 2018; hereafter, “Torbus”) teach Klotho is highly expressed in the brain, and many studies have demonstrated a neuroprotective role of Klotho (see pg. 1681, col. 1, para. 1). Torbus teaches that in the human brain, the secreted isoform of the Klotho protein plays a crucial role in neuronal activity, which is the key to aging and neurodegenerative processes (see pg. 1681, col. 1, para. 1). Torbus teaches that from a clinical point of view, the Klotho level in cerebral spinal fluid (CSF) can be used as a biomarker of MS severity (see pg. 1681, col. 1, para. 1). Torbus teaches that although it is still not known why Klotho suppresses aging, maintaining Klotho levels by stimulating endogenous Klotho production or administering exogenous Klotho protein may be a potential therapeutic target to slow down the aging process and reduce the incidence of age-related diseases (see pg. 1681, col. 1, para. 1). Torbus teaches, as a regulator of remyelination in the white matter, Klotho can become a new therapeutic substance for MS and other demyelinating and neurodegenerative diseases (see pg. 1681, col. 1, para. 1).
The predictability or lack thereof in the art – In view of the prior art above, Klotho appears to have an art-recognized potential as a therapeutic agent and/or a biomarker for certain diseases. However, there are numerous issues that are raised by the prior art that would require further direction or guidance to enable a person of ordinary skill in the art to use Klotho for these purposes as claimed:
1) The art teaches that Klotho levels are associated with multiple diseases and conditions, as well as factors such as age, sex, height, weight, diet, and demographics. Hence, it would not be possible to determine an individual’s health status based on Klotho levels alone, because low levels of Klotho are not associated with a single health status. Accordingly, two individuals with two different diseases may show decreased levels of Klotho, but this would not be indicative of them having the same health status. Furthermore, if a low Klotho level can be used to determine the presence of a disease, but can also be used to determine an individual’s biological age, a person of ordinary skill would not be able to determine whether a measurement indicating low Klotho content is due to the presence of a disease or due to the individual’s advanced biological age. Furthermore, individuals having different sexes, ages, and diet may show significantly different Klotho levels for reasons unrelated to the disease or condition of interest. Hence, this measurement cannot reliably be used to determine an individual’s health status without the consideration of additional factors.
2) The art teaches that several different forms of Klotho have been found in biological fluids, including at least two different forms of soluble Klotho in serum, which Pedersen teaches must be evaluated as separate factors in order to be used as biomarkers for disease. As these different forms have different responses to different assays, a person of ordinary skill would not be able to predict which assays and which factors (i.e., antibodies, conjugates) would need to be utilized in order to make a useful determination. If, for example, two immunoassays can be used to obtain different results, because one is more selective of a particular form of Klotho than the other, further guidance would be required in order to determine which tests can or cannot be relied upon in order to obtain a useful result.
3) The art does not teach there to be any reliable, universal correlation between Klotho content in saliva and Klotho content in serum. Kaufman et al. (previously cited; hereafter, “Kaufman”) teach that, in general, serum and salivary levels of protein hormones are not well-correlated, and the serum levels of many protein hormones cannot be accurately monitored by means of salivary analysis (pg. 205, col. 1, para. 2). Kaufman teaches that for accurate results, a constant and predictable correlation must exist between salivary and serum hormone levels (see pg. 205, col. 1, para. 3). In addition, Kaufman teaches that many hormones exhibit marked circadian variations, wherein the timing of saliva collection may affect the results (see pg. 205, col. 1, para. 3). Kaufman teaches salivary flow rate can also affect the concentrations of certain hormones, and an increase in salivary flow rate will usually result in reduced concentrations of molecules that reach saliva by diffusion (see pg. 205, col. 1, para. 3). Kaufman teaches all of these factors have to be considered when saliva is evaluated as an alternative for the evaluation of serum hormone levels (see pg. 205, col. 1, para. 3).
MPEP 2164.03 states “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)”.
The amount of direction or guidance present – The present specification states that the inventive method of the disclosure “is based on the surprising finding of the inventors that the Klotho level in especially saliva proportionally corresponds very well with the Klotho levels that have been determined in serum samples” and “[a]ccordingly, the method of the present invention is preferably performed with saliva” (see pg. 11, lines 28-31). Examiner notes that this “surprising finding” appears to relate to the data provided in Figs. 1-5 and the Description of the Figures which will be further discussed in the next section of this rejection (“the presence or absence of working examples”).
The specification states that “[t]he present method was compared with the HPLC-technique whereby comparable results were found” and that “[t]he already existing results are surprising in that there is a significant difference of Klotho levels in serum and saliva between patients and healthy volunteers” (see pg. 12, lines 3-7). However, there is no HPLC data provided in the specification, no further mention of HPLC, and no further discussion regarding these results.
The specification discloses evidence from the prior art linking Klotho with various diseases of the invention on pages 3-8. However, there is almost zero discussion in the disclosure regarding any evidence linking low Klotho concentrations with organ fibrosis, erectile dysfunction, sepsis, autoimmune diseases and arteriosclerosis (though they are recited in the claims). While these conditions are recited per se as being included in preferred embodiments (see pg. 13, lines 5-11), there is no corresponding guidance, discussion, or evidence provided in the disclosure to support their inclusion in the claimed invention. Furthermore, the specification states that “diseases or conditions which are accompanied by a comparatively low Klotho level” that are “described in the prior art and in the introductory part of the present specification” do “not exclude further diseases for which a decreased Klotho level might only be recognized in the future … Thus, further diagnostic methods can be applied to detect or exclude severe diseases” (see pg. 12, lines 27-31; pg. 13, lines 2-3). Here, the teachings set forth in the specification provide no more than a plan or invitation for those of skill in the art to experiment with the aforementioned diseases or conditions in order to arrive at the claimed invention.
The specification states that the actual correlation between the values obtained in an immunoassay using serum vs. saliva “can be easily determined or verified for any assay format” (see pg. 14, lines 23-24) and “normal values” can also be determined by providing test results for an appropriately similar cohort of persons which are considered “healthy” (see page 14, lines 30-31). The specification states that such cohorts can be selected from “persons of a similar age, the same sex, similar living circumstances, etc.” and values reported in the literature can be included to select “normal” values “under certain circumstances” (see pg. 15, lines 2-4). Examiner notes there is no discussion in the disclosure comparing “normal” Klotho values in serum and/or saliva to any “abnormal values” associated with the diseases or conditions themselves (with the exception of the brief description of Figures 4-5 which will be discussed below). Hence, while the specification may provide an impression or gist of what may be considered a “normal” value, a person of ordinary skill would not be apprised as to which values predictably correspond to which conditions, and would be required to discover these values for themselves, assuming any such values exist.
The presence or absence of working examples – The only experimental data provided by the present inventors is disclosed in Figs. 1-5 and the Description of the Figures on pages 22-23.
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. It is understood in view of the disclosure (see e.g., pg. 15, lines 15-18), that this data is used to determine the Klotho levels in serum by measuring Klotho levels in saliva (e.g., by multiplying the result using saliva by a factor of 3.6). However, there is zero disclosure regarding the sample size of the population or any relevant characteristics (e.g., health status, age, sex, etc.) of those who were tested. Furthermore, there is no explanation of the inventors’ methodology, data collection strategy, or analysis. Hence, the results demonstrated in Figure 1 cannot be replicated by a person of ordinary skill and fail to address the issues raised by the prior art. For example, factors such as age, sex, height, weight, current and past medical history, and the timing of the tests are all relevant factors which are not addressed by the data. Furthermore, a skilled artisan would not be able to determine the reliability of the data without knowing the sample size and conditions of the data collection. In view of the prior art of record, the correlation between serum and saliva in testing is unpredictable, and the data presented is inadequate to support Applicant’s assertion that measuring Klotho levels in saliva is “surprisingly” reliable for determining Klotho levels in serum.
Figure 2 shows the results of the determination of Klotho levels in the serum of 467 probes obtained from “healthy persons” in Munich. Figure 3 shows a comparison of the Figure 2 data compared to a cohort of blood donors in Ulm including 96 probands. It is understood that “Munich” and “Ulm” are cities in Germany. However, while a sample size is provided for both groups, there is no disclosure regarding any relevant characteristics of either population (e.g., age, sex, medical history, etc.), other than the Munich group comprising “healthy persons”. Furthermore, the inventors do not disclose what factors were used to determine these individuals to be “healthy”. The description of Figure 3 discusses differences between the groups “concerning age and gender”, but there is no data provided regarding age or gender.
Figure 4 shows a comparison between the Munich data (i.e., Fig. 2) and Klotho serum levels of patients with chronic kidney disease state III and IV and patients on dialysis, wherein the Klotho levels of the Munich cohort (“healthy persons”) appear to be elevated compared to the patient populations with CKD and on dialysis. Figure 5 shows the Klotho levels in serum measured in normal controls and in patients with neurodegenerative disease, wherein the normal controls appear to be elevated relative to the patients with neurodegenerative disease. Examiner notes that it is not disclosed what testing method was used for the patients with CKD, the patients on dialysis, or the patients with neurodegenerative disease. Furthermore, it is not specified which neurodegenerative diseases were involved in the study.
Pedersen, discussed above, teaches that no correlation was found between serum Klotho levels using a TRF immunoassay and Klotho levels using an ELISA immunoassay, which Pedersen suggests may have been due to the different forms of Klotho in serum. Here, the data collected for Figure 1 were obtained using the TRF method, while the data collected for at least Figures 2-3 were obtained using ELISA (manufactured by Cloud Clone Corporation). Hence, there is uncertainty in view of the prior art as to how this data can be relied upon, given the discrepancies reported by Pedersen and the incomplete disclosure provided in the specification regarding the inventors’ experimental methods. According to the specification, “[a]n example of the sandwich assay is the sandwich ELISA” (see pg. 18, lines 30-33), indicating that the testing methods of the claims (e.g., claim 29) include the Cloud Clone ELISA used in Applicant’s experiments. Examiner notes that the product page for this assay, “SEH757HU” (see specification at pg. 23, line 26), identifies this assay as a double-antibody sandwich assay (see https://www.cloud-clone.com/products/SEH757Hu.html) which clearly satisfies the limitations of claim 29. Hence, even if the experimental data used to obtain the ratio of “about 3.6 to 1” could be relied upon in some way, it is uncertain whether this ratio would be expected to correlate to any results obtained by ELISA in view of Pedersen.
Thus, Applicant’s working examples are inadequate to overcome the lack of predictability in the art and the lack of guidance or direction in the specification as a whole. There are zero working examples wherein any health status, disease, or condition was successfully determined by measuring Klotho levels in saliva or successfully treated in response to making such determination. The only test using saliva (i.e., Fig. 1) is not disclosed as making such a determination, and the data provided in this example cannot be relied upon given the absence of relevant factors (e.g., What health statuses were present in this population? How many individuals were tested? What control factors were used?). Furthermore, the data showing decreased Klotho levels in the serum of cohorts having certain conditions (i.e., Figs. 4 and 5) do not actually demonstrate the application of the claimed method or test kit using saliva. Hence, the limited experimental data provided in the specification is not sufficient to show proof of enablement by way of even a single working example.
The quantity of experimentation necessary – In order for a person of ordinary skill in the art to make and use the claimed invention, they must first discover for themselves many additional factors that have not been enabled by the disclosure. Examples of such factors include:
1) what testing methods can be used to determine different forms of Klotho in saliva,
2) how Klotho levels determined by saliva correlate to Klotho levels in serum for the given testing method,
3) which forms of Klotho are detectable by the given testing method,
4) which forms of Klotho correspond to each health status, disease, or condition,
5) what levels of Klotho correspond to each health status, disease, or condition,
6) what additional factors (e.g., biomarkers, age, sex, medical history, etc.) need to be assessed in order to effectively monitor each disease or condition, and
7) how to resolve potential interference due to co-morbidity, e.g., when multiple diseases and/or physiological conditions are present in the same individual.
The relative skill of those in the art – While the level of skill in the art is high, predictability in the art is low due to the state of the prior art at the time of filing. Moreover, there is no guidance provided in the specification as filed which could reasonably enable one to be able to effectively monitor and treat any health condition in any individual by measuring the content of Klotho in saliva. As set forth above, there are numerous factors and questions which remain unaddressed and unanswered by the specification, yet they are required in order for a person of ordinary skill to make and use the full scope of the claimed invention.
Accordingly, the quantity of experimentation required to resolve these questions constitutes an invitation to experiment without any reasonable expectation of success even given the relative skill of those in the art.
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 16-30 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.
Claims 16-30 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 “the method comprising: measuring a content of Klotho in saliva of the patient via a diagnostic kit to determine whether the content of Klotho is at or above a pre-selected threshold…” The claim further recites administering at least one treatment to the patient to increase the content of the Klotho “in response to the content of the Klotho being below the pre-selected threshold”. Here, the recited step of “administering” is a conditional step, because the claim only requires this step if the content of Klotho is below the pre-determined threshold. Hence, the claim only requires the step of measuring a content of Klotho in a patient’s saliva in order to make a determination.
-Claim 17 recites “wherein the patient has an existing or previous disease or condition which correlates with a Klotho level that is below the pre-selected threshold.”
-Claims 18-20 depend from claim 17 and further specify the disease or condition.
-Claim 21 is drawn to the method of claim 16, wherein the administering of the at least one treatment to the patient comprises injecting stem cells that express Klotho into the patient.
-Claim 22 is drawn to the method of claim 16, wherein the administering of the at least one treatment to the patient comprises “causing” the patient to undergo muscle training.
-Claim 23 is drawn to the method of claim 16, wherein the administering of the at least one treatment to the patient comprises administering a therapeutically effective number of mesenchymal stem cells that produce Klotho.
-Claims 24 and 25 are drawn to the method of claim 16, wherein the pre-selected threshold corresponds to 100pg/ml or 200 pg/ml in serum, as determined from the ratio of serum-saliva of 3.6:1.
-Claim 26 is drawn to the method of claim 16, wherein the administering the at least one treatment comprises administering mesenchymal stem cells which produce Klotho and/or cells containing a nucleic acid vector encoding Klotho.
-Claim 27 is drawn to the method of claim 16, wherein the measuring of the content of Klotho via the diagnostic kit takes less than or equal to 15 minutes.
Claim 28 is drawn to the method of claim 16, wherein the diagnostic kit comprises an immune assay having at least one antibody or aptamer that binds to Klotho.
Claim 29 is drawn to the method of claim 16, wherein the diagnostic kit comprises a double antibody sandwich assay or a competitive assay.
Claim 30 is drawn to the method of claim 16, wherein the diagnostic kit comprises a lateral flow assay.
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 and to further administer a treatment if said biomarker is below a pre-selected threshold. This 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
Independent claim 16 recites the step of administering “in response to the content of the Klotho being below the pre-selected threshold”. Here, the step of administering Klotho is a conditional step. In other words, if the levels are not found to be below the pre-selected threshold, no treatment is provided, meaning that these embodiments end after 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”. Similarly, the observation of Klotho content is performed merely to inform others of a need (i.e., to begin, continue, change, or cease a treatment) if Klotho content is determined to be a certain value. Hence, this is not a practical integration of the judicial exception, because the claims encompass embodiments where no such treatment step is required.
Amended claim 16 now recites measuring the content of Klotho in saliva of the patient “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 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.
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, which may conditionally comprise (but do not require) a further step of administration, 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 16-30 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 16-30 are rejected under 35 U.S.C. 103 as being unpatentable over Tarsio (previously cited), and further in view of Dubal et al. (US 20180015151 A1; cited on Form 892), hereafter, “Dubal”.
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, and/or amyotrophic lateral sclerosis (ALS) (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 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 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 teaches that the biological sample obtained from the patient may include saliva (see pg. 11, para. [0032]). Dubal 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 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 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 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 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 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 17, Tarsio teaches that circulating levels of soluble Klotho proteins decrease with age and this decrease is implicated in (i.e., correlates to) a number of aging-related conditions, as discussed above. Dubal teaches obtaining a sample from a patient to measure a quantity or activity and comparing the quantity or activity to a control value (i.e., pre-selected threshold) to determine an effective dose, as discussed above. Hence, it would have been obvious to have applied the method wherein the patient has a disease or condition which correlates with a Klotho level that is below a pre-selected threshold.
Regarding claim 18, Tarsio teaches the method wherein the disease or condition is a neurodegenerative disease (see pg. 78, para. [0454]).
Regarding claim 19, Tarsio teaches the method wherein the disease or condition is Parkinson’s Disease (see pg. 78, para. [0454]).
Regarding claim 20, Tarsio teaches the method wherein the disease or condition is multiple sclerosis (MS) (see pg. 78, para. [0454]).
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 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 1. 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 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, as applied to claims 16-30 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, 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 does 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;
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.
Examiner notes that the phrase “the sample comprising saliva” in part “a)” is not a structural limitation of the test kit, and is directed to an intended use.
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).
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 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 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. 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.
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 enablement rejection, 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. The claims as amended herein fully resolve the issues raised in the Office Action and are fully enabled. For example, pages 13-21 of the Specification fully enable these claims and there are specific working examples of the method discussed in the claims, which is also acknowledged in the Office Action (QA at 20).
Applicant’s arguments have been fully considered but are not persuasive for the following reasons:
(1) The previous rejection was not only based on whether a detected level of Klotho can be used to identify a particular type of disease or condition. An issue which remains, and is presently addressed under Scope of Enablement, is that the specification does not provide enough enabling guidance and exemplification for a person of ordinary skill to make and use the claimed invention for any patient having any disease. This lack of enabling guidance is at issue due to the lack of predictability in the art at the time of filing, as well as the scope of the claims.
(2) To clarify, the “specific working examples” discussed on page 20 of the Office Action were not acknowledged by the examiner as being enabling. In fact, the examiner specifically states in the penultimate paragraph of page 22 (which summarizes the examiner’s analysis of Applicant’s “working examples”) that “Applicant’s working examples are inadequate to overcome the lack of predictability in the art and lack of guidance or direction in the specification as a whole”.
In response to the patentable subject matter rejection under 35 U.S.C. 101, Applicant argues that the previously presented claims were rejected as being directed to an abstract idea. 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).
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) The claims were not rejected as being directed to an abstract idea, but as being directed to the observation of a natural phenomenon without significantly more.
(2) 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”). 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.
(3) 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 (see current OA at pg. 24). Note that in the previous rejection, this same argument was applied in the rejection of claim 28, which was the method “wherein the Klotho content is determined via immune assay” (see claim set filed 09/07/2022 and previous OA at pg. 30).
Regarding the rejection of claims under 35 U.S.C. 102 in view of Rubinek, Applicant argues that the Rubinek disclosure is not directed to determining a content of Klotho in a sample of saliva. Instead, Rubinek is directed to detecting the presence of a particular type of Klotho functional variant. The "KLOTHO functional variant" term used in Rubinek "refers to the presence of at least one single nucleotide polymorphism (SNP) or several SNPs in the KLOTHO gene/mRNA/protein, which are known to be in complete linkage disequilibrium (Arking DE et al., 2002, Proc Natl Acad Sci 99: 856-861 )." (Rubinek, at paragraph 54, see also id. at paragraphs 55-60).
Applicant’s arguments with respect to the previous rejection under 35 U.S.C. 102 have been fully considered and are persuasive. Accordingly, the rejection has been withdrawn.
On page 8 of Applicant’s Remarks (“Claims 16-30 Are Allowable”), Applicant argues that the Office Action acknowledges that “The art does not explicitly teach the measuring of Klotho in saliva.” (OA at 16). The Office Action also acknowledges that serum and salivary levels of protein hormones are not well-correlated, and the serum levels of many protein hormones cannot be accurately monitored by means of salivary analysis.” (OA at 16). Thus, there is no teaching or suggestion of any use of a diagnostic kit to evaluate saliva to determine whether the saliva has a pre-selected threshold content of Klotho. Nor is there any teaching or suggestion to provide any type of treatment in response to such a threshold not being met.
Applicant’s arguments have been fully considered but are not persuasive for the following reasons:
(1) Applicant’s argument appears to relate to the novelty of the invention, but it is not specifically pointed out which rejection(s) or which applied reference(s) this argument is addressing. Applicant is reminded that under 37 CFR 1.111(c), the applicant or patent owner must clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. In the instant case, it is not clear which prior art rejection Applicant is arguing against, which is relevant because different statutes (e.g., 102 versus 103) require different considerations. Applicant is advised that citing the relevant statute or rejection header as well as the applicable reference(s) used in the rejection allows for the examiner to respond to Applicant’s argument in a manner that is beneficial to advancing prosecution.
(2) Examiner’s statements cited by Applicant were part of an analysis relating to the Enablement requirement. Here, the examiner was merely stating that the prior art used in the analysis, which were cited based on their relevance to the state and predictability of the prior art, did not explicitly teach or specifically detail the measuring of Klotho in saliva. Hence, this statement was not a conclusion regarding the novelty of the invention or the prior art as a whole, but was in regard to the prior art found to be most useful for determining the level of predictability in the art, which is one of the factors in Wands. Applicant is encouraged to present arguments based on evidence from the prior art of record, including those cited by the examiner, but it is important to specifically point-out how he or she thinks this evidence supports the novelty and/or nonobviousness of the invention, as discussed above.
Applicant further argues that “As acknowledged [i]n the Office Action, there is no teaching or suggestion in the art to evaluate a content of klotho in a saliva sample for comparing that content to a threshold so that a treatment can be administered when the pre-selected threshold is not met.”
Examiner respectfully disagrees. No acknowledgement was made in the previous office action that “there is no teaching or suggestion in the art” regarding the recited limitations. See also the response to Page 8 of Applicant’s Remarks (“Claims 16-30 Are Allowable”) above.
Furthermore, Applicant's arguments regarding claims 16-30 (“Claims 16-30 Are Allowable” on pgs. 8-10) fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references. Apart from the Rubinek reference, no mention is made of any of the other references applied in the prior art rejections of claims 1-30. For example, the teachings of neither Tarsio or Koczula are specifically addressed in any of Applicant’s arguments.
Note that in the previous Office Action, claims 16-18, 21 and 27 were rejected under 35 U.S.C. 102 in view of Rubinek; claims 19-20, 22-26 and 28-29 under 35 U.S.C. 103 in view of Rubinek and Tarsio; and claim 30 in further view of Koczula. As such, Applicant’s arguments presented under the header, “Claims 1-30 Are Allowable” fail to specifically point how the language of the claims patentably distinguishes them from the references, because Applicant fails to even acknowledge the teachings of these references in their arguments, particularly as they relate to the rejections under 35 U.S.C. 103.
Regarding claims 24-25 and 27, 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. Also, 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 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 teaches the testing of Klotho activity in saliva; (5) Tarsio teaches a diagnostic kit for measuring Klotho; and (6) the diagnostic kit taking less than or equal to 15 minutes 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, 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 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.
Conclusion
No claims are allowed.
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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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651